Identification of 2-[2-(4-tert-butylphenyl)ethyl]-N-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-6-sulfonamide (29) as an orally available MGAT2 inhibitor

Bioorg Med Chem. 2015 Sep 1;23(17):5922-31. doi: 10.1016/j.bmc.2015.06.065. Epub 2015 Jul 2.

Abstract

MGAT2 (monoacylglycerol acyltransferase 2) is expected to be an attractive target for the drug treatment of obesity, diabetes, and other disease. We describe our exploration and structure-activity relationship (SAR) study of 2,3-dihydro-1H-isoindole-5-sulfonamide derivatives. In this study, we identified 29 as an orally available inhibitor of MGAT2 through optimization especially in terms of solubility. This compound exhibited moderate potency in the enzyme inhibitory assay (IC50 = 1522 nM) and significant suppression of fat absorption (57% inhibition) in mice oral lipid tolerance test.

Keywords: Fat absorption; MGAT2; Monoacylglycerol acyltransferase; Oral lipid tolerance test; Tetrahydroisoquinoline.

MeSH terms

  • Animals
  • Diabetes Mellitus / drug therapy*
  • Humans
  • Mice
  • N-Acetylglucosaminyltransferases / antagonists & inhibitors*
  • Obesity / drug therapy*
  • Structure-Activity Relationship
  • Sulfonamides / chemistry*
  • Tetrahydroisoquinolines / chemistry*

Substances

  • Sulfonamides
  • Tetrahydroisoquinolines
  • N-Acetylglucosaminyltransferases
  • alpha-1,6-mannosyl-glycoprotein beta-1,2-N-acetylglucosaminyltransferase