Pair your accounts.

Export articles to Mendeley

Get article recommendations from ACS based on references in your Mendeley library.

Pair your accounts.

Export articles to Mendeley

Get article recommendations from ACS based on references in your Mendeley library.

You’ve supercharged your research process with ACS and Mendeley!

STEP 1:
Click to create an ACS ID

Please note: If you switch to a different device, you may be asked to login again with only your ACS ID.

Please note: If you switch to a different device, you may be asked to login again with only your ACS ID.

Please note: If you switch to a different device, you may be asked to login again with only your ACS ID.

MENDELEY PAIRING EXPIRED
Your Mendeley pairing has expired. Please reconnect
ACS Publications. Most Trusted. Most Cited. Most Read
My Activity
CONTENT TYPES

Figure 1Loading Img

Structural Alert/Reactive Metabolite Concept as Applied in Medicinal Chemistry to Mitigate the Risk of Idiosyncratic Drug Toxicity: A Perspective Based on the Critical Examination of Trends in the Top 200 Drugs Marketed in the United States

View Author Information
§ Worldwide Medicinal Chemistry, Pharmacokinetics, Dynamics and Metabolism, and §Investigative Toxicology, Pfizer Worldwide Research and Development, Groton, Connecticut 06340, United States
Department of Medicinal Chemistry, School of Pharmacy, University of Washington, Seattle, Washington, 98195
Phone: (860) 715-2433. Fax: (860) 441 1128. E-mail: [email protected]
Cite this: Chem. Res. Toxicol. 2011, 24, 9, 1345–1410
Publication Date (Web):June 24, 2011
https://doi.org/10.1021/tx200168d
Copyright © 2011 American Chemical Society

    Article Views

    23486

    Altmetric

    -

    Citations

    LEARN ABOUT THESE METRICS
    Other access options
    Supporting Info (1)»

    Abstract

    Abstract Image

    Because of a preconceived notion that eliminating reactive metabolite (RM) formation with new drug candidates could mitigate the risk of idiosyncratic drug toxicity, the potential for RM formation is routinely examined as part of lead optimization efforts in drug discovery. Likewise, avoidance of “structural alerts” is almost a norm in drug design. However, there is a growing concern that the perceived safety hazards associated with structural alerts and/or RM screening tools as standalone predictors of toxicity risks may be over exaggerated. In addition, the multifactorial nature of idiosyncratic toxicity is now well recognized based upon observations that mechanisms other than RM formation (e.g., mitochondrial toxicity and inhibition of bile salt export pump (BSEP)) also can account for certain target organ toxicities. Hence, fundamental questions arise such as: When is a molecule that contains a structural alert (RM positive or negative) a cause for concern? Could the molecule in its parent form exert toxicity? Can a low dose drug candidate truly mitigate metabolism-dependent and -independent idiosyncratic toxicity risks? In an effort to address these questions, we have retrospectively examined 68 drugs (recalled or associated with a black box warning due to idiosyncratic toxicity) and the top 200 drugs (prescription and sales) in the United States in 2009 for trends in physiochemical characteristics, daily doses, presence of structural alerts, evidence for RM formation as well as toxicity mechanism(s) potentially mediated by parent drugs. Collectively, our analysis revealed that a significant proportion (∼78–86%) of drugs associated with toxicity contained structural alerts and evidence indicating that RM formation as a causative factor for toxicity has been presented in 62–69% of these molecules. In several cases, mitochondrial toxicity and BSEP inhibition mediated by parent drugs were also noted as potential causative factors. Most drugs were administered at daily doses exceeding several hundred milligrams. There was no obvious link between idiosyncratic toxicity and physicochemical properties such as molecular weight, lipophilicity, etc. Approximately half of the top 200 drugs for 2009 (prescription and sales) also contained one or more alerts in their chemical architecture, and many were found to be RM-positive. Several instances of BSEP and mitochondrial liabilities were also noted with agents in the top 200 category. However, with relatively few exceptions, the vast majority of these drugs are rarely associated with idiosyncratic toxicity, despite years of patient use. The major differentiating factor appeared to be the daily dose; most of the drugs in the top 200 list are administered at low daily doses. In addition, competing detoxication pathways and/or alternate nonmetabolic clearance routes provided suitable justifications for the safety records of RM-positive drugs in the top 200 category. Thus, while RM elimination may be a useful and pragmatic starting point in mitigating idiosyncratic toxicity risks, our analysis suggests a need for a more integrated screening paradigm for chemical hazard identification in drug discovery. Thus, in addition to a detailed assessment of RM formation potential (in relationship to the overall elimination mechanisms of the compound(s)) for lead compounds, effects on cellular health (e.g., cytotoxicity assays), BSEP inhibition, and mitochondrial toxicity are the recommended suite of assays to characterize compound liabilities. However, the prospective use of such data in compound selection will require further validation of the cellular assays using marketed agents. Until we gain a better understanding of the pathophysiological mechanisms associated with idiosyncratic toxicities, improving pharmacokinetics and intrinsic potency as means of decreasing the dose size and the associated “body burden” of the parent drug and its metabolites will remain an overarching goal in drug discovery.

    Read this article

    To access this article, please review the available access options below.

    Get instant access

    Purchase Access

    Read this article for 48 hours. Check out below using your ACS ID or as a guest.

    Recommended

    Access through Your Institution

    You may have access to this article through your institution.

    Your institution does not have access to this content. You can change your affiliated institution below.

    Supporting Information

    ARTICLE SECTIONS
    Jump To

    Structures, indication, physiochemical attributes, structural alerts, RM data, and the maximum recommended daily doses of the top 180 drugs in the US market by prescription and by sales in 2009. This material is available free of charge via the Internet at http://pubs.acs.org.

    Terms & Conditions

    Most electronic Supporting Information files are available without a subscription to ACS Web Editions. Such files may be downloaded by article for research use (if there is a public use license linked to the relevant article, that license may permit other uses). Permission may be obtained from ACS for other uses through requests via the RightsLink permission system: http://pubs.acs.org/page/copyright/permissions.html.

    Cited By

    This article is cited by 560 publications.

