Discovery of LY3325656: A GPR142 agonist suitable for clinical testing in human

[Display omitted] The discovery and optimization of a novel series of GPR142 agonists are described. These led to the identification of compound 21 (LY3325656), which demonstrated anti-diabetic benefits in pre-clinical studies and ADME/PK properties suitable for human dosing. Compound 21 is the firs...

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Veröffentlicht in:	Bioorganic & medicinal chemistry letters 2020-03, Vol.30 (5), p.126857, Article 126857
Hauptverfasser:	Liu, Lian Zhu, Ma, Tianwei, Zhou, Jingye, Long Hu, Zhi, Jun Zhang, Xue, Zhen Zhang, Hai, Zeng, Mi, Liu, Jia, Li, Lei, Jiang, Yi, Zou, Zack, Wang, Fan, Zhang, Lei, Xu, Jianfeng, Wang, Jingru, Xiao, Fei, Fang, Xiankang, Zou, Haixia, Efanov, Alexander M., Thomas, Melissa K, Lin, Hua V., Chen, Jiehao
Format:	Artikel
Sprache:	eng
Schlagworte:	Animals Benzamides - chemical synthesis Benzamides - pharmacokinetics Benzamides - therapeutic use Diabetes Mellitus, Experimental - drug therapy Dogs Drug Discovery Drug Evaluation, Preclinical Gene Knockout Techniques Glucose-dependent insulin secretion GPR142 agonist Humans Hypoglycemic Agents - chemical synthesis Hypoglycemic Agents - pharmacokinetics Hypoglycemic Agents - therapeutic use Metabolism Mice, Knockout Molecular Structure Rats Receptors, G-Protein-Coupled - agonists Receptors, G-Protein-Coupled - genetics Structure-Activity Relationship Triazoles - chemical synthesis Triazoles - pharmacokinetics Triazoles - therapeutic use Type 2 diabetes
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Zusammenfassung:	[Display omitted] The discovery and optimization of a novel series of GPR142 agonists are described. These led to the identification of compound 21 (LY3325656), which demonstrated anti-diabetic benefits in pre-clinical studies and ADME/PK properties suitable for human dosing. Compound 21 is the first GPR142 agonist molecule advancing to phase 1 clinic trials for the treatment of Type 2 diabetes.
ISSN:	0960-894X 1464-3405
DOI:	10.1016/j.bmcl.2019.126857