prucalopride and Cognition-Disorders

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.

Topics: Alzheimer Disease; Animals; Cognition Disorders; Dogs; Dose-Response Relationship, Drug; Drug Design; Drug Partial Agonism; Humans; Molecular Structure; Pyridines; Rats; Receptors, Serotonin, 5-HT4; Structure-Activity Relationship

The cognitive impairments observed in Alzheimer's disease (AD) are in part a consequence of reduced acetylcholine (ACh) levels resulting from a loss of cholinergic neurons. Preclinically, serotonin 4 receptor (5-HT(4)) agonists are reported to modulate cholinergic function and therefore may provide a new mechanistic approach for treating cognitive deficits associated with AD. Herein we communicate the design and synthesis of potent, selective, and brain penetrant 5-HT(4) agonists. The overall goal of the medicinal chemistry strategy was identification of structurally diverse clinical candidates with varying intrinsic activities. The exposure-response relationships between binding affinity, intrinsic activity, receptor occupancy, drug exposure, and pharmacodynamic activity in relevant preclinical models of AD were utilized as key selection criteria for advancing compounds. On the basis of their excellent balance of pharmacokinetic attributes and safety, two lead 5-HT(4) partial agonist candidates 2d and 3 were chosen for clinical development.

Topics: Alzheimer Disease; Animals; ATP Binding Cassette Transporter, Subfamily B, Member 1; CHO Cells; Cognition Disorders; Cricetinae; Cricetulus; Cyclic AMP; Dogs; Drug Partial Agonism; Haplorhini; HEK293 Cells; Humans; In Vitro Techniques; Indoles; Madin Darby Canine Kidney Cells; Male; Microsomes, Liver; Permeability; Piperidines; Protein Isoforms; Pyrans; Rats; Rats, Sprague-Dawley; Receptors, Serotonin, 5-HT4; Serotonin 5-HT4 Receptor Agonists; Stereoisomerism; Structure-Activity Relationship