ABSTRACT
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
The design, synthesis and SAR of novel tetrahydrocarbazole derivatives having 5-HT(6) receptor antagonist activity is presented. The racemic compound 15e was found to possess desirable pharmacokinetic properties, adequate brain penetration and activity in animal models of cognition.
