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Late-Stage Microsomal Oxidation Reduces Drug–Drug Interaction and Identifies Phosphodiesterase 2A Inhibitor PF-06815189
ACS Medicinal Chemistry Letters ( IF 4.2 ) Pub Date : 2018-01-30 00:00:00 , DOI: 10.1021/acsmedchemlett.7b00343
Antonia F. Stepan 1 , Tuan P. Tran 2 , Christopher J. Helal 2 , Maria S. Brown 2 , Cheng Chang 2 , Rebecca E. O’Connor 2 , Michael De Vivo 1 , Shawn D. Doran 2 , Ethan L. Fisher 2 , Stephen Jenkinson 3 , David Karanian 2 , Bethany L. Kormos 1 , Raman Sharma 2 , Gregory S. Walker 2 , Ann S. Wright 2 , Edward X. Yang 2 , Michael A. Brodney 1 , Travis T. Wager 1 , Patrick R. Verhoest 1 , R. Scott Obach 2
Affiliation  

Late-stage oxidation using liver microsomes was applied to phosphodiesterase 2 inhibitor 1 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 (2) with improved physicochemical properties and a mixed metabolic profile. This example highlights the importance of C–H diversification methods to drug discovery.

中文翻译:

后期微粒体氧化可减少药物相互作用,并鉴定磷酸二酯酶2A抑制剂PF-06815189

使用肝微粒体的后期氧化作用被用于磷酸二酯酶2抑制剂1,以减少其被细胞色素P450酶清除的作用,引入肾脏清除作用并最大程度地减少受害人药物相互作用的风险。该方法产生具有改善的物理化学性质和混合的代谢谱的PF-06815189(2)。这个例子强调了CH多样化方法对药物发现的重要性。
更新日期:2018-01-30
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