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.
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Nirogi R, Mohammed AR, Shinde AK, Bogaraju N, Gagginapalli SR, Ravella SR, Kota L, Bhyrapuneni G, Muddana NR, Benade V, Palacharla RC, Jayarajan P, Subramanian R, Goyal VK
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.
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- 26363507 [ View in PubMed]
- 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.