晚期微粒体氧化减少药物相互作用并鉴定出磷酸二酯酶2A抑制剂PF-06815189。
Late-Stage Microsomal Oxidation Reduces Drug-Drug Interaction and Identifies Phosphodiesterase 2A Inhibitor PF-06815189.
作者信息
Stepan Antonia F, Tran Tuan P, Helal Christopher J, Brown Maria S, Chang Cheng, O'Connor Rebecca E, De Vivo Michael, Doran Shawn D, Fisher Ethan L, Jenkinson Stephen, Karanian David, Kormos Bethany L, Sharma Raman, Walker Gregory S, Wright Ann S, Yang Edward X, Brodney Michael A, Wager Travis T, Verhoest Patrick R, Obach R Scott
机构信息
Pfizer Worldwide Research and Development, 610 Main Street, Cambridge, Massachusetts 02139, United States.
Pfizer Worldwide Research and Development, Eastern Point Road, Groton, Connecticut 06340, United States.
出版信息
ACS Med Chem Lett. 2018 Jan 4;9(2):68-72. doi: 10.1021/acsmedchemlett.7b00343. eCollection 2018 Feb 8.
Late-stage oxidation using liver microsomes was applied to phosphodiesterase 2 inhibitor to reduce its clearance by cytochrome P450 enzymes, introduce renal clearance, and minimize the risk for victim drug-drug interactions. This approach yielded PF-06815189 () with improved physicochemical properties and a mixed metabolic profile. This example highlights the importance of C-H diversification methods to drug discovery.
使用肝微粒体进行后期氧化应用于磷酸二酯酶2抑制剂，以降低其被细胞色素P450酶清除的速率，引入肾清除率，并将受害者药物-药物相互作用的风险降至最低。这种方法产生了具有改善的物理化学性质和混合代谢谱的PF-06815189（）。这个例子突出了C-H多样化方法对药物发现的重要性。
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