ABSTRACT
A series of chemical optimizations, which was guided by inâ vitro affinity at histamine H3 receptor (H3 R), modulation of lipophilicity, ADME properties and preclinical efficacy resulted in the identification of 1-[2-(1-cyclobutylpiperidin-4-yloxy)-6,7-dihydro-4H-thiazolo[5,4-c]pyridin-5-yl]propan-1-one (45 e) as a potent and selective (Ki =4.0â nM) H3 R inverse agonist. Dipsogenia induced by (R)-α-methylhistamine was dose dependently antagonized by 45 e, confirming its functional antagonism at H3 R. It is devoid of hERG and phospholipidosis issues. Compound 45 e has adequate oral exposures and favorable half-life in both rats and dogs. It has demonstrated high receptor occupancy (ED80 =0.22â mg/kg) and robust efficacy in object recognition task and, dose dependently increased acetylcholine levels in brain. The sub-therapeutic doses of 45 e in combination with donepezil significantly increased acetylcholine levels. The potent affinity, selectivity, inâ vivo efficacy and drug like properties together with safety, warrant for further development of this molecule for potential treatment of cognitive disorders associated with Alzheimer's disease.
Subject(s)
Disease Models, Animal , Drug Inverse Agonism , Histamine Agonists/pharmacology , Receptors, Histamine H3/metabolism , Animals , Dogs , Dose-Response Relationship, Drug , Female , Histamine Agonists/chemical synthesis , Histamine Agonists/chemistry , Humans , Male , Microsomes, Liver/chemistry , Microsomes, Liver/metabolism , Molecular Structure , Rats , Rats, Wistar , Structure-Activity RelationshipABSTRACT
A series of chemical optimizations guided by in vitro affinity at a histamine H3 receptor (H3R), physicochemical properties, and pharmacokinetics in rats resulted in identification of N-[4-(1-cyclobutyl-piperidin-4-yloxy)phenyl]-2-(morpholin-4-yl)acetamide dihydrochloride (17v, SUVN-G3031) as a clinical candidate. Compound 17v is a potent (hH3R Ki = 8.73 nM) inverse agonist at H3R with selectivity over other 70 targets, Compound 17v has adequate oral exposures and favorable elimination half-lives both in rats and dogs. It demonstrated high receptor occupancy and marked wake-promoting effects with decreased rapid-eye-movement sleep in orexin-B saporin lesioned rats supporting its potential therapeutic utility in treating human sleep disorders. It had no effect on the locomotor activity at doses several fold higher than its efficacious dose. It is devoid of hERG and phospholipidosis issues. Phase-1 evaluation for safety, tolerability, and pharmacokinetics, and long-term safety studies in animals have been successfully completed without any concern for further development.
Subject(s)
Drug Development , Drug Discovery , Drug Inverse Agonism , Histamine Agonists/pharmacology , Morpholines/pharmacology , Piperidines/pharmacology , Receptors, Histamine H3/drug effects , Wakefulness/drug effects , Administration, Oral , Animals , Caco-2 Cells , Dogs , Histamine Agonists/administration & dosage , Histamine Agonists/chemistry , Humans , Male , Morpholines/administration & dosage , Morpholines/chemistry , Morpholines/pharmacokinetics , Piperidines/administration & dosage , Piperidines/chemistry , Rats , Rats, Wistar , Structure-Activity RelationshipABSTRACT
Optimization of a novel series of 3-(piperazinylmethyl) indole derivatives as 5-hydroxytryptamine-6 receptor (5-HT6R) antagonists resulted in identification of 1-[(2-bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-1-piperazinyl)methyl]-1H-indole dimesylate monohydrate (5al, SUVN-502) as a clinical candidate for potential treatment of cognitive disorders. It has high affinity at human 5-HT6R (Ki = 2.04 nM) and selectivity over 100 target sites which include receptors, enzymes, peptides, growth factors, ion channels, steroids, immunological factors, second messengers, and prostaglandins. It has high selectivity over 5-HT2A receptor. It is orally bioavailable and brain penetrant with robust preclinical efficacy. The combination of 5al, donepezil, and memantine (triple combination) produces synergistic effects in extracellular levels of acetylcholine in the ventral hippocampus. Preclinical efficacy in triple combination and high selectivity over 5-HT2A receptors are the differentiating features which culminated in selection of 5al for further development. The Phase-1 evaluation of safety and pharmacokinetics has been completed, allowing for the initiation of a Phase-2 proof of concept study.
Subject(s)
Alzheimer Disease/drug therapy , Indoles/pharmacology , Piperazines/pharmacology , Receptors, Serotonin/drug effects , Serotonin Antagonists/pharmacology , Administration, Oral , Animals , Drug Discovery , Humans , Indoles/administration & dosage , Indoles/chemistry , Indoles/pharmacokinetics , Male , Piperazines/administration & dosage , Piperazines/chemistry , Piperazines/pharmacokinetics , Rats , Rats, Wistar , Serotonin Antagonists/pharmacokinetics , Serotonin Antagonists/therapeutic useABSTRACT
Our initial findings around aryl sulfonamide series led to N-(3,5-dichloro-2-methoxyphenyl)-3-(1-methylpiperidin-4-ylamino)-4-methoxy benzenesulfonamide as potent and selective 5-HT(6) receptor (5-HT(6)R) antagonist with reasonable pharmacokinetic properties and activity in animal models of cognition. However, lack of brain penetration and P-glycoprotein liability makes this scaffold unsuitable for further development. Our goal was to identify small molecule 5-HT(6)R antagonist with adequate brain penetration, acceptable ADME properties, no P-glycoprotein, and no hERG liability. Several structural modifications including bringing conformational constraint around the sulfonamide -NH group and introduction of a heteroatom to modulate the physicochemical properties were attempted. This effort culminated in the discovery of series of novel, potent, selective, orally bioavailable, and adequately brain penetrant compounds with no hERG liability. These compounds showed activity in animal models of cognition like object recognition task and water maze and in brain microdialysis studies at lower doses.
