Structural Optimization of Ghrelin Receptor Inverse Agonists to Improve Lipophilicity and Avoid Mechanism-Based CYP3A4 Inactivation

Chem Pharm Bull (Tokyo). 2015;63(10):825-32. doi: 10.1248/cpb.c15-00285.

Abstract

Structural optimization of 2-aminonicotinamide derivatives as ghrelin receptor inverse agonists is reported. So as to avoid mechanism-based inactivation (MBI) of CYP3A4, 1,3-benzodioxol ring of the lead compound was modified. Improvement of the main activity and lipophilicity was achieved simultaneously, leading to compound 18a, which showed high lipophilic ligand efficiency (LLE) and low MBI activity.

MeSH terms

  • 6-Aminonicotinamide / analogs & derivatives*
  • 6-Aminonicotinamide / metabolism
  • 6-Aminonicotinamide / pharmacology*
  • Anti-Obesity Agents / chemistry*
  • Anti-Obesity Agents / metabolism
  • Anti-Obesity Agents / pharmacology*
  • Cytochrome P-450 CYP3A / metabolism*
  • Drug Discovery
  • Drug Inverse Agonism*
  • Humans
  • Microsomes, Liver / metabolism
  • Obesity / drug therapy
  • Receptors, Ghrelin / agonists*
  • Receptors, Ghrelin / metabolism

Substances

  • Anti-Obesity Agents
  • Receptors, Ghrelin
  • 6-Aminonicotinamide
  • Cytochrome P-450 CYP3A