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Opportunities and Challenges in Developing Stearoyl-Coenzyme A Desaturase-1 Inhibitors as Novel Therapeutics for Human Disease

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Signalchem Lifesciences Corp., 550-5600 Parkwood Way, Richmond, British Columbia, V6V 2M2, Canada
Novartis Institute for Biomedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States
§ Xenon Pharmaceuticals Inc, 3650 Gilmore Way, Burnaby, British Columbia, V5G 4W8, Canada
*Phone: 604-871-0321. E-mail: [email protected]
Cite this: J. Med. Chem. 2014, 57, 12, 5039–5056
Publication Date (Web):December 2, 2013
https://doi.org/10.1021/jm401516c
Copyright © 2013 American Chemical Society
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Abstract

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This review provides an overview of stearoyl-coenzyme A desaturase-1 (SCD1) as a novel therapeutic target for metabolic disorders and other indications. Target validation is reviewed, and limitations due to incomplete knowledge of the relevant biological systems are described. Assay development, particularly for high throughput screening, and characterization of SCD1 inhibition are summarized. The progress and evolution in medicinal chemistry are discussed, specifically focusing on key attributes of the most advanced SCD1 inhibitors described in the primary literature and in patent applications. This work culminated in numerous companies identifying potent selective inhibitors, some of which progressed to early clinical development. The status of current SCD1 drug discovery programs is reviewed. Challenges are discussed, and potential new directions are indicated.

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