Journal of medicinal chemistry · 2020
Discovery of PF-06835919: A Potent Inhibitor of Ketohexokinase (KHK) for the Treatment of Metabolic Disorders Driven by the Overconsumption of Fructose.
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Futatsugi Kentaro, Smith Aaron C, Tu Meihua, Raymer Brian, Ahn Kay, Coffey Steven B, Dowling Matthew S, Fernando Dilinie P, Gutierrez Jemy A, Huard Kim, Jasti Jayasankar, Kalgutkar Amit S, Knafels John D, Pandit Jayvardhan, Parris Kevin D, Perez Sylvie, Pfefferkorn Jeffrey A, Price David A, Ryder Tim, Shavnya Andre, Stock Ingrid A, Tsai Andy S, Tesz Gregory J, Thuma Benjamin A, Weng Yan, Wisniewska Hanna M, Xing Gang, Zhou Jun, Magee Thomas V
Аннотация
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.