An HTS against human DGAT-1 lead to the identification of a novel pyrazolo[1,5-a]pyramidin-7-amine pharmacophore that was subsequently optimized to afford the potent, selective and orally bioavailable compound A-970781. Oral administration at dose > 0.03 mg/kg significantly reduced postprandial triglycerides in mice following an oral lipid challenge. Further assessment in both acute and chronic safety pharmacology abd toxicology studies demonstrated a clean profile up to high plasma levels, thus culminating in the nomination of A-970781 as a development candidate for the treatment of postprandial hypertriglyceridemia and other metabolic disorders.

Discovery of A-970781 as a potent, safe, and orally efficacious inhibitor of acyl CoA: Diacylglycerol acyltransferase 1

243rd National Meeting (2012)

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