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1.
Bioorg Med Chem Lett ; 19(20): 5945-9, 2009 Oct 15.
Article in English | MEDLINE | ID: mdl-19733067

ABSTRACT

We herein report the discovery of a novel class of antagonists of the human adenosine A2B receptor. This low molecular weight scaffold has been optimized to offer derivatives with potential utility for the alleviation of conditions associated with this receptor subtype, such as nociception, diabetes, asthma and COPD. Furthermore, preliminary pharmacokinetic analysis has revealed compounds with profiles suitable for either inhaled or systemic routes of administration.


Subject(s)
Adenosine A2 Receptor Antagonists , Pyrimidines/chemistry , Administration, Inhalation , Animals , Asthma/drug therapy , Drug Design , Humans , Pulmonary Disease, Chronic Obstructive/drug therapy , Pyrimidines/chemical synthesis , Pyrimidines/pharmacokinetics , Rats , Receptor, Adenosine A2A/metabolism , Receptor, Adenosine A2B/metabolism
2.
J Med Chem ; 52(1): 33-47, 2009 Jan 08.
Article in English | MEDLINE | ID: mdl-19072055

ABSTRACT

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 Relationship
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