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
datasetposted on 2017-10-16, 00:00 authored by Ping Lan, F. Anthony Romero, Dariusz Wodka, Andrew J. Kassick, Qun Dang, Tony Gibson, Daniel Cashion, Gaochao Zhou, Yuli Chen, Xiaoping Zhang, Aihua Zhang, Ying Li, Maria E. Trujillo, Qing Shao, Margaret Wu, Shiyao Xu, Huaibing He, Deidre MacKenna, Jocelyn Staunton, Kevin T. Chapman, Ann Weber, Iyassu K. Sebhat, Gergely M. Makara
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 42 exhibited robust target engagement in mouse liver following oral dosing, leading to improved lipid metabolism and insulin sensitization in mice.
Dysregulated lipidbenzoBenzimidazole-Based ActivatorsHit-to-Lead Optimizationhit-to-lead effortinsulin sensitizationMKlipid metabolismNovel Classenergy sensormouse livertype 2 diabetes mellitusT 2DMAMPK activatorsimidazol -2-ylmaster regulatorinsulin resistanceAMP-Activated Protein Kinase AMP-activated protein kinasecarbohydrate metabolismtarget engagement