    1. Ximei Li, Lihua Xin, Lan Yang, Yi Yang, Wei Li, Mingyu Zhang, Yufen Liao, Chen Sun, Weiwei Li, Ying Peng, Jiang Zheng. Identification of an Epoxide Metabolite of Amitriptyline In Vitro and In Vivo. Chemical Research in Toxicology 2024, 37 (6) , 935-943. https://doi.org/10.1021/acs.chemrestox.4c00008
    2. Xiusheng Miao, Gordon J. Dear, Claire Beaumont, Giovanni Vitulli, Gary Collins, Peter D. Gorycki, Andrew W. Harrell, Melanie Z. Sakatis. Cyanide Trapping of Iminium Ion Reactive Metabolites: Implications for Clinical Hepatotoxicity. Chemical Research in Toxicology 2024, 37 (5) , 698-710. https://doi.org/10.1021/acs.chemrestox.3c00402
    3. Marielle Rath, James Wellnitz, Holli-Joi Martin, Cleber Melo-Filho, Joshua E. Hochuli, Guilherme Martins Silva, Jon-Michael Beasley, Maxfield Travis, Zoe L. Sessions, Konstantin I. Popov, Alexey V. Zakharov, Artem Cherkasov, Vinicius Alves, Eugene N. Muratov, Alexander Tropsha. Pharmacokinetics Profiler (PhaKinPro): Model Development, Validation, and Implementation as a Web Tool for Triaging Compounds with Undesired Pharmacokinetics Profiles. Journal of Medicinal Chemistry 2024, 67 (8) , 6508-6518. https://doi.org/10.1021/acs.jmedchem.3c02446
    4. Christophe Peixoto, Agnes Joncour, Taouès Temal-Laib, Amynata Tirera, Aurélie Dos Santos, Hélène Jary, Denis Bucher, Wendy Laenen, Anna Pereira Fernandes, Stephanie Lavazais, Carole Delachaume, Didier Merciris, Corinne Saccomani, Michael Drennan, Miriam López-Ramos, Emanuelle Wakselman, Sonia Dupont, Monica Borgonovi, Carlos Roca Magadan, Alain Monjardet, Reginald Brys, Steve De Vos, Martin Andrews, Juan-Miguel Jimenez, David Amantini, Nicolas Desroy. Discovery of Clinical Candidate GLPG3970: A Potent and Selective Dual SIK2/SIK3 Inhibitor for the Treatment of Autoimmune and Inflammatory Diseases. Journal of Medicinal Chemistry 2024, 67 (7) , 5233-5258. https://doi.org/10.1021/acs.jmedchem.3c02246
    5. Masahito Abe, Jeremy S. Coleman, Christopher C. Presley, Nathan D. Schley, Craig W. Lindsley. Rapid sp3-Enriched Scaffold Generation via a Selective Aziridine Amide Ring-Opening Reaction. The Journal of Organic Chemistry 2024, 89 (5) , 3500-3508. https://doi.org/10.1021/acs.joc.3c02952
    6. Emilie Werner, Milena Wiegand, Joseph Moran, David Lebœuf. Rapid Access to Densely Functionalized Cyclopentenyl Sulfoximines through a Sc-Catalyzed Aza-Piancatelli Reaction. Organic Letters 2024, 26 (2) , 547-552. https://doi.org/10.1021/acs.orglett.3c04095
    7. Shuai Wang, T. Eric Ballard, Lisa J. Christopher, Robert S. Foti, Chungang Gu, S. Cyrus Khojasteh, Joyce Liu, Shuguang Ma, Bin Ma, R. Scott Obach, Simone Schadt, Zhoupeng Zhang, Donglu Zhang. The Importance of Tracking “Missing” Metabolites: How and Why?. Journal of Medicinal Chemistry 2023, 66 (23) , 15586-15612. https://doi.org/10.1021/acs.jmedchem.3c01293
    8. Jarvis Hill, Robert M. Jones, David Crich. Discovery of a Hydroxylamine-Based Brain-Penetrant EGFR Inhibitor for Metastatic Non-Small-Cell Lung Cancer. Journal of Medicinal Chemistry 2023, 66 (22) , 15477-15492. https://doi.org/10.1021/acs.jmedchem.3c01669
    9. Wenxuan Wu, Jiayu Qian, Changjie Liang, Jingya Yang, Guangbo Ge, Qingping Zhou, Xiaoqing Guan. GeoDILI: A Robust and Interpretable Model for Drug-Induced Liver Injury Prediction Using Graph Neural Network-Based Molecular Geometric Representation. Chemical Research in Toxicology 2023, 36 (11) , 1717-1730. https://doi.org/10.1021/acs.chemrestox.3c00199
    10. Anh T. Tran, James J. Crawford, Debashis Mandal, Tezcan Guney, Jamie Karmel. DRUG-INDUCED LIVER INJURY: MECHANISMS, METHODS FOR PRE-CLINICAL ASSESSMENT, AND A MEDICINAL CHEMIST’S PERSPECTIVE. , 473-500. https://doi.org/10.1021/mc-2023-vol58.ch19
    11. Maxime Sansoucy, Jean-François Naud. Using Proteins As Markers for Anabolic Steroid Abuse: A New Perspective in Doping Control?. Chemical Research in Toxicology 2023, 36 (8) , 1168-1173. https://doi.org/10.1021/acs.chemrestox.3c00166
    12. Feyza Kelleci̇ Çeli̇k, Gül Karaduman. Machine Learning-Based Prediction of Drug-Induced Hepatotoxicity: An OvA-QSTR Approach. Journal of Chemical Information and Modeling 2023, 63 (15) , 4602-4614. https://doi.org/10.1021/acs.jcim.3c00687
    13. Raju Jannapu Reddy, Nunavath Sharadha, Gamidi Rama Krishna. Pd(II)-Catalyzed Tandem Cycloannulative-Alkenylation of o-Alkynyl-Phenols/Anilines with (E)-β-Iodovinyl Sulfones: A Direct Strategy To Construct 3-(Vinyl sulfonyl)benzoheterole Derivatives. The Journal of Organic Chemistry 2023, 88 (13) , 8889-8903. https://doi.org/10.1021/acs.joc.3c00671
    14. Raman Sharma, Matthew S. Dowling, Kentaro Futatsugi, Amit S. Kalgutkar. Mitigating a Bioactivation Liability with an Azetidine-Based Inhibitor of Diacylglycerol Acyltransferase 2 (DGAT2) En Route to the Discovery of the Clinical Candidate Ervogastat. Chemical Research in Toxicology 2023, 36 (6) , 934-946. https://doi.org/10.1021/acs.chemrestox.3c00054
    15. Noah R. Flynn, S. Joshua Swamidass. Message Passing Neural Networks Improve Prediction of Metabolite Authenticity. Journal of Chemical Information and Modeling 2023, 63 (6) , 1675-1694. https://doi.org/10.1021/acs.jcim.2c01383
    16. Jichong Li, Shuai Shen, Zijian Liu, Hongwei Zhao, Siyang Liu, Qingbo Liu, Guo-Dong Yao, Shao-Jiang Song. Synthesis and Structure–Activity Analysis of Icaritin Derivatives as Potential Tumor Growth Inhibitors of Hepatocellular Carcinoma Cells. Journal of Natural Products 2023, 86 (2) , 290-306. https://doi.org/10.1021/acs.jnatprod.2c00908
    17. Sven Thamm, Marina K. Willwacher, Gary E. Aspnes, Tom Bretschneider, Nicholas F. Brown, Silke Buschbom-Helmke, Thomas Fox, Emanuele M. Gargano, Daniel Grabowski, Christoph Hoenke, Damian Matera, Katja Mueck, Stefan Peters, Sophia Reindl, Doris Riether, Matthias Schmid, Christofer S. Tautermann, Aaron M. Teitelbaum, Cornelius Trünkle, Thomas Veser, Martin Winter, Lars Wortmann. Discovery of a Novel Potent and Selective HSD17B13 Inhibitor, BI-3231, a Well-Characterized Chemical Probe Available for Open Science. Journal of Medicinal Chemistry 2023, 66 (4) , 2832-2850. https://doi.org/10.1021/acs.jmedchem.2c01884
