Discovery of DS-3801b, a non-macrolide GPR38 agonist with N-methylanilide structure

Bioorg Med Chem Lett. 2022 Mar 1:59:128554. doi: 10.1016/j.bmcl.2022.128554. Epub 2022 Jan 18.

Abstract

Motilin is a 22-amino-acid gastrointestinal (GI) hormone and is involved in the regulation of GI motility through binding to GPR38, the motilin receptor which is expressed on smooth muscle cells in the GI tract. Therefore, GPR38 agonists are expected to be novel gastrointestinal prokinetic agents for the treatment of functional gastrointestinal disorders such as gastroparesis and chronic constipation. We identified a series of N-methylanilide derivatives as novel non-macrolide GPR38 agonists. Among them, 12 di-l-tartrate (DS-3801b) was selected as a clinical candidate for further evaluation.

Keywords: Constipation; DS-3801; GPR38; Motilin; Motilin receptor agonist.

MeSH terms

  • Aniline Compounds / chemistry
  • Aniline Compounds / pharmacology*
  • Animals
  • Cyclohexanes / chemical synthesis
  • Cyclohexanes / chemistry
  • Cyclohexanes / pharmacology*
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • Gastrointestinal Agents / chemical synthesis
  • Gastrointestinal Agents / chemistry
  • Gastrointestinal Agents / pharmacology*
  • Gastroparesis / drug therapy*
  • Gastroparesis / metabolism
  • Humans
  • Molecular Structure
  • Piperazines / chemical synthesis
  • Piperazines / chemistry
  • Piperazines / pharmacology*
  • Rabbits
  • Receptors, G-Protein-Coupled / agonists*
  • Receptors, G-Protein-Coupled / metabolism
  • Structure-Activity Relationship

Substances

  • Aniline Compounds
  • Cyclohexanes
  • DS-3801b
  • GPR39 protein, human
  • Gastrointestinal Agents
  • Piperazines
  • Receptors, G-Protein-Coupled
  • methylaniline