Design of Next-Generation DGAT2 Inhibitor PF-07202954 with Longer Predicted Half-Life

  • ACS Med Chem Lett. 2023 Oct 2;14(10):1427-1433. doi: 10.1021/acsmedchemlett.3c00330.
Kevin J Filipski  1 ,  David J Edmonds  1 ,  Michelle R Garnsey  1  2 ,  Daniel J Smaltz  1  2 ,  Karen Coffman  2 ,  Kentaro Futatsugi  1 ,  Jack Lee  2 ,  Steven V O'Neil  2 ,  Ann Wright  2 ,  Deane Nason  2 ,  James R Gosset  1 ,  Christine C Orozco  2 ,  Dan Blackler  1 ,  Guila Fakhoury  1 ,  Jemy A Gutierrez  1 ,  Sylvie Perez  1 ,  Trenton Ross  1 ,  Ingrid Stock  2 ,  Gregory Tesz  1 ,  Robert Dullea  1
Affiliations
  • 1. Pfizer Research & Development, 1 Portland Street, Cambridge, Massachusetts 02139, United States.
  • 2. Pfizer Research & Development, 558 Eastern Point Road, Groton, Connecticut 06340, United States.
PMID: 37849537 DOI: 10.1021/acsmedchemlett.3c00330
Abstract

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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