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

Autor:	Futatsugi K; Pfizer Inc. Medicine Design, 1 Portland Street, Cambridge, Massachusetts 02139, United States., Smith AC; Pfizer Inc. Medicine Design, Eastern Point Road, Groton, Connecticut 06340, United States., Tu M; Pfizer Inc. Medicine Design, 1 Portland Street, Cambridge, Massachusetts 02139, United States., Raymer B; Pfizer Inc. Medicine Design, 1 Portland Street, Cambridge, Massachusetts 02139, United States., Ahn K; Pfizer Inc. Internal Medicine Research Unit, 1 Portland Street, Cambridge, Massachusetts 02139, United States., Coffey SB; Pfizer Inc. Medicine Design, Eastern Point Road, Groton, Connecticut 06340, United States., Dowling MS; Pfizer Inc. Medicine Design, Eastern Point Road, Groton, Connecticut 06340, United States., Fernando DP; Pfizer Inc. Medicine Design, Eastern Point Road, Groton, Connecticut 06340, United States., Gutierrez JA; Pfizer Inc. Internal Medicine Research Unit, 1 Portland Street, Cambridge, Massachusetts 02139, United States., Huard K; Pfizer Inc. Medicine Design, 1 Portland Street, Cambridge, Massachusetts 02139, United States., Jasti J; Pfizer Inc. Medicine Design, Eastern Point Road, Groton, Connecticut 06340, United States., Kalgutkar AS; Pfizer Inc. Medicine Design, 1 Portland Street, Cambridge, Massachusetts 02139, United States., Knafels JD; Pfizer Inc. Medicine Design, Eastern Point Road, Groton, Connecticut 06340, United States., Pandit J; Pfizer Inc. Medicine Design, Eastern Point Road, Groton, Connecticut 06340, United States., Parris KD; Pfizer Inc. Medicine Design, Eastern Point Road, Groton, Connecticut 06340, United States., Perez S; Pfizer Inc. Internal Medicine Research Unit, 1 Portland Street, Cambridge, Massachusetts 02139, United States., Pfefferkorn JA; Pfizer Inc. Internal Medicine Research Unit, 1 Portland Street, Cambridge, Massachusetts 02139, United States., Price DA; Pfizer Inc. Medicine Design, 1 Portland Street, Cambridge, Massachusetts 02139, United States., Ryder T; Pfizer Inc. Medicine Design, Eastern Point Road, Groton, Connecticut 06340, United States., Shavnya A; Pfizer Inc. Medicine Design, Eastern Point Road, Groton, Connecticut 06340, United States., Stock IA; Pfizer Inc. Medicine Design, Eastern Point Road, Groton, Connecticut 06340, United States., Tsai AS; Pfizer Inc. Medicine Design, Eastern Point Road, Groton, Connecticut 06340, United States., Tesz GJ; Pfizer Inc. Internal Medicine Research Unit, 1 Portland Street, Cambridge, Massachusetts 02139, United States., Thuma BA; Pfizer Inc. Medicine Design, Eastern Point Road, Groton, Connecticut 06340, United States., Weng Y; Pfizer Inc. Medicine Design, 1 Portland Street, Cambridge, Massachusetts 02139, United States., Wisniewska HM; Pfizer Inc. Medicine Design, Eastern Point Road, Groton, Connecticut 06340, United States., Xing G; Pfizer Inc. Internal Medicine Research Unit, 1 Portland Street, Cambridge, Massachusetts 02139, United States., Zhou J; Pfizer Inc. Drug Safety R&D, Eastern Point Road, Groton, Connecticut 06340, United States., Magee TV; Pfizer Inc. Medicine Design, 1 Portland Street, Cambridge, Massachusetts 02139, United States.
Jazyk:	angličtina
Zdroj:	Journal of medicinal chemistry [J Med Chem] 2020 Nov 25; Vol. 63 (22), pp. 13546-13560. Date of Electronic Publication: 2020 Sep 27.
DOI:	10.1021/acs.jmedchem.0c00944
Abstrakt:	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.
Databáze:	MEDLINE
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