Discovery of PF-06835919: A Potent Inhibitor of Ketohexokinase (KHK) for the Treatment of Metabolic Disorders Driven by the Overconsumption of Fructose

  • J Med Chem. 2020 Nov 25;63(22):13546-13560. doi: 10.1021/acs.jmedchem.0c00944.
Kentaro Futatsugi  1 ,  Aaron C Smith  2 ,  Meihua Tu  1 ,  Brian Raymer  1 ,  Kay Ahn  3 ,  Steven B Coffey  2 ,  Matthew S Dowling  2 ,  Dilinie P Fernando  2 ,  Jemy A Gutierrez  3 ,  Kim Huard  1 ,  Jayasankar Jasti  2 ,  Amit S Kalgutkar  1 ,  John D Knafels  2 ,  Jayvardhan Pandit  2 ,  Kevin D Parris  2 ,  Sylvie Perez  3 ,  Jeffrey A Pfefferkorn  3 ,  David A Price  1 ,  Tim Ryder  2 ,  Andre Shavnya  2 ,  Ingrid A Stock  2 ,  Andy S Tsai  2 ,  Gregory J Tesz  3 ,  Benjamin A Thuma  2 ,  Yan Weng  1 ,  Hanna M Wisniewska  2 ,  Gang Xing  3 ,  Jun Zhou  4 ,  Thomas V Magee  1
Affiliations
  • 1. Pfizer Inc. Medicine Design, 1 Portland Street, Cambridge, Massachusetts 02139, United States.
  • 2. Pfizer Inc. Medicine Design, Eastern Point Road, Groton, Connecticut 06340, United States.
  • 3. Pfizer Inc. Internal Medicine Research Unit, 1 Portland Street, Cambridge, Massachusetts 02139, United States.
  • 4. Pfizer Inc. Drug Safety R&D, Eastern Point Road, Groton, Connecticut 06340, United States.
PMID: 32910646 DOI: 10.1021/acs.jmedchem.0c00944
Abstract

Increased fructose consumption and its subsequent metabolism have been implicated in metabolic disorders such as nonalcoholic fatty liver disease and steatohepatitis (NAFLD/NASH) and Insulin resistance. Ketohexokinase (KHK) converts fructose to fructose-1-phosphate (F1P) in the first step of the metabolic cascade. Herein we report the discovery of a first-in-class KHK inhibitor, PF-06835919 (8), currently in phase 2 clinical trials. The discovery of 8 was built upon our originally reported, fragment-derived lead 1 and the recognition of an alternative, rotated binding mode upon changing the ribose-pocket binding moiety from a pyrrolidinyl to an azetidinyl ring system. This new binding mode enabled efficient exploration of the vector directed at the Arg-108 residue, leading to the identification of highly potent 3-azabicyclo[3.1.0]hexane acetic acid-based KHK inhibitors by combined use of parallel medicinal chemistry and structure-based drug design.