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
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.
Subject(s)
Adenosine A2 Receptor Antagonists , Azoles/chemical synthesis , Azoles/pharmacology , Drug Design , Pyrimidines/chemical synthesis , Pyrimidines/pharmacology , Amines/chemistry , Animals , Azoles/chemistry , Azoles/therapeutic use , Drug Evaluation, Preclinical , Gait Disorders, Neurologic/chemically induced , Gait Disorders, Neurologic/drug therapy , Haloperidol/pharmacology , Humans , Mice , Molecular Structure , Pyrimidines/chemistry , Pyrimidines/therapeutic use , Rats , Receptor, Adenosine A2A/classification , Receptor, Adenosine A2A/metabolism , Structure-Activity RelationshipABSTRACT
A series of pyrazolo[3,4-d]pyrimidine, pyrrolo[2,3-d]pyrimidine and 6-arylpurine adenosine A(2A) antagonists is described. Many examples were highly selective against the human A(1) receptor sub-type and were active in an in vivo model of Parkinson's disease.
Subject(s)
Adenosine A2 Receptor Antagonists , Antiparkinson Agents/therapeutic use , Drug Design , Parkinsonian Disorders/drug therapy , Purines/therapeutic use , Pyrazoles/therapeutic use , Pyrimidines/therapeutic use , Adenosine A1 Receptor Antagonists , Antiparkinson Agents/chemical synthesis , Humans , Models, Chemical , Purines/chemical synthesis , Pyrazoles/chemical synthesis , Pyrimidines/chemical synthesis , Stereoisomerism , Structure-Activity RelationshipABSTRACT
The (-)-(11R,2'S)-enantiomer of the antimalarial drug mefloquine has been found to be a reasonably potent and moderately selective adenosine A(2A) receptor antagonist. Further investigation of this compound has led to the discovery of a series of keto-aryl thieno[3,2-d]pyrimidine derivatives, which are potent and selective antagonists of the adenosine A(2A) receptor. These derivatives show selectivity against the A(1) receptor. Furthermore, some of these compounds have been shown to have in vivo activity in a commonly used model, suggesting the potential for the treatment of Parkinson's disease.
Subject(s)
Adenosine A2 Receptor Antagonists , Antimalarials/therapeutic use , Antiparkinson Agents/therapeutic use , Parkinsonian Disorders/drug therapy , Pyrimidines/therapeutic use , Antimalarials/chemical synthesis , Antiparkinson Agents/chemical synthesis , Humans , Models, Chemical , Pyrimidines/chemical synthesis , Stereoisomerism , Structure-Activity RelationshipABSTRACT
We describe herein the discovery and development of a series of 4-arylthieno[3,2-d]pyrimidines which are potent adenosine A(2A) receptor antagonists. These novel compounds show high degrees of selectivity against the human A(1), A(2B) and A(3) receptor sub-types. Moreover, a number of these compounds show promising activity in vivo, suggesting potential utility in the treatment of Parkinson's disease.
Subject(s)
Adenosine A2 Receptor Antagonists , Antiparkinson Agents/therapeutic use , Drug Design , Parkinsonian Disorders/drug therapy , Pyrimidines/therapeutic use , Adenosine A1 Receptor Antagonists , Adenosine A3 Receptor Antagonists , Antiparkinson Agents/chemical synthesis , Humans , Models, Chemical , Pyrimidines/chemical synthesis , Stereoisomerism , Structure-Activity RelationshipABSTRACT
Database searching led to the identification of potent A(2A) antagonists which do not contain the privileged furan moiety and which show selectivity over A(1) receptors. Simple substructure searching on a proprietary database identified compounds with activities in the low nM range. A targeted approach to the identification of non-furan containing compounds resulted in the identification of two novel series, with potency, selectivity and directional SAR from screening 113 compounds.