    18. Gustave Adouvi, Laura Isigkeit, Úrsula López-García, Apirat Chaikuad, Julian A. Marschner, Manfred Schubert-Zsilavecz, Daniel Merk. Rational Design of a New RXR Agonist Scaffold Enabling Single-Subtype Preference for RXRα, RXRβ, and RXRγ. Journal of Medicinal Chemistry 2023, 66 (1) , 333-344. https://doi.org/10.1021/acs.jmedchem.2c01266
    19. Robert A. Craig, II, Brian M. Fox, Cheng Hu, Katrina W. Lexa, Maksim Osipov, Arun P. Thottumkara, Martin Larhammar, Takashi Miyamoto, Anil Rana, Lesley A. Kane, Ernie Yulyaningsih, Hilda Solanoy, Hoang Nguyen, Roni Chau, Timothy Earr, Yuji Kajiwara, Daniel Fleck, Anthony Lucas, Patrick C. G. Haddick, Ryan H. Takahashi, Vincent Tong, Jing Wang, Mark J. Canet, Suresh B. Poda, Kimberly Scearce-Levie, Ankita Srivastava, Zachary K. Sweeney, Musheng Xu, Rui Zhang, Jianrong He, Yanan Lei, Zheng Zhuo, Javier de Vicente. Discovery of Potent and Selective Dual Leucine Zipper Kinase/Leucine Zipper-Bearing Kinase Inhibitors with Neuroprotective Properties in In Vitro and In Vivo Models of Amyotrophic Lateral Sclerosis. Journal of Medicinal Chemistry 2022, 65 (24) , 16290-16312. https://doi.org/10.1021/acs.jmedchem.2c01056
    20. David J. Ponting, Krista L. Dobo, Michelle O. Kenyon, Amit S. Kalgutkar. Strategies for Assessing Acceptable Intakes for Novel N-Nitrosamines Derived from Active Pharmaceutical Ingredients. Journal of Medicinal Chemistry 2022, 65 (23) , 15584-15607. https://doi.org/10.1021/acs.jmedchem.2c01498
    21. Payal Rana, Sanaa Khan, Seda Arat, David Potter, Nasir Khan. Nonclinical Safety Signals in PharmaPendium Improve the Predictability of Human Drug-Induced Liver Injury. Chemical Research in Toxicology 2022, 35 (11) , 2133-2144. https://doi.org/10.1021/acs.chemrestox.2c00243
    22. Peter W. Kenny. Hydrogen-Bond Donors in Drug Design. Journal of Medicinal Chemistry 2022, 65 (21) , 14261-14275. https://doi.org/10.1021/acs.jmedchem.2c01147
    23. Jack Uetrecht. Idiosyncratic Drug Reactions: A 35-Year Chemical Research in Toxicology Perspective. Chemical Research in Toxicology 2022, 35 (10) , 1649-1654. https://doi.org/10.1021/acs.chemrestox.2c00090
    24. Jeffrey J. Jackson, Grant M. Shibuya, Buvana Ravishankar, Lavanya Adusumilli, Delia Bradford, Dirk G. Brockstedt, Cyril Bucher, Minna Bui, Cynthia Cho, Christoph Colas, Gene Cutler, Adrian Dukes, Xinping Han, Dennis X. Hu, Scott Jacobson, Paul D. Kassner, George E. Katibah, Michelle Yoo Min Ko, Urvi Kolhatkar, Paul R. Leger, Anqi Ma, Lisa Marshall, Jack Maung, Andrew A. Ng, Akinori Okano, Deepa Pookot, Daniel Poon, Chandru Ramana, Maureen K. Reilly, Omar Robles, Jacob B. Schwarz, Anton A. Shakhmin, Hunter P. Shunatona, Raashi Sreenivasan, Parcharee Tivitmahaisoon, Mengshu Xu, Thant Zaw, David J. Wustrow, Mikhail Zibinsky. Potent GCN2 Inhibitor Capable of Reversing MDSC-Driven T Cell Suppression Demonstrates In Vivo Efficacy as a Single Agent and in Combination with Anti-Angiogenesis Therapy. Journal of Medicinal Chemistry 2022, 65 (19) , 12895-12924. https://doi.org/10.1021/acs.jmedchem.2c00736
    25. Qiuying Zhang, Hui Liu, Dongmei Wu, Hongyan Yu, Kun Wang, Weijie Jiao, Xu Zhao. Methysticin Acts as a Mechanism-Based Inactivator of Cytochrome P450 2C9. Chemical Research in Toxicology 2022, 35 (6) , 1117-1124. https://doi.org/10.1021/acs.chemrestox.2c00098
    26. Zhengyu Lu, Yangzhi Cao, Dan Zhang, Xin Meng, Bin Guo, Deyu Kong, Yushe Yang. Discovery of Thieno[2,3-e]indazole Derivatives as Novel Oral Selective Estrogen Receptor Degraders with Highly Improved Antitumor Effect and Favorable Druggability. Journal of Medicinal Chemistry 2022, 65 (7) , 5724-5750. https://doi.org/10.1021/acs.jmedchem.2c00008
    27. Dongzhu Tu, Jing Ning, Liwei Zou, Ping Wang, Yani Zhang, Xiangge Tian, Feng Zhang, Jiang Zheng, Guangbo Ge. Unique Oxidative Metabolism of Bufalin Generates Two Reactive Metabolites That Strongly Inactivate Human Cytochrome P450 3A. Journal of Medicinal Chemistry 2022, 65 (5) , 4018-4029. https://doi.org/10.1021/acs.jmedchem.1c01875
    28. Konrad W. Wurm, Frieda-Marie Bartz, Lukas Schulig, Anja Bodtke, Patrick J. Bednarski, Andreas Link. Modifications of the Triaminoaryl Metabophore of Flupirtine and Retigabine Aimed at Avoiding Quinone Diimine Formation. ACS Omega 2022, 7 (9) , 7989-8012. https://doi.org/10.1021/acsomega.1c07103
    29. Suqing Zheng, Lei Wang, Jun Xiong, Guang Liang, Yong Xu, Fu Lin. Consensus Prediction of Human Gut Microbiota-Mediated Metabolism Susceptibility for Small Molecules by Machine Learning, Structural Alerts, and Dietary Compounds-Based Average Similarity Methods. Journal of Chemical Information and Modeling 2022, 62 (4) , 1078-1099. https://doi.org/10.1021/acs.jcim.1c00948
    30. Matthew G. Bursavich, Bryce A. Harrison, Raksha Acharya, Donald E. Costa, Emily A. Freeman, Lori A. Hrdlicka, Hong Jin, Sudarshan Kapadnis, Jeffrey S. Moffit, Deirdre Murphy, Scott J. Nolan, Holger Patzke, Cuyue Tang, Hilliary E. Van Voorhies, Melody Wen, Gerhard Koenig, Jean-François Blain, Duane A. Burnett. Discovery of the Oxadiazine FRM-024: A Potent CNS-Penetrant Gamma Secretase Modulator. Journal of Medicinal Chemistry 2021, 64 (19) , 14426-14447. https://doi.org/10.1021/acs.jmedchem.1c00904
    31. Yongtian Xing, Han Xing, Yongcheng Ma, Qingwang Liu, Suyan Xu. In Vitro and In Vivo Studies of Metabolic Activation of Marrubiin, a Bioactive Constituent from Marrubium Vulgare. Chemical Research in Toxicology 2021, 34 (9) , 2157-2165. https://doi.org/10.1021/acs.chemrestox.1c00250
