MK-8722

MK-8722 is a potent, direct, orally bioavailable allosteric activator of all twelve mammalian heterotrimeric complexes of AMP-activated protein kinase (AMPK), the master cellular energy sensor that coordinates catabolic and anabolic metabolic pathways in response to energetic stress. Discovered at Merck Research Laboratories through a medicinal chemistry optimization campaign starting from the thienopyridone lead series and published in two landmark reports (Myers et al., Science, 2017; Feng et al., ACS Medicinal Chemistry Letters, 2018), MK-8722 binds the allosteric drug and metabolite (ADaM) site at the interface of the alpha-subunit kinase domain and the beta-subunit carbohydrate-binding module and produces dose-dependent activation of AMPK complexes containing both the beta-1 and beta-2 regulatory subunits.

The pharmacological consequence of systemic pan-AMPK activation by MK-8722 in preclinical species is a robust, durable, insulin-independent increase in skeletal muscle glucose uptake and glycogen synthesis, with resultant improvements in whole-body glycemia and glucose tolerance in lean and obese rodent models and in spontaneously diabetic rhesus monkeys. The glucose-lowering effect is mediated predominantly through AMPK-dependent translocation of glucose transporter type 4 (GLUT4) to the sarcolemma in skeletal muscle and does not produce hypoglycemia at efficacious doses. Positron emission tomography with [18F]fluorodeoxyglucose ([18F]FDG-PET) confirmed increased skeletal muscle glucose uptake in both rodents and non-human primates following MK-8722 administration. Pharmacokinetic properties in preclinical species supported once-daily oral dosing for chronic studies.

The principal liability that precluded clinical advancement of MK-8722 was on-mechanism cardiac hypertrophy and cardiac glycogen accumulation observed during chronic dosing in both rodent and non-human primate models. In Sprague-Dawley rats, 4-week oral administration at doses achieving efficacious plasma exposures produced dose-dependent increases in heart weight and left ventricular wall thickness. In rhesus monkeys, 8-week oral administration produced similar cardiac hypertrophy with increased cardiac glycogen content. Echocardiographic assessment demonstrated preserved systolic and diastolic function despite the structural remodeling, and the cardiac hypertrophy appeared partially reversible on drug washout at the highest dose levels, though lower doses did not demonstrate full regression during the studied washout period. No arrhythmias or functional cardiac impairment were detected. The cardiac hypertrophy was attributed to pan-AMPK activation in cardiomyocytes, where AMPK-driven glucose uptake and glycogen synthesis produced pathological glycogen accumulation analogous to the phenotype observed in glycogen storage cardiomyopathy associated with activating mutations in the PRKAG2 gene encoding the AMPK gamma-2 subunit.

MK-8722 has not entered human clinical trials. The compound remains an important pharmacological tool for the study of systemic AMPK activation in metabolic disease and a reference standard for structure-activity relationship studies in the ADaM-site AMPK activator class. A selectivity screen against 115 enzymes, transporters, and receptors identified modest off-target activity at the serotonin 5-HT2A receptor (Ki approximately 2.8 micromolar) and three additional targets at 3 to 10 micromolar, none of which are anticipated to produce pharmacologically significant effects at AMPK-relevant exposures. This monograph reviews the chemistry, synthesis, and stereochemistry of MK-8722; the molecular pharmacology of AMPK activation through the ADaM site; the preclinical pharmacokinetic and pharmacodynamic profile; the cardiac safety signal; sourcing and quality verification for research applications; reconstitution and handling; stack-interaction considerations for combination studies; adverse-event characterization; and a structured comparative assessment of five alternative AMPK activators against MK-8722 on five competency standards.