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.
Ramakrishna Nirogi  1 ,  Abdul Rasheed Mohammed  2 ,  Anil K Shinde  2 ,  Narsimha Bogaraju  2 ,  Shankar Reddy Gagginapalli  2 ,  Srinivasa Rao Ravella  2 ,  Laxman Kota  2 ,  Gopinadh Bhyrapuneni  2 ,  Nageswara Rao Muddana  2 ,  Vijay Benade  2 ,  Raghava Chowdary Palacharla  2 ,  Pradeep Jayarajan  2 ,  Ramkumar Subramanian  2 ,  Vinod Kumar Goyal  2
Affiliations
  • 1. Discovery Research, Suven Life Sciences Ltd., Serene Chambers, Road-5, Avenue-7, Banjara Hills, Hyderabad, 500 034, India. Electronic address: [email protected].
  • 2. Discovery Research, Suven Life Sciences Ltd., Serene Chambers, Road-5, Avenue-7, Banjara Hills, Hyderabad, 500 034, India.
PMID: 26363507 DOI: 10.1016/j.ejmech.2015.08.051
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.