    32. Pengcheng Shao. A New Era in ER+ Breast Cancer: Best-in-Class Oral Selective Estrogen Receptor Degrader (SERD) Designed as an Endocrine Backbone Treatment. Journal of Medicinal Chemistry 2021, 64 (16) , 11837-11840. https://doi.org/10.1021/acs.jmedchem.1c01268
    33. Chaitanya K. Jaladanki, Samima Khatun, Holger Gohlke, Prasad V. Bharatam. Reactive Metabolites from Thiazole-Containing Drugs: Quantum Chemical Insights into Biotransformation and Toxicity. Chemical Research in Toxicology 2021, 34 (6) , 1503-1517. https://doi.org/10.1021/acs.chemrestox.0c00450
    34. Arpan Mukherjee, An Su, Krishna Rajan. Deep Learning Model for Identifying Critical Structural Motifs in Potential Endocrine Disruptors. Journal of Chemical Information and Modeling 2021, 61 (5) , 2187-2197. https://doi.org/10.1021/acs.jcim.0c01409
    35. Tamara Halkina, Jaclyn L. Henderson, Edward Y. Lin, Martin K. Himmelbauer, J. Howard Jones, Marta Nevalainen, Jun Feng, Kristopher King, Michael Rooney, Joshua L. Johnson, Douglas J. Marcotte, Jayanth V. Chodaparambil, P. Rajesh Kumar, Thomas A. Patterson, Paramasivam Murugan, Eli Schuman, LaiYee Wong, Thomas Hesson, Sarah Lamore, Channa Bao, Michael Calhoun, Hannah Certo, Brenda Amaral, Gregory M. Dillon, Rab Gilfillan, Felix Gonzalez-Lopez de Turiso. Discovery of Potent and Brain-Penetrant Tau Tubulin Kinase 1 (TTBK1) Inhibitors that Lower Tau Phosphorylation In Vivo. Journal of Medicinal Chemistry 2021, 64 (9) , 6358-6380. https://doi.org/10.1021/acs.jmedchem.1c00382
    36. Yuji Koriyama, Akihiro Hori, Hisanori Ito, Shuji Yonezawa, Yoshiyasu Baba, Norihiko Tanimoto, Tatsuhiko Ueno, Shiho Yamamoto, Takahiko Yamamoto, Naoya Asada, Kenji Morimoto, Shunsuke Einaru, Katsunori Sakai, Takushi Kanazu, Akihiro Matsuda, Yoshitaka Yamaguchi, Takuya Oguma, Maarten Timmers, Luc Tritsmans, Ken-ichi Kusakabe, Akira Kato, Gaku Sakaguchi. Discovery of Atabecestat (JNJ-54861911): A Thiazine-Based β-Amyloid Precursor Protein Cleaving Enzyme 1 Inhibitor Advanced to the Phase 2b/3 EARLY Clinical Trial. Journal of Medicinal Chemistry 2021, 64 (4) , 1873-1888. https://doi.org/10.1021/acs.jmedchem.0c01917
    37. Tyler B. Hughes, Noah Flynn, Na Le Dang, S. Joshua Swamidass. Modeling the Bioactivation and Subsequent Reactivity of Drugs. Chemical Research in Toxicology 2021, 34 (2) , 584-600. https://doi.org/10.1021/acs.chemrestox.0c00417
    38. Andrew J. Wedlake, Timothy E. H. Allen, Jonathan M. Goodman, Steve Gutsell, Predrag Kukic, Paul J. Russell. Confidence in Inactive and Active Predictions from Structural Alerts. Chemical Research in Toxicology 2020, 33 (12) , 3010-3022. https://doi.org/10.1021/acs.chemrestox.0c00332
    39. Yutao Liu, Chang Liu, Yamei Liu, Quanli Ge, Chen Sun. Cytochrome P450 Mediated Bioactivation of Rutaevin, a Bioactive and Potentially Hepatotoxic Component of Evodia Rutaecarpa. Chemical Research in Toxicology 2020, 33 (12) , 3054-3064. https://doi.org/10.1021/acs.chemrestox.0c00475
    40. Julia Shanu-Wilson, Liam Evans, Stephen Wrigley, Jonathan Steele, James Atherton, Jason Boer. Biotransformation: Impact and Application of Metabolism in Drug Discovery. ACS Medicinal Chemistry Letters 2020, 11 (11) , 2087-2107. https://doi.org/10.1021/acsmedchemlett.0c00202
    41. Tyler B. Hughes, Na Le Dang, Ayush Kumar, Noah R. Flynn, S. Joshua Swamidass. Metabolic Forest: Predicting the Diverse Structures of Drug Metabolites. Journal of Chemical Information and Modeling 2020, 60 (10) , 4702-4716. https://doi.org/10.1021/acs.jcim.0c00360
    42. Bryan H. Norman. Drug Induced Liver Injury (DILI). Mechanisms and Medicinal Chemistry Avoidance/Mitigation Strategies. Journal of Medicinal Chemistry 2020, 63 (20) , 11397-11419. https://doi.org/10.1021/acs.jmedchem.0c00524
    43. Taylor M. Sodano, Logan A. Combee, Corey R. J. Stephenson. Recent Advances and Outlook for the Isosteric Replacement of Anilines. ACS Medicinal Chemistry Letters 2020, 11 (10) , 1785-1788. https://doi.org/10.1021/acsmedchemlett.9b00687
    44. Marta Serafini, Sarah Cargnin, Alberto Massarotti, Tracey Pirali, Armando A. Genazzani. Essential Medicinal Chemistry of Essential Medicines. Journal of Medicinal Chemistry 2020, 63 (18) , 10170-10187. https://doi.org/10.1021/acs.jmedchem.0c00415
    45. Lei Zhang, Qingwang Liu, Yajuan Pan, Xianfang Qi, Yuanlong Li, Ci Chen, Jun Sun. Cytochrome P450 3A4-Mediated Bioactivation and Its Role in Nomilin-Induced Hepatotoxicity. Chemical Research in Toxicology 2020, 33 (8) , 2208-2217. https://doi.org/10.1021/acs.chemrestox.0c00228
    46. Shenzhi Zhou, Wei Li, Min Tian, Na Zhang, Xiaojing Yang, Weiwei Li, Ying Peng, Jiang Zheng. Metabolic Activation of Pirfenidone Mediated by Cytochrome P450s and Sulfotransferases. Journal of Medicinal Chemistry 2020, 63 (15) , 8059-8068. https://doi.org/10.1021/acs.jmedchem.9b02073
    47. Falgun Shah, Ian M. Bell. Cutaneous Adverse Events Caused by Sulfonamide-Containing Drugs: Reality or Perception?. Journal of Medicinal Chemistry 2020, 63 (14) , 7447-7457. https://doi.org/10.1021/acs.jmedchem.9b01932
    48. Ali Alhoshani, Fawaz E. Alanazi, Moureq R. Alotaibi, Mohamed W. Attwa, Adnan A. Kadi, Abdullah Aldhfyan, Sabah Akhtar, Shireen Hourani, Abdelali Agouni, Asad Zeidan, Hesham M. Korashy. EGFR Inhibitor Gefitinib Induces Cardiotoxicity through the Modulation of Cardiac PTEN/Akt/FoxO3a Pathway and Reactive Metabolites Formation: In Vivo and in Vitro Rat Studies. Chemical Research in Toxicology 2020, 33 (7) , 1719-1728. https://doi.org/10.1021/acs.chemrestox.0c00005
    49. Payal Rana, Stephen Kogut, Xuerong Wen, Fatemeh Akhlaghi, Michael D. Aleo. Most Influential Physicochemical and In Vitro Assay Descriptors for Hepatotoxicity and Nephrotoxicity Prediction. Chemical Research in Toxicology 2020, 33 (7) , 1780-1790. https://doi.org/10.1021/acs.chemrestox.0c00040
