5-Amino-1MQ vs GW-0742

Metabolic

Metabolic

Research Only

Research Only

NNMT methylates nicotinamide using S-adenosylmethionine (SAM), producing 1-methylnicotinamide (MNA) and depleting both the NAD+ salvage precursor pool and the SAM methyl donor pool. By inhibiting NNMT, 5-Amino-1MQ lowers intracellular MNA and raises intracellular NAD+ and SAM. In adipocytes this has been reported to suppress lipogenesis and reduce adipocyte size in rodent models. Downstream links to SIRT1 activation and fat oxidation are frequently proposed but are not firmly established in vivo.

GW-0742 is a high-affinity, highly selective agonist of human PPARδ (EC50 = 1.1 nM for hPPARδ transactivation vs ~1.1 µM for hPPARα and ~2 µM for hPPARγ), conferring ~1000-fold selectivity for PPARδ over the other PPAR subtypes. Upon activation, PPARδ heterodimerizes with RXR and binds PPAR-response elements (PPREs) to alter transcription of genes governing fatty-acid oxidation, glucose utilization, and inflammatory signaling. In mice, however, GW-0742-induced hepatomegaly, hepatic/skeletal-muscle peroxisome proliferation, and skeletal myopathy were shown to be predominantly mediated by off-target PPARα cross-activation rather than PPARδ—a mechanism-based toxicity concern at animal-study exposures.

Not established in humans; rodent PK supports once-daily dosing in research studies