Probing Mechanisms of CYP3A Time-Dependent Inhibition Using a Truncated Model System
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- 作者：Xiaojing Wang ; Minghua Sun ; Connie New ; Spencer Nam ; Wesley P. Blackaby ; Alastair J. Hodges ; David Nash ; Mizio Matteucci ; Joseph P. Lyssikatos ; Peter W. Fan ; Suzanne Tay ; Jae H. Chang
- 刊名：ACS Medicinal Chemistry Letters
- 出版年：2015
- 出版时间：August 13, 2015
- 年：2015
- 卷：6
- 期：8
- 页码：925-929
- 全文大小：307K
- ISSN：1948-5875
文摘
Time-dependent inhibition (TDI) of cytochrome P450 (CYP) enzymes may incur serious undesirable drug鈥揹rug interactions and in rare cases drug-induced idiosyncratic toxicity. The reactive metabolites are often generated through multiple sequential biotransformations and form adducts with CYP enzymes to inactivate their function. The complexity of these processes makes addressing TDI liability very challenging. Strategies to mitigate TDI are therefore highly valuable in discovering safe therapies to benefit patients. In this Letter, we disclose our simplified approach toward addressing CYP3A TDI liabilities, guided by metabolic mechanism hypotheses. By adding a methyl group onto the 伪 carbon of a basic amine, TDI activities of both the truncated and full molecules (7a and 11) were completely eliminated. We propose that truncated molecules, albeit with caveats, may be used as surrogates for full molecules to investigate TDI.