    50. Chenghong Zhang, James J. Crawford, Matthew L. Landry, Huifen Chen, Jane R. Kenny, S. Cyrus Khojasteh, Wendy Lee, Shuguang Ma, Wendy B. Young. Strategies to Mitigate the Bioactivation of Aryl Amines. Chemical Research in Toxicology 2020, 33 (7) , 1950-1959. https://doi.org/10.1021/acs.chemrestox.0c00138
    51. Haining Zhou, Qingwang Liu, Juan Zhang, Jianning Yao, Chunfeng Wang, Yanzhen Zhang, Yanle Li, Xuexiu Zhang, Lianfeng Zhang. Cytochrome P450-Mediated Bioactivation: Implication for the Liver Injury Induced by Fraxinellone, A Bioactive Constituent from Dictamni Cortex. Chemical Research in Toxicology 2020, 33 (7) , 1960-1968. https://doi.org/10.1021/acs.chemrestox.0c00141
    52. Amit S. Kalgutkar. Designing around Structural Alerts in Drug Discovery. Journal of Medicinal Chemistry 2020, 63 (12) , 6276-6302. https://doi.org/10.1021/acs.jmedchem.9b00917
    53. Matthew A. Cerny, Amit S. Kalgutkar, R. Scott Obach, Raman Sharma, Douglas K. Spracklin, Gregory S. Walker. Effective Application of Metabolite Profiling in Drug Design and Discovery. Journal of Medicinal Chemistry 2020, 63 (12) , 6387-6406. https://doi.org/10.1021/acs.jmedchem.9b01840
    54. Hongbin Yang, Chaofeng Lou, Weihua Li, Guixia Liu, Yun Tang. Computational Approaches to Identify Structural Alerts and Their Applications in Environmental Toxicology and Drug Discovery. Chemical Research in Toxicology 2020, 33 (6) , 1312-1322. https://doi.org/10.1021/acs.chemrestox.0c00006
    55. Zi-Yi Yang, Jun-Hong He, Ai-Ping Lu, Ting-Jun Hou, Dong-Sheng Cao. Application of Negative Design To Design a More Desirable Virtual Screening Library. Journal of Medicinal Chemistry 2020, 63 (9) , 4411-4429. https://doi.org/10.1021/acs.jmedchem.9b01476
    56. Jiaping Pei, Wen Xiao, Danyan Zhu, Xiaowei Ji, Liping Shi, Xiaozhao Deng. Cytochrome P450 Enzyme-Mediated Bioactivation as an Underlying Mechanism of Columbin-Induced Hepatotoxicity. Chemical Research in Toxicology 2020, 33 (4) , 940-947. https://doi.org/10.1021/acs.chemrestox.9b00486
    57. Na Le Dang, Matthew K. Matlock, Tyler B. Hughes, S. Joshua Swamidass. The Metabolic Rainbow: Deep Learning Phase I Metabolism in Five Colors. Journal of Chemical Information and Modeling 2020, 60 (3) , 1146-1164. https://doi.org/10.1021/acs.jcim.9b00836
    58. Andrew J. Wedlake, Maria Folia, Sam Piechota, Timothy E. H. Allen, Jonathan M. Goodman, Steve Gutsell, Paul J. Russell. Structural Alerts and Random Forest Models in a Consensus Approach for Receptor Binding Molecular Initiating Events. Chemical Research in Toxicology 2020, 33 (2) , 388-401. https://doi.org/10.1021/acs.chemrestox.9b00325
    59. Marie-Noëlle Paludetto, Jean-Luc Stigliani, Anne Robert, Vania Bernardes-Génisson, Etienne Chatelut, Florent Puisset, Cécile Arellano. Involvement of Pazopanib and Sunitinib Aldehyde Reactive Metabolites in Toxicity and Drug–Drug Interactions in Vitro and in Patient Samples. Chemical Research in Toxicology 2020, 33 (1) , 181-190. https://doi.org/10.1021/acs.chemrestox.9b00205
    60. Michael D. Aleo, Falgun Shah, Scott Allen, Hugh A. Barton, Chester Costales, Sarah Lazzaro, Louis Leung, Andrea Nilson, R. Scott Obach, A. David Rodrigues, Yvonne Will. Moving beyond Binary Predictions of Human Drug-Induced Liver Injury (DILI) toward Contrasting Relative Risk Potential. Chemical Research in Toxicology 2020, 33 (1) , 223-238. https://doi.org/10.1021/acs.chemrestox.9b00262
    61. Dominic P. Williams, Stanley E. Lazic, Alison J. Foster, Elizaveta Semenova, Paul Morgan. Predicting Drug-Induced Liver Injury with Bayesian Machine Learning. Chemical Research in Toxicology 2020, 33 (1) , 239-248. https://doi.org/10.1021/acs.chemrestox.9b00264
    62. Yusra Sajid Kiani, Ishrat Jabeen. Lipophilic Metabolic Efficiency (LipMetE) and Drug Efficiency Indices to Explore the Metabolic Properties of the Substrates of Selected Cytochrome P450 Isoforms. ACS Omega 2020, 5 (1) , 179-188. https://doi.org/10.1021/acsomega.9b02344
    63. Thilo Focken, Kristen Burford, Michael E. Grimwood, Alla Zenova, Jean-Christophe Andrez, Wei Gong, Michael Wilson, Matt Taron, Shannon Decker, Verner Lofstrand, Sultan Chowdhury, Noah Shuart, Sophia Lin, Samuel J. Goodchild, Clint Young, Maegan Soriano, Parisa K. Tari, Matthew Waldbrook, Karen Nelkenbrecher, Rainbow Kwan, Andrea Lindgren, Gina de Boer, Stephanie Lee, Luis Sojo, Robert J. DeVita, Charles J. Cohen, Steven S. Wesolowski, J. P. Johnson, Jr., Christoph M. Dehnhardt, James R. Empfield. Identification of CNS-Penetrant Aryl Sulfonamides as Isoform-Selective NaV1.6 Inhibitors with Efficacy in Mouse Models of Epilepsy. Journal of Medicinal Chemistry 2019, 62 (21) , 9618-9641. https://doi.org/10.1021/acs.jmedchem.9b01032
    64. Genta Tadano, Kazuo Komano, Shuhei Yoshida, Shinji Suzuki, Kenji Nakahara, Kouki Fuchino, Kazuki Fujimoto, Eriko Matsuoka, Takahiko Yamamoto, Naoya Asada, Hisanori Ito, Gaku Sakaguchi, Naoki Kanegawa, Yasuto Kido, Shigeru Ando, Tamio Fukushima, Ard Teisman, Vijay Urmaliya, Deborah Dhuyvetter, Herman Borghys, An Van Den Bergh, Nigel Austin, Harrie J. M. Gijsen, Yoshinori Yamano, Yasuyoshi Iso, Ken-ichi Kusakabe. Discovery of an Extremely Potent Thiazine-Based β-Secretase Inhibitor with Reduced Cardiovascular and Liver Toxicity at a Low Projected Human Dose. Journal of Medicinal Chemistry 2019, 62 (20) , 9331-9337. https://doi.org/10.1021/acs.jmedchem.9b01140
    65. Pengcheng Wang, Junjie Zhu, Amina I. Shehu, Jie Lu, Jing Chen, Xiao-bo Zhong, Xiaochao Ma. Enzymes and Pathways of Kavain Bioactivation and Biotransformation. Chemical Research in Toxicology 2019, 32 (7) , 1335-1342. https://doi.org/10.1021/acs.chemrestox.9b00098
    66. Hui Li, Zhengyu Zhang, Xiaojing Yang, Xu Mao, Ying Wang, Jian Wang, Ying Peng, Jiang Zheng. Electron Deficiency of Nitro Group Determines Hepatic Cytotoxicity of Nitrofurantoin. Chemical Research in Toxicology 2019, 32 (4) , 681-690. https://doi.org/10.1021/acs.chemrestox.8b00362
