Cart
Article
CYP2C9 Structure−Metabolism Relationships: Optimizing the Metabolic Stability of COX-2 Inhibitors
Full Text HTML
Hi-Res PDFPurchase the full-text
- PDF/HTML,
figures/images,
references and tables,
(where available)
Section:Abstract
The cytochrome P450 (CYP) family is composed of a large group of monooxygenases that mediate the metabolism of xenobiotics and endogenous compounds. CYP2C9, one of the major isoforms of the CYP family, is responsible for the phase I metabolism of a variety of drugs. The aim of the present investigation is to use rational design together with MetaSite, a metabolism site prediction program, to synthesize compounds that retain their pharmacological effects but that are metabolically more stable in the presence of CYP2C9. The model compound for the study is the nonsteroidal anti-inflammatory drug celecoxib, a COX-2 selective inhibitor and known CYP2C9 substrate. Thirteen analogs of celecoxib were designed, synthesized, and evaluated with regard to their metabolic properties and pharmacologic effects. The docking solutions and the predictions from MetaSite gave useful information leading to the design of new compounds with improved metabolic properties.
Citing Articles
Citation data is made available by participants in CrossRef's Cited-by Linking service. For a more comprehensive list of citations to this article, users are encouraged to perform a search in SciFinder.
This article has been cited by 5 ACS Journal articles (5 most recent appear below).
A Novel Approach for Predicting P-Glycoprotein (ABCB1) Inhibition Using Molecular Interaction Fields
Fabio Broccatelli, Emanuele Carosati, Annalisa Neri, Maria Frosini, Laura Goracci, Tudor I. Oprea, and Gabriele CrucianiJournal of Medicinal Chemistry2011 54 (6), 1740-1751A Novel Approach for Predicting P-Glycoprotein (ABCB1) Inhibition Using Molecular Interaction Fields
Fabio Broccatelli, Emanuele Carosati, Annalisa Neri, Maria Frosini, Laura Goracci, Tudor I. Oprea, and Gabriele CrucianiJournal of Medicinal Chemistry2011 54 (6), 1740-1751P-glycoprotein (Pgp or ABCB1) is an ABC transporter protein involved in intestinal absorption, drug metabolism, and brain penetration, and its inhibition can seriously alter a drug's bioavailability and safety. In addition, inhibitors of Pgp can be used ...
FLAP: GRID Molecular Interaction Fields in Virtual Screening. Validation using the DUD Data Set
Simon Cross, Massimo Baroni, Emanuele Carosati, Paolo Benedetti and Sergio ClementiJournal of Chemical Information and Modeling2010 50 (8), 1442-1450FLAP: GRID Molecular Interaction Fields in Virtual Screening. Validation using the DUD Data Set
Simon Cross, Massimo Baroni, Emanuele Carosati, Paolo Benedetti and Sergio ClementiJournal of Chemical Information and Modeling2010 50 (8), 1442-1450The performance of FLAP (Fingerprints for Ligands and Proteins) in virtual screening is assessed using a subset of the DUD (Directory of Useful Decoys) benchmarking data set containing 13 targets each with more than 15 different chemotype classes. A ...
EaMEAD: Activation Energy Prediction of Cytochrome P450 Mediated Metabolism with Effective Atomic Descriptors
Doo Nam Kim, Kwang-Hwi Cho, Won Seok Oh, Chang Joon Lee, Sung Kwang Lee, Jihoon Jung and Kyoung Tai NoJournal of Chemical Information and Modeling2009 49 (7), 1643-1654EaMEAD: Activation Energy Prediction of Cytochrome P450 Mediated Metabolism with Effective Atomic Descriptors
Doo Nam Kim, Kwang-Hwi Cho, Won Seok Oh, Chang Joon Lee, Sung Kwang Lee, Jihoon Jung and Kyoung Tai NoJournal of Chemical Information and Modeling2009 49 (7), 1643-1654In an effort to improve drug design and predictions for pharmacokinetics (PK), an empirical model was developed to predict the activation energies (Ea) of cytochrome P450 (CYP450) mediated metabolism. The model, EaMEAD (Activation energy of Metabolism ...
An Improved and Scalable Process for Celecoxib: A Selective Cyclooxygenase-2 Inhibitor
Anumula Raghupathi Reddy, Alla Sampath, Gilla Goverdhan, Bojja Yakambaram, Kagga Mukkanti and Padi Pratap ReddyOrganic Process Research & Development2009 13 (1), 98-101An Improved and Scalable Process for Celecoxib: A Selective Cyclooxygenase-2 Inhibitor
Anumula Raghupathi Reddy, Alla Sampath, Gilla Goverdhan, Bojja Yakambaram, Kagga Mukkanti and Padi Pratap ReddyOrganic Process Research & Development2009 13 (1), 98-101An improved, scalable and commercially viable process is developed for an active pharmaceutical ingredient, celecoxib.
CYP2C9 Structure−Metabolism Relationships: Substrates, Inhibitors, and Metabolites
Marie M. Ahlström, Marianne Ridderström, and Ismael ZamoraJournal of Medicinal Chemistry2007 50 (22), 5382-5391CYP2C9 Structure−Metabolism Relationships: Substrates, Inhibitors, and Metabolites
Marie M. Ahlström, Marianne Ridderström, and Ismael ZamoraJournal of Medicinal Chemistry2007 50 (22), 5382-5391The cytochrome P450 (CYP) family is composed of monooxygenases, which mediate the metabolism of xenobiotics and endogenous compounds. The characterization of the interactions between these enzymes and candidate drugs is an important part of the drug ...
Tools
-
Add to Favorites
-
Download Citation
-
Email a Colleague -
Permalink
Order Reprints
Rights & Permissions
Citation Alerts
Accession Codes
History
- Published In Issue September 06, 2007
- Received May 2, 2007
ACS
Network
Facebook
Tweet This
CiteULike
Newsvine
Digg This
Delicious
