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

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

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.

Figures
Products