Research paper Synthesis and SAR of Imidazo[1,5-a]pyridine derivatives as 5-HT 4 receptor partial agonists for the treatment of cognitive disorders associated with Alzheimer's disease Ramakrishna Nirogi * , Abdul Rasheed Mohammed, Anil K. Shinde, Narsimha Bogaraju, Shankar Reddy Gagginapalli, Srinivasa Rao Ravella, Laxman Kota, Gopinadh Bhyrapuneni, Nageswara Rao Muddana, Vijay Benade, Raghava Chowdary Palacharla, Pradeep Jayarajan, Ramkumar Subramanian, Vinod Kumar Goyal Discovery Research, Suven Life Sciences Ltd., Serene Chambers, Road-5, Avenue-7, Banjara Hills, Hyderabad, 500 034, India article info Article history: Received 9 July 2015 Received in revised form 25 August 2015 Accepted 26 August 2015 Available online 1 September 2015 Keywords: 5-HT 4 receptor Imidazo[1,5-a]pyridines Cognitive impairment sAPPa Disease modifying 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-hydroxytryptamine 4 receptor (5- HT 4 R) 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-HT 4 R 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. © 2015 Elsevier Masson SAS. All rights reserved. 1. Introduction Dementia is a prevalent disease with estimated 36 million people currently affected. Alzheimer's disease (AD) is the most common disease representing such patient pool. AD is a progres- sive neurodegenerative disorder with ageing as the major risk factor. Extracellular beta amyloid deposits and intracellular tau tangles in brain provide the best differentiator of AD from other forms of dementia. Current therapies treat only the disease symptoms and are associated with modest efficacy, offset by dose- limiting side effects [1]. The 5-HT 4 R belonged to serotonin (5-HT) receptor superfamily and is positively coupled to adenylate cyclase thereby increases the cAMP production. These receptors are widely expressed throughout the body, and the highest density is observed in the cortex and hippocampus regions of brain associated with learning [2]. In brain microdialysis experiment, an increase in acetylcholine level was observed in the rat frontal cortex and hip- pocampus upon intracerebroventricular injection of 5-HT 4 R ago- nists [3]. Behavioral studies in animal models of learning and memory supports the role of 5-HT 4 R agonists in cognition [4,5]. 5- HT 4 R also regulates the production of the neurotoxic amyloid b- peptide (Ab), which is one of the major pathogenic pathways in AD [6,7]. The 5-HT 4 R agonists can also stimulate the non- amyloidogenic pathway leading to the release of soluble form of amyloid precursor protein (sAPPa) in the experimental animal studies, which has putative neurotropic and neuroprotective properties [8e10]. 5-HT 4 receptors therefore, attracts as a potential Abbreviations: AD, Alzheimer's disease; SAR, structureeactivity relationships; CNS, central nervous system; 5-HT, serotonin; cAMP, cyclic adenosine mono- phosphate; ADAS-Cog, Alzheimer's disease assessment scale e cognitive subscale; ADME, absorption, distribution, metabolism, and excretion; PK study, pharmaco- kinetic study; IBS, irritable bowel syndrome; 5-HT 4 R, 5-hydroxytryptamine 4 Re- ceptor; RO, receptor occupancy; NORT, novel object recognition task; RAM, radial arm maze; IND, investigational new drug; DAST, diethylaminosulfurtrifluoride; TLC, thin layer chromatography; min, minutes; LC-MS/MS, liquid chromatography-mass spectrometry p.o., oral dosing; s.c., subcutaneous dosing; min, minutes; mm, millimeter; rpm, rounds per minute; cps, counts per second; hERG, human ether-  a-go-go-related gene; CHO cells, Chinese hamster ovary cells; WFI, water for injection. * Corresponding author. E-mail address: nvsrk@suven.com (R. Nirogi). Contents lists available at ScienceDirect European Journal of Medicinal Chemistry journal homepage: http://www.elsevier.com/locate/ejmech http://dx.doi.org/10.1016/j.ejmech.2015.08.051 0223-5234/© 2015 Elsevier Masson SAS. All rights reserved. European Journal of Medicinal Chemistry 103 (2015) 289e301