Calcitonin gene-related peptide (CGRP) receptor antagonists: Heterocyclic modification of a novel azepinone lead

Bioorg Med Chem Lett. 2021 Jul 1:43:128077. doi: 10.1016/j.bmcl.2021.128077. Epub 2021 Apr 29.

Abstract

In our efforts to identify orally bioavailable CGRP receptor antagonists, we previously discovered a novel series of orally available azepinone derivatives that unfortunately also exhibited the unwanted property of potent time-dependent human CYP3A4 inhibition. Through heterocyclic replacement of the indazole ring, we discovered a series of heterocycle derivatives as high-affinity CGRP receptor antagonists. Some of them showed reasonable oral exposures, and the imidazolone derivatives that showed good oral exposure also exhibited substantially reduced time-dependent CYP3A4 inhibition. Several compounds showed strong in vivo efficacy in our marmoset facial blood flow assay with up to 87% inhibition of CGRP-induced activity. However, oral bioavailability generally remained low, emphasizing the challenges we and others encountered in discovering clinical development candidates for this difficult Class B GPCR target.

Keywords: CGRP receptor antagonist; Imidazolone; Migraine; Time-dependent CYP3A4 inhibition.

MeSH terms

  • Azepines / chemical synthesis
  • Azepines / chemistry
  • Azepines / pharmacology*
  • Calcitonin Gene-Related Peptide Receptor Antagonists / chemical synthesis
  • Calcitonin Gene-Related Peptide Receptor Antagonists / chemistry
  • Calcitonin Gene-Related Peptide Receptor Antagonists / pharmacology*
  • Dose-Response Relationship, Drug
  • Humans
  • Molecular Structure
  • Receptors, Calcitonin Gene-Related Peptide / metabolism*
  • Structure-Activity Relationship

Substances

  • Azepines
  • Calcitonin Gene-Related Peptide Receptor Antagonists
  • Receptors, Calcitonin Gene-Related Peptide