ABSTRACT
The pharmacokinetic based optimisation of a novel series of indole-2-carboxamide antagonists of the cannabinoid CB(1) receptor is disclosed. Compound 24 was found to be a highly potent and selective cannabinoid CB(1) antagonist with high predicted human oral bioavailability.
Subject(s)
Indoles/pharmacokinetics , Receptor, Cannabinoid, CB1/antagonists & inhibitors , Administration, Oral , Biological Availability , Humans , Indoles/administration & dosage , Indoles/chemistry , Structure-Activity RelationshipABSTRACT
The discovery and structure-activity relationship of a novel series of indole-2-carboxamide antagonists of the cannabinoid CB(1) receptor is disclosed. Compound 26i was found to be a high potency, selective cannabinoid CB(1) antagonist.
Subject(s)
Amides/chemistry , Indoles/chemistry , Receptor, Cannabinoid, CB1/antagonists & inhibitors , Amides/chemical synthesis , Amides/pharmacokinetics , Animals , Dogs , Drug Evaluation, Preclinical , Indoles/chemical synthesis , Indoles/pharmacokinetics , Male , Mice , Models, Molecular , Rats , Rats, Wistar , Receptor, Cannabinoid, CB1/metabolism , Structure-Activity RelationshipABSTRACT
Antagonists of the 5-HT(6) receptor have been shown to improve cognitive function in a wide range of animal models and as such may prove to be attractive agents for the symptomatic treatment of cognitive disorders such as Alzheimer's disease (AD) and schizophrenia. We report herein the identification and SAR around N-(2-aminoalkyl)-1-(arylsulfonyl)indoline-3-carboxamides-a novel chemotype of 5-HT(6) antagonists.
