Compound 991

Compound 991 is a synthetic benzimidazole-derived small-molecule allosteric activator of AMP-activated protein kinase (AMPK), originally developed by Merck Sharp and Dohme and Metabasis Therapeutics as a potent research tool to probe AMPK biology rather than as a therapeutic drug. It binds at the AMPK allosteric drug and metabolite (ADaM) site formed between the kinase domain of the α-subunit and the carbohydrate-binding module of the β-subunit, producing strong allosteric activation and protection against dephosphorylation, with 5–10-fold higher potency and tighter binding than the first-generation activator A-769662.[1][7][11] Compound 991 activates both β1- and β2-containing AMPK complexes (with preference for β1), robustly stimulates α1- and α2-containing complexes including muscle-specific α2β2γ3, increases phosphorylation of canonical AMPK substrates such as acetyl-CoA carboxylase (ACC) and RAPTOR, and enhances glucose uptake in skeletal muscle and hepatocytes in preclinical models.[1][7][11] It has been used in vitro and ex vivo to study metabolic regulation, protection from dexamethasone-induced osteoblast death, and anti-fibrotic macrophage reprogramming, but systemic administration in mice as a free drug causes significant toxicity, including liver injury and hematologic effects, which has motivated exploratory work on nanoparticle-based delivery systems rather than direct clinical development.[1][2][3]

Other names

AMPK activator 991benzimidazole derivative 991