학술논문
Hit-to-Lead Optimization and Discovery of 5-((5-([1,1′-Biphenyl]-4-yl)-6-chloro-1H-benzo[d]imidazol-2-yl)oxy)-2-methylbenzoic Acid (MK-3903): A Novel Class of Benzimidazole-Based Activators of AMP-Activated Protein Kinase
Document Type
Article
Author
Lan, Ping; Romero, F. Anthony; Wodka, Dariusz; Kassick, Andrew J.; Dang, Qun; Gibson, Tony; Cashion, Daniel; Zhou, Gaochao; Chen, Yuli; Zhang, Xiaoping; Zhang, Aihua; Li, Ying; Trujillo, Maria E.; Shao, Qing; Wu, Margaret; Xu, Shiyao; He, Huaibing; MacKenna, Deidre; Staunton, Jocelyn; Chapman, Kevin T.; Weber, Ann; Sebhat, Iyassu K.; Makara, Gergely M.
Source
Journal of Medicinal Chemistry; 20240101, Issue: Preprints
Subject
Language
ISSN
00222623; 15204804
Abstract
AMP-activated protein kinase (AMPK) plays an essential role as a cellular energy sensor and master regulator of metabolism in eukaryotes. Dysregulated lipid and carbohydrate metabolism resulting from insulin resistance leads to hyperglycemia, the hallmark of type 2 diabetes mellitus (T2DM). While pharmacological activation of AMPK is anticipated to improve these parameters, the discovery of selective, direct activators has proven challenging. We now describe a hit-to-lead effort resulting in the discovery of a potent and selective class of benzimidazole-based direct AMPK activators, exemplified by 5-((5-([1,1′-biphenyl]-4-yl)-6-chloro-1H-benzo[d]imidazol-2-yl)oxy)-2-methylbenzoic acid, 42(MK-3903). Compound 42exhibited robust target engagement in mouse liver following oral dosing, leading to improved lipid metabolism and insulin sensitization in mice.