ABSTRACT
Serotonin type 3 (5-HT3) receptor partial agonists have been targeted as potential new drugs for the symptomatic relief of irritable bowel syndrome (IBS). Multiple diazepinone-based compounds have been discovered, which exhibit nanomolar binding affinity for the h5-HT3A receptor and display a range of intrinsic activities (IA=7-87% of 5-HT Emax) in HEK cells heterologously expressing the h5-HT3A receptor. Favorable physicochemical properties and in vitro ADME profile coupled with oral activity in the murine von Bezold-Jarisch reflex model demonstrates the series has promise for producing low to moderate IA partial agonists suitable for an IBS indication.
Subject(s)
Azepines/pharmacology , Drug Discovery , Irritable Bowel Syndrome/drug therapy , Receptors, Serotonin, 5-HT3/metabolism , Administration, Oral , Animals , Azepines/administration & dosage , Azepines/chemistry , Disease Models, Animal , Dose-Response Relationship, Drug , HEK293 Cells , Humans , Mice , Molecular Structure , Structure-Activity RelationshipABSTRACT
A new series of epiminocyclohepta[b]indoles with potent 5-HT(6) antagonist activity were discovered and optimized using in vitro protocols. One compound from this series was progressed to advanced pharmacokinetic (PK) studies followed by 5-HT(6) receptor occupancy studies. The compound was found to have excellent oral absorption, a highly favorable PK profile and demonstrated pharmacodynamic interaction with the 5-HT(6) receptor as shown by ex vivo autoradiography.
Subject(s)
Indoles/pharmacokinetics , Receptors, Serotonin/metabolism , Serotonin Antagonists , Administration, Oral , Animals , Caco-2 Cells , Humans , Indoles/administration & dosage , Indoles/chemistry , Indoles/pharmacology , Molecular Structure , Protein Binding/drug effects , Purinergic P1 Receptor Antagonists , Rats , Rats, Sprague-Dawley , Receptors, Serotonin/chemistry , Serotonin Antagonists/administration & dosage , Serotonin Antagonists/pharmacokinetics , Serotonin Antagonists/pharmacology , Structure-Activity RelationshipABSTRACT
Serotonin type 3 (5-HT(3)) receptor partial agonists are being targeted as potential new drugs for the treatment of irritable bowel syndrome (IBS). Two new chemical series bearing indazole and indole cores have exhibited nanomolar binding affinity for the h5-HT(3)A receptor. A range of partial agonist activities in HEK cells heterologously expressing the h5-HT(3)A receptor were measured for the indazole series. Excellent 5-HT(3) receptor selectivity, favorable in vitro metabolic stability and CYP inhibition properties, and good oral in vivo potency in the murine von Bezold-Jarisch reflex model is exemplified thereby indicating the series to have potential utility as improved IBS agents.
Subject(s)
Irritable Bowel Syndrome/drug therapy , Receptors, Serotonin, 5-HT3/chemistry , Serotonin 5-HT3 Receptor Agonists/chemistry , Animals , Cell Line , Disease Models, Animal , Humans , Imidazoles/chemistry , Indoles/chemistry , Mice , Microsomes, Liver/metabolism , Receptors, Serotonin, 5-HT3/metabolism , Serotonin 5-HT3 Receptor Agonists/chemical synthesis , Serotonin 5-HT3 Receptor Agonists/therapeutic useABSTRACT
A new class of 2-substituted benzoxazole carboxamides are presented as potent functional 5-HT(3) receptor antagonists. The chemical series possesses nanomolar in vitro activity against human 5-HT(3)A receptors. A chemistry optimization program was conducted and identified 2-aminobenzoxazoles as orally active 5-HT(3) receptor antagonists with good metabolic stability. These novel analogues possess drug-like characteristics and have potential utility for the treatment of diseases attributable to improper 5-HT(3) receptor function, especially diarrhea predominant irritable bowel syndrome (IBS-D).