    67. Chenghui Shi, Yinyong Zhang, Ting Wang, Wenchao Lu, Shuhua Zhang, Bin Guo, Qian Chen, Cheng Luo, Xianli Zhou, Yushe Yang. Design, Synthesis, and Biological Evaluation of Novel DNA Gyrase-Inhibiting Spiropyrimidinetriones as Potent Antibiotics for Treatment of Infections Caused by Multidrug-Resistant Gram-Positive Bacteria. Journal of Medicinal Chemistry 2019, 62 (6) , 2950-2973. https://doi.org/10.1021/acs.jmedchem.8b01750
    68. Kenneth L. Granberg, Zhong-Qing Yuan, Bo Lindmark, Karl Edman, Johan Kajanus, Anders Hogner, Marcus Malmgren, Gavin O’Mahony, Anneli Nordqvist, Jan Lindberg, Stefan Tångefjord, Michael Kossenjans, Christian Löfberg, Jonas Brånalt, Dongmei Liu, Nidhal Selmi, Grigorios Nikitidis, Peter Nordberg, Ahlke Hayen, Anna Aagaard, Eva Hansson, Majlis Hermansson, Ida Ivarsson, Rasmus Jansson-Löfmark, Ulla Karlsson, Ulrika Johansson, Lena William-Olsson, Judith Hartleib-Geschwindner, Krister Bamberg. Identification of Mineralocorticoid Receptor Modulators with Low Impact on Electrolyte Homeostasis but Maintained Organ Protection. Journal of Medicinal Chemistry 2019, 62 (3) , 1385-1406. https://doi.org/10.1021/acs.jmedchem.8b01523
    69. Mihirbaran Mandal, Kaushik Mitra, Diane Grotz, Xinjie Lin, Jairam Palamanda, Pramila Kumari, Alexei Buevich, John P. Caldwell, Xia Chen, Kathleen Cox, Leonard Favreau, Lynn Hyde, Matthew E. Kennedy, Reshma Kuvelkar, Xiaoxiang Liu, Robert D. Mazzola, Eric Parker, Diane Rindgen, Edward Sherer, Hongwu Wang, Zhaoning Zhu, Andrew W. Stamford, Jared N. Cumming. Overcoming Time-Dependent Inhibition (TDI) of Cytochrome P450 3A4 (CYP3A4) Resulting from Bioactivation of a Fluoropyrimidine Moiety. Journal of Medicinal Chemistry 2018, 61 (23) , 10700-10708. https://doi.org/10.1021/acs.jmedchem.8b01326
    70. Yen S. Low, Vinicius M. Alves, Denis Fourches, Alexander Sedykh, Carolina Horta Andrade, Eugene N. Muratov, Ivan Rusyn, Alexander Tropsha. Chemistry-Wide Association Studies (CWAS): A Novel Framework for Identifying and Interpreting Structure–Activity Relationships. Journal of Chemical Information and Modeling 2018, 58 (11) , 2203-2213. https://doi.org/10.1021/acs.jcim.8b00450
    71. Kevin M. Foote, J. Willem M. Nissink, Thomas McGuire, Paul Turner, Sylvie Guichard, James W. T. Yates, Alan Lau, Kevin Blades, Dan Heathcote, Rajesh Odedra, Gary Wilkinson, Zena Wilson, Christine M. Wood, Philip J. Jewsbury. Discovery and Characterization of AZD6738, a Potent Inhibitor of Ataxia Telangiectasia Mutated and Rad3 Related (ATR) Kinase with Application as an Anticancer Agent. Journal of Medicinal Chemistry 2018, 61 (22) , 9889-9907. https://doi.org/10.1021/acs.jmedchem.8b01187
    72. Dorothée Bardiot, Mohamed Koukni, Wim Smets, Gunter Carlens, Michael McNaughton, Suzanne Kaptein, Kai Dallmeier, Patrick Chaltin, Johan Neyts, Arnaud Marchand. Discovery of Indole Derivatives as Novel and Potent Dengue Virus Inhibitors. Journal of Medicinal Chemistry 2018, 61 (18) , 8390-8401. https://doi.org/10.1021/acs.jmedchem.8b00913
    73. Tim F. Ryder, Matthew F. Calabrese, Gregory S. Walker, Kimberly O. Cameron, Allan R. Reyes, Kris A. Borzilleri, Jake Delmore, Russell Miller, Ravi G. Kurumbail, Jessica Ward, Daniel W. Kung, Janice A. Brown, David J. Edmonds, Heather Eng, Angela C. Wolford, Amit S. Kalgutkar. Acyl Glucuronide Metabolites of 6-Chloro-5-[4-(1-hydroxycyclobutyl)phenyl]-1H-indole-3-carboxylic Acid (PF-06409577) and Related Indole-3-carboxylic Acid Derivatives are Direct Activators of Adenosine Monophosphate-Activated Protein Kinase (AMPK). Journal of Medicinal Chemistry 2018, 61 (16) , 7273-7288. https://doi.org/10.1021/acs.jmedchem.8b00807
    74. Nicholas A. Meanwell. Fluorine and Fluorinated Motifs in the Design and Application of Bioisosteres for Drug Design. Journal of Medicinal Chemistry 2018, 61 (14) , 5822-5880. https://doi.org/10.1021/acs.jmedchem.7b01788
    75. Gracia M. Amaya, Rebecca Durandis, David S. Bourgeois, James A. Perkins, Arsany A. Abouda, Kahari J. Wines, Mohamed Mohamud, Samuel A. Starks, R. Nathan Daniels, Klarissa D. Jackson. Cytochromes P450 1A2 and 3A4 Catalyze the Metabolic Activation of Sunitinib. Chemical Research in Toxicology 2018, 31 (7) , 570-584. https://doi.org/10.1021/acs.chemrestox.8b00005
    76. Paul D. Leeson. Impact of Physicochemical Properties on Dose and Hepatotoxicity of Oral Drugs. Chemical Research in Toxicology 2018, 31 (6) , 494-505. https://doi.org/10.1021/acs.chemrestox.8b00044
    77. Alf Claesson, Alexander Minidis. Systematic Approach to Organizing Structural Alerts for Reactive Metabolite Formation from Potential Drugs. Chemical Research in Toxicology 2018, 31 (6) , 389-411. https://doi.org/10.1021/acs.chemrestox.8b00046
    78. Keith Fraser, Dylan M. Bruckner, Jonathan S. Dordick. Advancing Predictive Hepatotoxicity at the Intersection of Experimental, in Silico, and Artificial Intelligence Technologies. Chemical Research in Toxicology 2018, 31 (6) , 412-430. https://doi.org/10.1021/acs.chemrestox.8b00054
    79. Dinakaran Murugesan, Peter C. Ray, Tracy Bayliss, Gareth A. Prosser, Justin R. Harrison, Kirsteen Green, Candice Soares de Melo, Tzu-Shean Feng, Leslie J. Street, Kelly Chibale, Digby F. Warner, Valerie Mizrahi, Ola Epemolu, Paul Scullion, Lucy Ellis, Jennifer Riley, Yoko Shishikura, Liam Ferguson, Maria Osuna-Cabello, Kevin D. Read, Simon R. Green, Dirk A. Lamprecht, Peter M. Finin, Adrie J. C. Steyn, Thomas R. Ioerger, Jim Sacchettini, Kyu Y. Rhee, Kriti Arora, Clifton E. Barry, III, Paul G. Wyatt, Helena I. M. Boshoff. 2-Mercapto-Quinazolinones as Inhibitors of Type II NADH Dehydrogenase and Mycobacterium tuberculosis: Structure–Activity Relationships, Mechanism of Action and Absorption, Distribution, Metabolism, and Excretion Characterization. ACS Infectious Diseases 2018, 4 (6) , 954-969. https://doi.org/10.1021/acsinfecdis.7b00275
