CYP2C9 structure-metabolism relationships: optimizing the metabolic stability of COX-2 inhibitors.
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.
Ahlström
Marie M
MM
Discovery DMPK and Bioanalytical Chemistry, AstraZeneca R&D Mölndal, S-431 81 Mölndal, Sweden. marie.m.ahlstrom@astrazeneca.com
Ridderström
Marianne
M
Zamora
Ismael
I
Luthman
Kristina
K
D001189:Aryl Hydrocarbon Hydroxylases / Q000737:chemistry*; D001665:Binding Sites; D000068579:Celecoxib; D052246:Cyclooxygenase 2 Inhibitors / Q000138:chemical synthesis / Q000737:chemistry*; D065729:Cytochrome P-450 CYP2C9; D006801:Humans; D008954:Models, Biological; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry*; D011994:Recombinant Proteins / Q000138:chemical synthesis / Q000737:chemistry; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry*
D052246:Cyclooxygenase 2 Inhibitors; D011720:Pyrazoles; D011994:Recombinant Proteins; D013449:Sulfonamides; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; D000068579:Celecoxib