Synthesis and SAR of Imidazo[1,5-a]pyridine derivatives as 5-HT4 receptor partial agonists for the treatment of cognitive disorders associated with Alzheimer's disease

Eur J Med Chem. 2015 Oct 20:103:289-301. doi: 10.1016/j.ejmech.2015.08.051. Epub 2015 Sep 1.

Abstract

Alzheimer's disease (AD) is a neurodegenerative disease which has a higher prevalence and incidence in older people. The need for improved AD therapies is unmet. The 5-hydroxytryptamine4 receptor (5-HT4R) partial agonists may be of benefit for both the symptomatic and disease-modifying treatment of cognitive disorders associated with AD. Herein, we report the design, synthesis and SAR of imidazo[1,5-a] pyridine derivatives as 5-HT4R partial agonists. The focused SAR, optimization of ADME properties resulted the discovery of compound 5a as potent, selective, brain penetrant 5-HT4 partial agonist as a lead compound with good ADME properties and efficacy in both symptomatic and disease modifying animal models of cognition.

Keywords: 5-HT(4) receptor; Alzheimer's disease; Cognitive impairment; Disease modifying; Imidazo[1,5-a]pyridines; sAPPα.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / drug therapy*
  • Alzheimer Disease / metabolism
  • Animals
  • Cognition Disorders / drug therapy*
  • Cognition Disorders / metabolism
  • Dogs
  • Dose-Response Relationship, Drug
  • Drug Design
  • Drug Partial Agonism*
  • Humans
  • Molecular Structure
  • Pyridines / chemistry*
  • Pyridines / pharmacology*
  • Rats
  • Receptors, Serotonin, 5-HT4 / metabolism*
  • Structure-Activity Relationship

Substances

  • Pyridines
  • imidazo(1,5-a)pyridine
  • Receptors, Serotonin, 5-HT4