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Discovery of Potent, Selective Triazolothiadiazole-Containing c-Met Inhibitors.

ABSTRACT: Herein, we report a novel series of highly potent and selective triazolothiadiazole c-Met inhibitors. Starting with molecule 5, we have applied structure-based drug design principles to identify the triazolothiadiazole ring system. We successfully replaced the metabolically unstable phenolic moiety with a quinoline group. Further optimization around the 5,6 bicyclic moiety led to the identification of 21. Compound 21 suffered from PDE3 selectivity issues and subsequent, structurally informed design led to the discovery of compound 23. Compound 23 has exquisite kinase selectivity, excellent potency, favorable ADME profile, and showed dose-dependent antitumor efficacy in a SNU-5 gastric cancer xenograft model.

SUBMITTER: Tang Q

PROVIDER: S-EPMC8201751 | biostudies-literature | 2021 Jun

REPOSITORIES: biostudies-literature

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Discovery of Potent, Selective Triazolothiadiazole-Containing c-Met Inhibitors.

Tang Qing Q Aronov Alex M AM Deininger David D DD Giroux Simon S Lauffer David J DJ Li Pan P Liang Jianglin J McGinty Kira K Ronkin Steven S Swett Rebecca R Waal Nathan N Boucher Diane D Ford Pamella J PJ Moody Cameron S CS

ACS medicinal chemistry letters 20210524 6

Herein, we report a novel series of highly potent and selective triazolothiadiazole c-Met inhibitors. Starting with molecule 5, we have applied structure-based drug design principles to identify the triazolothiadiazole ring system. We successfully replaced the metabolically unstable phenolic moiety with a quinoline group. Further optimization around the 5,6 bicyclic moiety led to the identification of 21. Compound 21 suffered from PDE3 selectivity issues and subsequent, stru ...[more]

PMID: 34141080

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