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Systematic evaluation of amide bioisosteres leading to the discovery of novel and potent thiazolylimidazolidinone inhibitors of SCD1 for the treatment of metabolic diseases

Dales, Natalie and Hubbard, Brian and Winther, Michael and Zhang, Zaihui and Sun, Shaoyi and Leung, Po-Yee and Tran, Jennifer (2014) Systematic evaluation of amide bioisosteres leading to the discovery of novel and potent thiazolylimidazolidinone inhibitors of SCD1 for the treatment of metabolic diseases. Bioorganic and Medicinal Chemistry Letters, 24 (2). pp. 520-525. ISSN 0960-894X

Abstract

Several five- and six-membered heterocycles were introduced to replace the C2-position amide bond of the original 2-aminothiazole-based hit compound 5. Specifically, replacement of the amide bond with an imidazolidinone moiety yielded a novel and potent thiazolylimidazolidinone series of SCD1 inhibitors. XEN723 (compound 22) was identified after optimization of the thiazolylimidazolidinone series. This compound demonstrated a 560-fold improvement in in vitro potency and reduced plasma desaturation indices in a dose dependent manner, with an EC50 of 4.5 mg/kg. © 2013 Elsevier Ltd. All rights reserved.

Item Type: Article
Additional Information: This manuscript is a joint publication prepared by NIBR and Xenon scientists. The SCD joint-product committee has approved publication via the process outlined by the collaboration agreement. The manuscript has several authors that are no longer at either company.
Keywords: Amide bioisosteres Desaturation index SCD1 inhibitors Stearoyl-CoA desaturase-1 Thiazolylimidazolidinone
Date Deposited: 25 Nov 2017 00:45
Last Modified: 25 Jan 2019 00:46
URI: https://oak.novartis.com/id/eprint/9840

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