2. Academic Validation
  3. 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

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

Affiliations

  • 1 Discovery Research, Suven Life Sciences Ltd., Serene Chambers, Road-5, Avenue-7, Banjara Hills, Hyderabad, 500 034, India. Electronic address: nvsrk@suven.com.
  • 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.

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