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ABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Generation and Evaluation of a CYP2C9 Heteroactivation Pharmacophore

EST Chemical Computing (A.-C.E., S.B.) and High Throughput Screening (C.E., N.A), AstraZeneca R&D, Mölndal, Sweden; and School of Pharmacy and Pharmaceutical Sciences (A.E., B.H.), University of Manchester, Manchester, United Kingdom

Positive cooperativity (auto- and heteroactivation) of drug oxidation, a potential cause of drug interactions, is well established in vitro for cytochrome P450 (P450) 3A4 but to a much lesser extent for other drug-metabolizing P450 isoforms. Using a high throughput fluorescent-based CYP2C9 effector assay, we identified >30 heteroactivators from a set of 1504 structurally diverse compounds. Several potent heteroactivators of CYP2C9-mediated 7-methoxy-4-trifluoromethyl-coumarin metabolism are marketed drugs or endogenous compounds (amiodarone, niclosamide, liothyronine, meclofenemate, zafirlukast, estropipate, and dichlorphenamide, yielding 150% control reaction velocity at 0.04, 0.09, 0.5, 1, 1.2, 1.5, and 2.5 µM, respectively). Some heteroactivators are also known CYP2C9 substrates or inhibitors, suggesting potential multiple binding sites and substrate-dependent effects. v_150%, the concentration of effector giving 150% of control reaction velocity, was used as pharmacophore modeling parameter based on enzyme kinetic assumptions. The generated pharmacophore (training set: n = 36, v_150% 0.04–150 µM) contains one hydrogen bond acceptor, one aromatic ring, and two hydrophobes. v_150% values for 94% of the training set heteroactivators were predicted within 1 log unit for the residual (r [log observed v_150%] versus [log predicted v_150%] = 0.71; r² 0.50). The model also correctly identifies close to 70% of potent inhibitors (IC₅₀ < 1 µM) as high-affinity CYP2C9 binders, suggesting that heteroactivators and inhibitors share some common structural CYP2C9 binding features, supporting the previously suggested hypothesis that CYP2C9 heteroactivators can bind within the active site.

Address correspondence to: Ann-Charlotte Egnell, AstraZeneca R&D, EST Chemical Computing, S-431 83 Mölndal, Sweden. E-mail: ann-charlotte.egnell{at}astrazeneca.com

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