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

Journal Article · · Journal of Medicinal Chemistry
ORCiD logo [1];  [2];  [2];  [2];  [3];  [3];  [4];  [4];  [4];  [4];  [4];  [2];  [2];  [3];  [4];  [3];  [3];  [2];  [2];  [1] more »;  [1];  [2];  [4];  [4];  [3];  [2];  [4];  [1];  [4];  [1];  [3];  [2];  [2] « less
  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
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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.

Research Organization:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Organization:
INDUSTRY
OSTI ID:
1405008
Journal Information:
Journal of Medicinal Chemistry, Vol. 60, Issue 18; ISSN 0022-2623
Publisher:
American Chemical Society (ACS)
Country of Publication:
United States
Language:
ENGLISH

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Related Subjects

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY
60 APPLIED LIFE SCIENCES