亲脂性
效力
化学
甘油三酯
部分
药理学
医学
生物化学
立体化学
胆固醇
体外
作者
Kevin J. Filipski,David J. Edmonds,Michelle R. Garnsey,Daniel J. Smaltz,Karen J. Coffman,Kentaro Futatsugi,Jack C. Lee,Steven V. O’Neil,Andrew B. Wright,Deane M. Nason,J Gosset,Christine C. Orozco,Dan Blackler,Guila Fakhoury,Jemy A. Gutierrez,Sylvie Perez,Trenton T. Ross,Ingrid A. Stock,Gregory J. Tesz,Robert Dullea
标识
DOI:10.1021/acsmedchemlett.3c00330
摘要
Diacylglycerol O-acyltransferase 2 (DGAT2) inhibitors have been shown to lower liver triglyceride content and are being explored clinically as a treatment for non-alcoholic steatohepatitis (NASH). This work details efforts to find an extended-half-life DGAT2 inhibitor. A basic moiety was added to a known inhibitor template, and the basicity and lipophilicity were fine-tuned by the addition of electrophilic fluorines. A weakly basic profile was required to find an appropriate balance of potency, clearance, and permeability. This work culminated in the discovery of PF-07202954 (12), a weakly basic DGAT2 inhibitor that has advanced to clinical studies. This molecule displays a higher volume of distribution and longer half-life in preclinical species, in keeping with its physicochemical profile, and lowers liver triglyceride content in a Western-diet-fed rat model.
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