    80. Brian T. O’Neill, Elizabeth M. Beck, Christopher R. Butler, Charles E. Nolan, Cathleen Gonzales, Lei Zhang, Shawn D. Doran, Kimberly Lapham, Leanne M. Buzon, Jason K. Dutra, Gabriela Barreiro, Xinjun Hou, Luis A. Martinez-Alsina, Bruce N. Rogers, Anabella Villalobos, John C. Murray, Kevin Ogilvie, Erik A. LaChapelle, Cheng Chang, Lorraine F. Lanyon, Claire M. Steppan, Ashley Robshaw, Katherine Hales, Germaine G. Boucher, Karamjeet Pandher, Christopher Houle, Claude W. Ambroise, David Karanian, David Riddell, Kelly R. Bales, Michael A. Brodney. Design and Synthesis of Clinical Candidate PF-06751979: A Potent, Brain Penetrant, β-Site Amyloid Precursor Protein Cleaving Enzyme 1 (BACE1) Inhibitor Lacking Hypopigmentation. Journal of Medicinal Chemistry 2018, 61 (10) , 4476-4504. https://doi.org/10.1021/acs.jmedchem.8b00246
    81. Elnaz Menhaji-Klotz, Kevin D. Hesp, Allyn T. Londregan, Amit S. Kalgutkar, David W. Piotrowski, Markus Boehm, Kun Song, Tim Ryder, Kevin Beaumont, Rhys M. Jones, Karen Atkinson, Janice A. Brown, John Litchfield, Jun Xiao, Daniel P. Canterbury, Kristen Burford, Benjamin A. Thuma, Chris Limberakis, Wenhua Jiao, Scott W. Bagley, Saket Agarwal, Danielle Crowell, Stephen Pazdziorko, Jessica Ward, David A. Price, Valerie Clerin. Discovery of a Novel Small-Molecule Modulator of C–X–C Chemokine Receptor Type 7 as a Treatment for Cardiac Fibrosis. Journal of Medicinal Chemistry 2018, 61 (8) , 3685-3696. https://doi.org/10.1021/acs.jmedchem.8b00190
    82. James P. Driscoll, Aprajita S. Yadav, Nina R. Shah. Role of Glucuronidation and P450 Oxidation in the Bioactivation of Bromfenac. Chemical Research in Toxicology 2018, 31 (4) , 223-230. https://doi.org/10.1021/acs.chemrestox.7b00293
    83. Laura A. McAllister, Christopher R. Butler, Scot Mente, Steven V. O’Neil, Kari R. Fonseca, Justin R. Piro, Julie A. Cianfrogna, Timothy L. Foley, Adam M. Gilbert, Anthony R. Harris, Christopher J. Helal, Douglas S. Johnson, Justin I. Montgomery, Deane M. Nason, Stephen Noell, Jayvardhan Pandit, Bruce N. Rogers, Tarek A. Samad, Christopher L. Shaffer, Rafael G. da Silva, Daniel P. Uccello, Damien Webb, Michael A. Brodney. Discovery of Trifluoromethyl Glycol Carbamates as Potent and Selective Covalent Monoacylglycerol Lipase (MAGL) Inhibitors for Treatment of Neuroinflammation. Journal of Medicinal Chemistry 2018, 61 (7) , 3008-3026. https://doi.org/10.1021/acs.jmedchem.8b00070
    84. Joseph Derosa, Miriam L. O’Duill, Matthew Holcomb, Mark N. Boulous, Ryan L. Patman, Fen Wang, Michelle Tran-Dubé, Indrawan McAlpine, Keary M. Engle. Copper-Catalyzed Chan–Lam Cyclopropylation of Phenols and Azaheterocycles. The Journal of Organic Chemistry 2018, 83 (7) , 3417-3425. https://doi.org/10.1021/acs.joc.7b03100
    85. Bryan H. Norman, Matthew J. Fisher, Matthew A. Schiffler, Steven L. Kuklish, Norman E. Hughes, Boris A. Czeskis, Kenneth C. Cassidy, Trent L. Abraham, Jeffrey J. Alberts, Debra Luffer-Atlas. Identification and Mitigation of Reactive Metabolites of 2-Aminoimidazole-Containing Microsomal Prostaglandin E Synthase-1 Inhibitors Terminated Due to Clinical Drug-Induced Liver Injury. Journal of Medicinal Chemistry 2018, 61 (5) , 2041-2051. https://doi.org/10.1021/acs.jmedchem.7b01806
    86. Vinicius M. Alves, Stephen J. Capuzzi, Rodolpho C. Braga, Joyce V. B. Borba, Arthur C. Silva, Thomas Luechtefeld, Thomas Hartung, Carolina Horta Andrade, Eugene N. Muratov, Alexander Tropsha. A Perspective and a New Integrated Computational Strategy for Skin Sensitization Assessment. ACS Sustainable Chemistry & Engineering 2018, 6 (3) , 2845-2859. https://doi.org/10.1021/acssuschemeng.7b04220
    87. Na Le Dang, Tyler B. Hughes, Grover P. Miller, and S. Joshua Swamidass . Computationally Assessing the Bioactivation of Drugs by N-Dealkylation. Chemical Research in Toxicology 2018, 31 (2) , 68-80. https://doi.org/10.1021/acs.chemrestox.7b00191
    88. Jose I. Juncosa, Kenji Takaya, Hoang V. Le, Matthew J. Moschitto, Pathum M. Weerawarna, Romila Mascarenhas, Dali Liu, Stephen L. Dewey, and Richard B. Silverman . Design and Mechanism of (S)-3-Amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic Acid, a Highly Potent γ-Aminobutyric Acid Aminotransferase Inactivator for the Treatment of Addiction. Journal of the American Chemical Society 2018, 140 (6) , 2151-2164. https://doi.org/10.1021/jacs.7b10965
    89. Christopher J. Helal, Eric Arnold, Tracey Boyden, Cheng Chang, Thomas A. Chappie, Ethan Fisher, Mihaly Hajos, John F. Harms, William E. Hoffman, John M. Humphrey, Jayvardhan Pandit, Zhijun Kang, Robin J. Kleiman, Bethany L. Kormos, Che-Wah Lee, Jiemin Lu, Noha Maklad, Laura McDowell, Dina McGinnis, Rebecca E. O’Connor, Christopher J. O’Donnell, Adam Ogden, Mary Piotrowski, Christopher J. Schmidt, Patricia A. Seymour, Hirokazu Ueno, Nichole Vansell, Patrick R. Verhoest, and Edward X. Yang . Identification of a Potent, Highly Selective, and Brain Penetrant Phosphodiesterase 2A Inhibitor Clinical Candidate. Journal of Medicinal Chemistry 2018, 61 (3) , 1001-1018. https://doi.org/10.1021/acs.jmedchem.7b01466
    90. Melanie L. Aprahamian, Svetlana B. Tikunova, Morgan V. Price, Andres F. Cuesta, Jonathan P. Davis, and Steffen Lindert . Successful Identification of Cardiac Troponin Calcium Sensitizers Using a Combination of Virtual Screening and ROC Analysis of Known Troponin C Binders. Journal of Chemical Information and Modeling 2017, 57 (12) , 3056-3069. https://doi.org/10.1021/acs.jcim.7b00536
    91. James A. D. Good, Martina Kulén, Jim Silver, K. Syam Krishnan, Wael Bahnan, Carlos Núñez-Otero, Ingela Nilsson, Emma Wede, Esmee de Groot, Åsa Gylfe, Sven Bergström, and Fredrik Almqvist . Thiazolino 2-Pyridone Amide Isosteres As Inhibitors of Chlamydia trachomatis Infectivity. Journal of Medicinal Chemistry 2017, 60 (22) , 9393-9399. https://doi.org/10.1021/acs.jmedchem.7b00716
