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Discovery of thiazolylpyridinone SCD1 inhibitors with preferential liver distribution and reduced mechanism-based adverse effects

Dales, Natalie and Sun, Shaoyi and Zhang, Zaihui and Hubbard, Brian and Ferreira, Suzie and Winther, Michael (2014) Discovery of thiazolylpyridinone SCD1 inhibitors with preferential liver distribution and reduced mechanism-based adverse effects. Bioorganic and Medicinal Chemistry Letters, 24 (2). pp. 526-531. ISSN 0960-894X

Abstract

We discovered a series of novel and potent thiazolylpyridinone-based SCD1 inhibitors based on a 2-aminothiazole HTS hit by replacing the amide bond with a pyridinone moiety. Compound 19 demonstrated good potency against SCD1 in vitro and in vivo. The mouse liver microsomal SCD1 in vitro potency for 19 was improved by more than 240-fold compared to the original HTS hit. Furthermore, 19 demonstrated a dose-dependent reduction of plasma desaturation index with an ED50 of 6.3 mg/kg. Compound 19 demonstrated high liver to plasma and liver to eyelid exposures, indicating preferential liver distribution. The preliminary toxicology study with compound 19 did not demonstrate adverse effects related to SCD1 inhibition, suggesting a wide safety margin with respect to other known SCD1 inhibitors with wider distribution profiles. © 2013 Elsevier Ltd. All rights reserved.

Item Type: Article
Additional Information: This manuscript was prepared jointly between NIBR and Xenon scientists. The material disclosed was generated during the SCD1 NIBR-Xenon collaboration. The joint-product committee which is required to sign off on SCD publications has done so. Several of the authors are no longer at either company.
Keywords: Desaturation index Liver selective SCD1 inhibitors Stearoyl-CoA desaturase-1 Thiazolylpyridinone
Date Deposited: 14 Mar 2018 00:45
Last Modified: 25 Jan 2019 00:46
URI: https://oak.novartis.com/id/eprint/9843

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