ACS Publications. Most Trusted. Most Cited. Most Read
My Activity
CONTENT TYPES

Figure 1Loading Img

Discovery of Benzimidazole Oxazolidinediones as Novel and Selective Nonsteroidal Mineralocorticoid Receptor Antagonists

View Author Information
Merck Research Laboratories, Merck & Co., Kenilworth, New Jersey 07033, United States
Cite this: ACS Med. Chem. Lett. 2015, 6, 4, 461–465
Publication Date (Web):March 6, 2015
https://doi.org/10.1021/acsmedchemlett.5b00010
Copyright © 2015 American Chemical Society

    Article Views

    962

    Altmetric

    -

    Citations

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

    Abstract

    Abstract Image

    Elaboration of the oxazolidinedione series led to replacement of the exocyclic amides with substituted benzimidazoles. The structure–activity relationship (SAR) exploration resulted in the discovery of potent and selective nonsteroidal mineralocorticoid receptor (MR) antagonists with significantly improved microsomal stability and pharmacokinetic (PK) profile relative to the HTS hit 1a. One compound 2p possessed comparable efficacy as spironolactone (SPL) at 100 mg/kg (p.o.) in the rat natriuresis model. As such, this series was validated as a lead series for further optimization.

    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

    Experimental procedures, NMR, LC/MS data, and chiral separation. 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 13 publications.

    1. Aleksandra Murre, Kristin Erkman, Ivar Järving, Tõnis Kanger. Asymmetric Chemoenzymatic One-Pot Synthesis of α-Hydroxy Half-Esters. ACS Omega 2021, 6 (31) , 20686-20698. https://doi.org/10.1021/acsomega.1c02973
    2. Mercedes Martín-Martínez, Felipe L. Pérez-Gordillo, Diego Álvarez de la Rosa, Yoel Rodríguez, Guillermo Gerona-Navarro, Rosario González-Muñiz, and Ming-Ming Zhou . Modulating Mineralocorticoid Receptor with Non-steroidal Antagonists. New Opportunities for the Development of Potent and Selective Ligands without Off-Target Side Effects. Journal of Medicinal Chemistry 2017, 60 (7) , 2629-2650. https://doi.org/10.1021/acs.jmedchem.6b01065
    3. Takuya Kanemitsu, Miho Sato, Miyuki Yoshida, Eisuke Ozasa, Michiko Miyazaki, Yuki Odanaka, Kazuhiro Nagata, and Takashi Itoh . Enantioselective α-Benzoyloxylation of Malonic Diesters by Phase-Transfer Catalysis. Organic Letters 2016, 18 (21) , 5484-5487. https://doi.org/10.1021/acs.orglett.6b02682
    4. Shejuti Rahman Brishty, Md. Jamal Hossain, Mayeen Uddin Khandaker, Mohammad Rashed Iqbal Faruque, Hamid Osman, S. M. Abdur Rahman. A Comprehensive Account on Recent Progress in Pharmacological Activities of Benzimidazole Derivatives. Frontiers in Pharmacology 2021, 12 https://doi.org/10.3389/fphar.2021.762807
    5. Sara Meninno, Rosaria Villano, Alessandra Lattanzi. Magnesium Monoperphthalate (MMPP): a Convenient Oxidant for the Direct Rubottom Oxidation of Malonates, β‐Keto Esters, and Amides. European Journal of Organic Chemistry 2021, 2021 (11) , 1758-1762. https://doi.org/10.1002/ejoc.202100098
    6. Hua Wu, Qian Wang, Jieping Zhu. Catalytic Enantioselective Benzilic Ester Rearrangement. Angewandte Chemie 2020, 132 (18) , 7328-7332. https://doi.org/10.1002/ange.202001258
    7. Hua Wu, Qian Wang, Jieping Zhu. Catalytic Enantioselective Benzilic Ester Rearrangement. Angewandte Chemie International Edition 2020, 59 (18) , 7261-7265. https://doi.org/10.1002/anie.202001258
    8. Christopher R Heier, Qing Yu, Alyson A Fiorillo, Christopher B Tully, Asya Tucker, Davi A Mazala, Kitipong Uaesoontrachoon, Sadish Srinivassane, Jesse M Damsker, Eric P Hoffman, Kanneboyina Nagaraju, Christopher F Spurney. Vamorolone targets dual nuclear receptors to treat inflammation and dystrophic cardiomyopathy. Life Science Alliance 2019, 2 (1) , e201800186. https://doi.org/10.26508/lsa.201800186
    9. Anneli Nordqvist, Kenneth L. Granberg. Mineralocorticoid Receptor Antagonists. 2019, 151-188. https://doi.org/10.1016/bs.vh.2018.10.008
    10. Bohdan A. Chalyk, Kateryna V. Hrebeniuk, Konstantin S. Gavrilenko, Irene B. Kulik, Alexander B. Rozhenko, Dmitriy M. Volochnyuk, Oleksandr S. Liashuk, Oleksandr O. Grygorenko. Synthesis of 4‐Hetarylisoxazoles from Amino Acid‐Derived Halogenoximes and Push‐Pull Enamines. European Journal of Organic Chemistry 2018, 2018 (40) , 5585-5595. https://doi.org/10.1002/ejoc.201800753
    11. Hui Pei, Wei Wang, Di Zhao, Lei Wang, Guo-Hai Su, Zhuo Zhao. The use of a novel non-steroidal mineralocorticoid receptor antagonist finerenone for the treatment of chronic heart failure. Medicine 2018, 97 (16) , e0254. https://doi.org/10.1097/MD.0000000000010254
    12. Matthieu Collin, Frédéric Jaisser. Mineralocorticoid receptor antagonists: a patent evaluation of US20150284376A1. Expert Opinion on Therapeutic Patents 2016, 26 (10) , 1111-1114. https://doi.org/10.1080/13543776.2016.1227320
    13. Elise P. Gomez-Sanchez. Third-generation Mineralocorticoid Receptor Antagonists. Journal of Cardiovascular Pharmacology 2016, 67 (1) , 26-38. https://doi.org/10.1097/FJC.0000000000000329

    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