2. Academic Validation
  3. Design of Next-Generation DGAT2 Inhibitor PF-07202954 with Longer Predicted Half-Life

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

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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