ABSTRACT
A high-throughput screening campaign identified 4-((E)-styryl)-pyrimidin-2-ylamine (11) as a positive allosteric modulator of the metabotropic glutamate (mGlu) receptor subtype 4. An evaluation of the structure-activity relationships (SAR) of 11 is described and the efficacy of this compound in a haloperidol-induced catalepsy rat model following oral administration is presented.
Subject(s)
Pyrimidines/chemistry , Receptors, Metabotropic Glutamate/chemistry , Styrenes/chemistry , Administration, Oral , Allosteric Regulation , Animals , Catalepsy/chemically induced , Catalepsy/drug therapy , High-Throughput Screening Assays , Humans , Models, Animal , Motor Activity/physiology , Pyrimidines/chemical synthesis , Pyrimidines/therapeutic use , Rats , Rats, Sprague-Dawley , Receptors, Metabotropic Glutamate/metabolism , Structure-Activity Relationship , Styrenes/chemical synthesis , Styrenes/therapeutic useABSTRACT
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
Antagonism of the human A(2A) receptor has been implicated as a point of therapeutic intervention in the alleviation of the symptoms associated with Parkinson's disease. This is thought to occur, at least in part, by increasing the sensitivity of the dopaminergic neurons to the residual, depleted levels of striatal dopamine. We herein describe a novel series of functionalized triazolo[4,5-d]pyrimidine derivatives that display functional antagonism of the A(2A) receptor. Optimization of these compounds has resulted in improvements in potency, selectivity, and the pharmacokinetic properties of key derivatives. These efforts have led to the discovery of 60 (V2006/BIIB014), which demonstrates strong oral activity in commonly used models of Parkinson's disease. Furthermore, this derivative has shown excellent preclinical pharmacokinetics and has successfully completed phase I clinical studies. This compound is presently undergoing further clinical evaluation in collaboration with Biogen Idec.
