ABSTRACT
A series of oxadiazole derivatives were synthesized and evaluated as 5-hydroxytryptamine-4 receptor (5-HT4R) partial agonists for the treatment of cognitive deficits associated with Alzheimer's disease. Starting from a reported 5-HT4R antagonist, a systematic structure-activity relationship was conducted, which led to the discovery of potent and selective 5-HT4R partial agonist 1-isopropyl-3-{5-[1-(3-methoxypropyl) piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole oxalate (Usmarapride, 12l). It showed balanced physicochemical-pharmacokinetic properties with robust nonclinical efficacy in cognition models. It also showed disease-modifying potential, as it increased neuroprotective soluble amyloid precursor protein alpha levels, and dose-dependent target engagement and correlation of efficacy with oral exposures. Phase 1 clinical studies have been completed and projected efficacious concentration was achieved without any major safety concerns. Phase 2 enabling long-term safety studies have been completed with no concerns for further development.
Subject(s)
Alzheimer Disease/drug therapy , Cognition Disorders/drug therapy , Drug Discovery , Neuroprotective Agents/pharmacology , Receptors, Serotonin, 5-HT4/metabolism , Serotonin 5-HT4 Receptor Agonists/pharmacology , Alzheimer Disease/metabolism , Cognition Disorders/metabolism , Dose-Response Relationship, Drug , Humans , Molecular Structure , Neuroprotective Agents/chemical synthesis , Neuroprotective Agents/chemistry , Serotonin 5-HT4 Receptor Agonists/chemical synthesis , Serotonin 5-HT4 Receptor Agonists/chemistry , Structure-Activity RelationshipABSTRACT
A series of chemical optimizations guided by in vitro affinity at the α4ß2 receptor in combination with selectivity against the α3ß4 receptor, pharmacokinetic evaluation, and in vivo efficacy in a forced swim test resulted in identification of 3-(6-chloropyridine-3-yloxymethyl)-2-azabicyclo[3.1.0]hexane hydrochloride (9h, SUVN-911) as a clinical candidate. Compound 9h is a potent α4ß2 receptor ligand with a Ki value of 1.5 nM. It showed >10 µM binding affinity toward the ganglionic α3ß4 receptor apart from showing selectivity over 70 other targets. It is orally bioavailable and showed good brain penetration in rats. Marked antidepressant activity and dose-dependent receptor occupancy in rats support its potential therapeutic utility in the treatment of depression. It does not affect the locomotor activity at doses several folds higher than its efficacy dose. It is devoid of cardiovascular and gastrointestinal side effects. Successful long-term safety studies in animals and phase-1 evaluation in healthy humans for safety, tolerability, and pharmacokinetics paved the way for its further development.
Subject(s)
Antidepressive Agents/pharmacology , Nicotinic Antagonists/pharmacology , Pyridines/pharmacology , Receptors, Nicotinic/metabolism , Administration, Oral , Animals , Antidepressive Agents/administration & dosage , Antidepressive Agents/chemistry , Bridged Bicyclo Compounds/administration & dosage , Bridged Bicyclo Compounds/chemistry , Bridged Bicyclo Compounds/pharmacology , Depression/drug therapy , Halogenation , Humans , Male , Nicotinic Antagonists/administration & dosage , Nicotinic Antagonists/chemistry , Pyridines/administration & dosage , Pyridines/chemistry , Rats , Rats, WistarABSTRACT
Alzheimer's disease (AD) is a neurodegenerative disorder that has a higher prevalence and incidence in people older than 60 years. The need for improved AD therapies is unmet as the current therapies are symptomatic with modest efficacy. Partial agonists of the 5-HT4 receptor (5-HT4R) offer both symptomatic and disease-modifying treatments as they shift amyloid-precursor-protein (APP) processing from the amyloidogenic pathway to the nonamyloidogenic pathway by activating the α-secretase enzyme. In addition, they also offer symptomatic treatment by increasing levels of the neurotransmitter acetylcholine in the brain. Because of this fascinating dual mechanism of action, several chemical scaffolds having 5-HT4R pharmacophores were designed and evaluated. Most of the synthesized compounds showed potent in vitro affinities and in vivo efficacies. Upon analysis of focused structure-activity relationships, compound 4o was identified as a potent 5-HT4R partial agonist with favorable ADME properties and good in vivo efficacy. GR-125487, a selective 5-HT4R antagonist, attenuated the activity of compound 4o in the novel-object-recognition-test cognition model.
Subject(s)
Amides/chemistry , Oxadiazoles/chemistry , Oxadiazoles/pharmacology , Receptors, Serotonin, 5-HT4/metabolism , Serotonin 5-HT4 Receptor Agonists/chemistry , Serotonin 5-HT4 Receptor Agonists/pharmacology , Animals , Chemistry Techniques, Synthetic , Drug Evaluation, Preclinical , Humans , Male , Oxadiazoles/chemical synthesis , Oxadiazoles/pharmacokinetics , Rats , Rats, Wistar , Serotonin 5-HT4 Receptor Agonists/pharmacokinetics , Structure-Activity RelationshipABSTRACT
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.
