Synthesis of novel 7-imino-2-thioxo-3,7-dihydro-2H-thiazolo [4,5-d] pyrimidine derivatives as adenosine A2A receptor antagonists

• Published in: Bioorganic & medicinal chemistry letters 2010-02, Vol.20 (3), p.1214-1218
• Main Authors: Luthra, Pratibha Mehta, Mishra, Chandra Bhushan, Jha, Pawan Kumar, Barodia, Sandeep Kumar
• Format: Article
• Language: English
• Subjects: Adenosine A2 Receptor Antagonists; Biological and medical sciences; Cell Line; Humans; Medical sciences; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems; Pharmacology. Drug treatments; Protein Binding; Pyrimidines - chemical synthesis; Pyrimidines - metabolism; Pyrimidines - pharmacology; Receptor, Adenosine A2A - metabolism; Structure-Activity Relationship; Thiazoles - chemical synthesis; Thiazoles - metabolism; Thiazoles - pharmacology
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2009.11.133

Novel bicyclic thiazolopyrimidine compounds (15-26) were synthesized to develop adenosine A(2A) receptor (A(2A)R) antagonist for the treatment of Parkinson's disease (PD). The binding affinity of the compounds (15-26) with A(2A)R was evaluated using radioligand binding assay on isolated membranes from stably transfected HEK293 cells. Selectivity of the compounds towards A(2A)R was assessed by comparing their binding affinities with A(1) receptors (A(1)R). cAMP concentrations were measured from HEK293 cells treated with compounds (15-26) as compared to NECA (A(2A)R agonist). The compound (16) possessed strongest A(2A)R binding affinity (K(i) value=0.0038 nM) and selectivity (737-fold) versus A(1)R. Decrease in A(2A)R-coupled release of endogenous cAMP from HEK293 cells treated with compounds (15-26) is evocative of their potential as A(2A)R antagonist.