Discovery of 1,2,3-triazole-based fibroblast growth factor receptor modulators

Bioorg Med Chem Lett. 2019 Aug 15;29(16):2332-2337. doi: 10.1016/j.bmcl.2019.06.016. Epub 2019 Jun 18.

Abstract

To avoid production of a phospholipidosis-inducing metabolite, we replaced the amide structure of SUN13837 (1) with a 1,2,3-triazole. The resulting 1,2,3-triazole analog of 1 (compound 2) displayed greater neuroprotective activity than 1. Structural modification of 2 yielded compound 10, which showed improved neuroprotective activity and negligible mechanism-based inactivation against CYP3A4. In addition, installation of a methyl group at the 5-position of 1,2,3-triazole of 10 significantly boosted the neuroprotective activity. These 1,2,3-triazole derivatives displayed reduced phospholipidosis risk, sufficient systemic exposure, and high central nervous system penetration, and therefore may be potentially useful agents for the treatment of neurodegenerative diseases.

Keywords: 1,2,3-Triazole; FGF receptor modulator; MBI; Metabolic rate; Phospholipidosis.

MeSH terms

  • Cytochrome P-450 CYP3A / metabolism
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • Humans
  • Molecular Structure
  • Neurodegenerative Diseases / drug therapy
  • Neurodegenerative Diseases / metabolism
  • Neuroprotective Agents / chemical synthesis
  • Neuroprotective Agents / chemistry
  • Neuroprotective Agents / pharmacology*
  • Receptors, Fibroblast Growth Factor / antagonists & inhibitors*
  • Receptors, Fibroblast Growth Factor / metabolism
  • Structure-Activity Relationship
  • Triazoles / chemical synthesis
  • Triazoles / chemistry
  • Triazoles / pharmacology*

Substances

  • Neuroprotective Agents
  • Receptors, Fibroblast Growth Factor
  • Triazoles
  • Cytochrome P-450 CYP3A
  • CYP3A4 protein, human