2. Academic Validation
  3. Discovery of Fragment-Derived Small Molecules for in Vivo Inhibition of Ketohexokinase (KHK)

Discovery of Fragment-Derived Small Molecules for in Vivo Inhibition of Ketohexokinase (KHK)

  • J Med Chem. 2017 Sep 28;60(18):7835-7849. doi: 10.1021/acs.jmedchem.7b00947.
Kim Huard 1,  Kay Ahn 2,  Paul Amor 2,  David A Beebe 2,  Kris A Borzilleri 3,  Boris A Chrunyk 3,  Steven B Coffey 4,  Yang Cong 4,  Edward L Conn 4,  Jeffrey S Culp 4,  Matthew S Dowling 4,  Matthew F Gorgoglione 2,  Jemy A Gutierrez 2,  John D Knafels 3,  Erik A Lachapelle 4,  Jayvardhan Pandit 3,  Kevin D Parris 3,  Sylvie Perez 2,  Jeffrey A Pfefferkorn 2,  David A Price 1,  Brian Raymer 1,  Trenton T Ross 2,  Andre Shavnya 4,  Aaron C Smith 4,  Timothy A Subashi 3,  Gregory J Tesz 2,  Benjamin A Thuma 4,  Meihua Tu 1,  John D Weaver 4,  Yan Weng 1,  Jane M Withka 3,  Gang Xing 2,  Thomas V Magee 2
Affiliations

Affiliations

  • 1 Medicine Design, Pfizer Inc. , 1 Portland Street, Cambridge, Massachusetts 02139, United States.
  • 2 Internal Medicine, Pfizer Inc. , 1 Portland Street, Cambridge, Massachusetts 02139, United States.
  • 3 Structural Biology and Biophysics, Pfizer Inc. , Eastern Point Road, Groton, Connecticut 06340, United States.
  • 4 Medicine Design, Pfizer Inc. , Eastern Point Road, Groton, Connecticut 06340, United States.
PMID: 28853885 DOI: 10.1021/acs.jmedchem.7b00947
Abstract

Increased fructose consumption and its subsequent metabolism have been implicated in hepatic steatosis, dyslipidemia, obesity, and Insulin resistance in humans. Since ketohexokinase (KHK) is the principal Enzyme responsible for fructose metabolism, identification of a selective KHK inhibitor may help to further elucidate the effect of KHK inhibition on these metabolic disorders. Until now, studies on KHK inhibition with small molecules have been limited due to the lack of viable in vivo pharmacological tools. Herein we report the discovery of 12, a selective KHK inhibitor with potency and properties suitable for evaluating KHK inhibition in rat models. Key structural features interacting with KHK were discovered through fragment-based screening and subsequent optimization using structure-based drug design, and parallel medicinal chemistry led to the identification of pyridine 12.

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