Discovery of a Novel Series of <i>N</i>‑Phenylindoline-5-sulfonamide Derivatives as Potent, Selective, and Orally Bioavailable Acyl CoA:Monoacylglycerol Acyltransferase‑2 Inhibitors

Acyl CoA:monoacylglycerol acyltransferase-2 (MGAT2) has attracted interest as a novel target for the treatment of obesity and metabolic diseases. Starting from <i>N</i>-phenylbenzenesulfonamide derivative <b>1</b> with moderate potency for MGAT2 inhibition, we explored an effective location of the hydrophobic group at the 1-position to enhance MGAT2 inhibitory activity. Shifting the hydrophobic group to the adjacent position followed by introduction of a bicyclic central core to restrict the substituent orientation produced <i>N</i>-phenylindoline-5-sulfonamide derivative <b>10b</b>, which displayed much improved potency, with an IC₅₀ value of 1.0 nM. This compound also exhibited excellent selectivity (greater than 30,000-fold) against related acyltransferases (MGAT3, DGAT1, DGAT2, and ACAT1). Subsequent optimization efforts were directed toward improving pharmacokinetic profiles, which resulted in the identification of 5-[(2,4-difluorophenyl)­sulfamoyl]-7-(2-oxopyrrolidin-1-yl)-<i>N</i>-[4-(trifluoromethyl)­phenyl]-2,3-dihydro-1<i>H</i>-indole-1-carboxamide (<b>24d</b>) endowed with potent MGAT2 inhibitory activity (IC₅₀ = 3.4 nM) and high oral bioavailability (<i>F</i> = 52%, mouse). In a mouse oral fat tolerance test, oral administration of this compound effectively suppressed the elevation of plasma triacylglycerol levels