2. Academic Validation
  3. 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

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

  • J Med Chem. 2017 Nov 9;60(21):9040-9052. doi: 10.1021/acs.jmedchem.7b01344.
Ping Lan,  F Anthony Romero,  Dariusz Wodka,  Andrew J Kassick,  Qun Dang 1,  Tony Gibson 1,  Daniel Cashion 1,  Gaochao Zhou,  Yuli Chen,  Xiaoping Zhang,  Aihua Zhang,  Ying Li,  Maria E Trujillo,  Qing Shao,  Margaret Wu,  Shiyao Xu,  Huaibing He,  Deidre MacKenna 1,  Jocelyn Staunton 1,  Kevin T Chapman,  Ann Weber,  Iyassu K Sebhat,  Gergely M Makara
Affiliations

Affiliation

  • 1 Metabasis Therapeutics, Inc. , 11119 North Torrey Pines Road, La Jolla California 92037, United States.
PMID: 29035567 DOI: 10.1021/acs.jmedchem.7b01344
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 42 exhibited robust target engagement in mouse liver following oral dosing, leading to improved lipid metabolism and Insulin sensitization in mice.

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