title: 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.
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.
authors.affiliation: Discovery Research, Suven Life Sciences Ltd., Serene Chambers, Road-5, Avenue-7, Banjara Hills, Hyderabad, 500 034, India. Electronic address: nvsrk@suven.com.
authors.forename: Ramakrishna
authors.initials: R
authors.lastname: Nirogi
authors.affiliation: Discovery Research, Suven Life Sciences Ltd., Serene Chambers, Road-5, Avenue-7, Banjara Hills, Hyderabad, 500 034, India.
authors.forename: Abdul Rasheed
authors.initials: AR
authors.lastname: Mohammed
authors.affiliation: Discovery Research, Suven Life Sciences Ltd., Serene Chambers, Road-5, Avenue-7, Banjara Hills, Hyderabad, 500 034, India.
authors.forename: Anil K
authors.initials: AK
authors.lastname: Shinde
authors.affiliation: Discovery Research, Suven Life Sciences Ltd., Serene Chambers, Road-5, Avenue-7, Banjara Hills, Hyderabad, 500 034, India.
authors.forename: Narsimha
authors.initials: N
authors.lastname: Bogaraju
authors.affiliation: Discovery Research, Suven Life Sciences Ltd., Serene Chambers, Road-5, Avenue-7, Banjara Hills, Hyderabad, 500 034, India.
authors.forename: Shankar Reddy
authors.initials: SR
authors.lastname: Gagginapalli
authors.affiliation: Discovery Research, Suven Life Sciences Ltd., Serene Chambers, Road-5, Avenue-7, Banjara Hills, Hyderabad, 500 034, India.
authors.forename: Srinivasa Rao
authors.initials: SR
authors.lastname: Ravella
authors.affiliation: Discovery Research, Suven Life Sciences Ltd., Serene Chambers, Road-5, Avenue-7, Banjara Hills, Hyderabad, 500 034, India.
authors.forename: Laxman
authors.initials: L
authors.lastname: Kota
authors.affiliation: Discovery Research, Suven Life Sciences Ltd., Serene Chambers, Road-5, Avenue-7, Banjara Hills, Hyderabad, 500 034, India.
authors.forename: Gopinadh
authors.initials: G
authors.lastname: Bhyrapuneni
authors.affiliation: Discovery Research, Suven Life Sciences Ltd., Serene Chambers, Road-5, Avenue-7, Banjara Hills, Hyderabad, 500 034, India.
authors.forename: Nageswara Rao
authors.initials: NR
authors.lastname: Muddana
authors.affiliation: Discovery Research, Suven Life Sciences Ltd., Serene Chambers, Road-5, Avenue-7, Banjara Hills, Hyderabad, 500 034, India.
authors.forename: Vijay
authors.initials: V
authors.lastname: Benade
authors.affiliation: Discovery Research, Suven Life Sciences Ltd., Serene Chambers, Road-5, Avenue-7, Banjara Hills, Hyderabad, 500 034, India.
authors.forename: Raghava Chowdary
authors.initials: RC
authors.lastname: Palacharla
authors.affiliation: Discovery Research, Suven Life Sciences Ltd., Serene Chambers, Road-5, Avenue-7, Banjara Hills, Hyderabad, 500 034, India.
authors.forename: Pradeep
authors.initials: P
authors.lastname: Jayarajan
authors.affiliation: Discovery Research, Suven Life Sciences Ltd., Serene Chambers, Road-5, Avenue-7, Banjara Hills, Hyderabad, 500 034, India.
authors.forename: Ramkumar
authors.initials: R
authors.lastname: Subramanian
authors.affiliation: Discovery Research, Suven Life Sciences Ltd., Serene Chambers, Road-5, Avenue-7, Banjara Hills, Hyderabad, 500 034, India.
authors.forename: Vinod Kumar
authors.initials: VK
authors.lastname: Goyal
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism; D000818:Animals; D003072:Cognition Disorders / Q000188:drug therapy* / Q000378:metabolism; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D054333:Drug Partial Agonism; D006801:Humans; D015394:Molecular Structure; D011725:Pyridines / Q000737:chemistry* / Q000494:pharmacology*; D051381:Rats; D044422:Receptors, Serotonin, 5-HT4 / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D011725:Pyridines; C554655:imidazo(1,5-a)pyridine; D044422:Receptors, Serotonin, 5-HT4
keywords: 5-HT(4) receptor; Alzheimer's disease; Cognitive impairment; Disease modifying; Imidazo[1,5-a]pyridines; sAPPα