ABSTRACT
Antagonists of the human A(2A) receptor have been reported to have potential therapeutic benefit in the alleviation of the symptoms associated with neurodegenerative movement disorders such as Parkinson's disease. As part of our efforts to discover potent and selective antagonists of this receptor, we herein describe the detailed optimization and structure-activity relationships of a series of pyrimidine-4-carboxamides. These optimized derivatives display desirable physiochemical and pharmacokinetic profiles, which have led to promising oral activity in clinically relevant models of Parkinson's disease.
Subject(s)
Adenosine A2 Receptor Antagonists , Parkinson Disease/drug therapy , Pyrimidines/chemistry , Pyrimidines/pharmacology , Receptor, Adenosine A2A/metabolism , Animals , Humans , Locomotion/drug effects , Mice , Protein Binding , Pyrimidines/pharmacokinetics , Pyrimidines/therapeutic use , Structure-Activity RelationshipABSTRACT
A novel series of antagonists of the human A(2A) receptor have been identified and have been shown to display good potency and high degrees of selectivity over other receptor sub-types. Displaying in vivo potency in commonly used disease models and high oral bio-availability, this class of compounds may serve as clinically useful treatments for the relief of the symptoms associated with Parkinson's disease.
Subject(s)
Adenosine A2 Receptor Antagonists , Amides/chemical synthesis , Pyrimidines/chemistry , Administration, Oral , Amides/administration & dosage , Amides/chemistry , Animals , Disease Models, Animal , Humans , Mice , Receptor, Adenosine A2A/metabolismABSTRACT
A series of 1-(1-pyrrolo(iso)quinolinyl)-2-propylamines was synthesised and evaluated as 5-HT(2C) receptor agonists for the treatment of obesity. The general methods of synthesis of the precursor indoles are described. The functional efficacy and radioligand binding data for the compounds at 5-HT(2) receptor subtypes are reported. The analogue which showed the highest 5-HT(2C) binding affinity (27, 1.6nM) was found to be successful in reducing food intake in rats.