    92. Chaitanya K. Jaladanki, Akbar Shaikh, and Prasad V. Bharatam . Biotransformation of Isoniazid by Cytochromes P450: Analyzing the Molecular Mechanism using Density Functional Theory. Chemical Research in Toxicology 2017, 30 (11) , 2060-2073. https://doi.org/10.1021/acs.chemrestox.7b00129
    93. Rui Sun, Fuguo Shi, Keke Liu, Ling Fu, Caiping Tian, Yong Yang, Keri A. Tallman, Ned A. Porter, and Jing Yang . A Chemoproteomic Platform To Assess Bioactivation Potential of Drugs. Chemical Research in Toxicology 2017, 30 (10) , 1797-1803. https://doi.org/10.1021/acs.chemrestox.7b00183
    94. Antonia F. Stepan, Michelle M. Claffey, Matthew R. Reese, Gayatri Balan, Gabriela Barreiro, Jason Barricklow, Michael J. Bohanon, Brian P. Boscoe, Gregg D. Cappon, Lois K. Chenard, Julie Cianfrogna, Laigao Chen, Karen J. Coffman, Susan E. Drozda, Joshua R. Dunetz, Somraj Ghosh, Xinjun Hou, Christopher Houle, Kapil Karki, John T. Lazzaro, Jessica Y. Mancuso, John M. Marcek, Emily L. Miller, Mark A. Moen, Steven O’Neil, Isao Sakurada, Marc Skaddan, Vinod Parikh, Deborah L. Smith, Patrick Trapa, Jamison B. Tuttle, Patrick R. Verhoest, Daniel P. Walker, Annie Won, Ann S. Wright, Jessica Whritenour, Kenneth Zasadny, Margaret M. Zaleska, Lei Zhang, and Christopher L. Shaffer . Discovery and Characterization of (R)-6-Neopentyl-2-(pyridin-2-ylmethoxy)-6,7-dihydropyrimido[2,1-c][1,4]oxazin-4(9H)-one (PF-06462894), an Alkyne-Lacking Metabotropic Glutamate Receptor 5 Negative Allosteric Modulator Profiled in both Rat and Nonhuman Primates. Journal of Medicinal Chemistry 2017, 60 (18) , 7764-7780. https://doi.org/10.1021/acs.jmedchem.7b00604
    95. Wenfeng Lu, Yongqiang Liu, Haikuo Ma, Jiyue Zheng, Sheng Tian, Zhijian Sun, Lusong Luo, Jiajun Li, Hongjian Zhang, Zeng-Jie Yang, and Xiaohu Zhang . Design, Synthesis, and Structure–Activity Relationship of Tetrahydropyrido[4,3-d]pyrimidine Derivatives as Potent Smoothened Antagonists with in Vivo Activity. ACS Chemical Neuroscience 2017, 8 (9) , 1980-1994. https://doi.org/10.1021/acschemneuro.7b00153
    96. Nigel. A. Swain, Dave Batchelor, Serge Beaudoin, Bruce M. Bechle, Paul A. Bradley, Alan D. Brown, Bruce Brown, Ken J. Butcher, Richard P. Butt, Mark L. Chapman, Stephen Denton, David Ellis, Sebastien R. G. Galan, Steven M. Gaulier, Ben S. Greener, Marcel J. de Groot, Mel S. Glossop, Ian K. Gurrell, Jo Hannam, Matthew S. Johnson, Zhixin Lin, Christopher J. Markworth, Brian E. Marron, David S. Millan, Shoko Nakagawa, Andy Pike, David Printzenhoff, David J. Rawson, Sarah J. Ransley, Steven M. Reister, Kosuke Sasaki, R. Ian Storer, Paul A. Stupple, and Christopher W. West . Discovery of Clinical Candidate 4-[2-(5-Amino-1H-pyrazol-4-yl)-4-chlorophenoxy]-5-chloro-2-fluoro-N-1,3-thiazol-4-ylbenzenesulfonamide (PF-05089771): Design and Optimization of Diaryl Ether Aryl Sulfonamides as Selective Inhibitors of NaV1.7. Journal of Medicinal Chemistry 2017, 60 (16) , 7029-7042. https://doi.org/10.1021/acs.jmedchem.7b00598
    97. Landon R. Whitby, R. Scott Obach, Gabriel M. Simon, Matthew M. Hayward, and Benjamin F. Cravatt . Quantitative Chemical Proteomic Profiling of the in Vivo Targets of Reactive Drug Metabolites. ACS Chemical Biology 2017, 12 (8) , 2040-2050. https://doi.org/10.1021/acschembio.7b00346
    98. Russell F. Graceffa, Alessandro A. Boezio, Jessica Able, Steven Altmann, Loren M. Berry, Christiane Boezio, John R. Butler, Margaret Chu-Moyer, Melanie Cooke, Erin F. DiMauro, Thomas A. Dineen, Elma Feric Bojic, Robert S. Foti, Robert T. Fremeau, Jr., Angel Guzman-Perez, Hua Gao, Hakan Gunaydin, Hongbing Huang, Liyue Huang, Christopher Ilch, Michael Jarosh, Thomas Kornecook, Charles R. Kreiman, Daniel S. La, Joseph Ligutti, Benjamin C. Milgram, Min-Hwa Jasmine Lin, Isaac E. Marx, Hanh N. Nguyen, Emily A. Peterson, Gwen Rescourio, John Roberts, Laurie Schenkel, Roman Shimanovich, Brian A. Sparling, John Stellwagen, Kristin Taborn, Karina R. Vaida, Jean Wang, John Yeoman, Violeta Yu, Dawn Zhu, Bryan D. Moyer, and Matthew M. Weiss . Sulfonamides as Selective NaV1.7 Inhibitors: Optimizing Potency, Pharmacokinetics, and Metabolic Properties to Obtain Atropisomeric Quinolinone (AM-0466) that Affords Robust in Vivo Activity. Journal of Medicinal Chemistry 2017, 60 (14) , 5990-6017. https://doi.org/10.1021/acs.jmedchem.6b01850
    99. Matthew M. Weiss, Thomas A. Dineen, Isaac E. Marx, Steven Altmann, Alessandro Boezio, Howard Bregman, Margaret Chu-Moyer, Erin F. DiMauro, Elma Feric Bojic, Robert S. Foti, Hua Gao, Russell Graceffa, Hakan Gunaydin, Angel Guzman-Perez, Hongbing Huang, Liyue Huang, Michael Jarosh, Thomas Kornecook, Charles R. Kreiman, Joseph Ligutti, Daniel S. La, Min-Hwa Jasmine Lin, Dong Liu, Bryan D. Moyer, Hanh N. Nguyen, Emily A. Peterson, Paul E. Rose, Kristin Taborn, Beth D. Youngblood, Violeta Yu, and Robert T. Fremeau, Jr. . Sulfonamides as Selective NaV1.7 Inhibitors: Optimizing Potency and Pharmacokinetics While Mitigating Metabolic Liabilities. Journal of Medicinal Chemistry 2017, 60 (14) , 5969-5989. https://doi.org/10.1021/acs.jmedchem.6b01851
    100. Christopher J. Helal, Eric P. Arnold, Tracey L. Boyden, Cheng Chang, Thomas A. Chappie, Kimberly F. Fennell, Michael D. Forman, Mihaly Hajos, John F. Harms, William E. Hoffman, John M. Humphrey, Zhijun Kang, Robin J. Kleiman, Bethany L. Kormos, Che-Wah Lee, Jiemin Lu, Noha Maklad, Laura McDowell, Scot Mente, Rebecca E. O’Connor, Jayvardhan Pandit, Mary Piotrowski, Anne W. Schmidt, Christopher J. Schmidt, Hirokazu Ueno, Patrick R. Verhoest, and Edward X. Yang . Application of Structure-Based Design and Parallel Chemistry to Identify a Potent, Selective, and Brain Penetrant Phosphodiesterase 2A Inhibitor. Journal of Medicinal Chemistry 2017, 60 (13) , 5673-5698. https://doi.org/10.1021/acs.jmedchem.7b00397
    Load more citations