Developments in purine and pyridimidine receptor-based therapeutics

Progress in the identification of novel P1 and P2 receptor ligands has continued to lag behind the explosion in receptor cloning, especially in the P2 area. Nonetheless, a number of novel chemical entities and natural receptor ligands are continuing to advance in clinical trials or, alternatively have become important new teals to study receptor function. Compounds of note with activity at the P1 receptor family include NNC 21-0136 (A(1) agonist; preclinical; stroke); SCH 59761 (nonselective P1 agonist; preclinical; cardiovascular disorders); the A(1) antagonists, KFM-19 (BIIP-20; phase II) and MDL 102,503 development (status unknown) that may have therapeutic potential as cognition enhancers. KF 17837 and related A(2A)-antagonists such as KW 6002 represent potential novel treatments for Parkinson's disease. SCH 58261 (A(2A) receptor antagonist; preclinical) is a novel nonxanthine antagonist ligand. KW 3902 (phase II), FK-453/FK 113453 (possibly discontinued) and CVT-124 (phase I) are A(1) receptor-selective xanthine-based antagonists that have potential in the treatment of renal diseases. NNC 53-0055 (preclinical) is the first of a new series of selective A(3) receptor agonists that modulate cytokine production. MRS 1067, MRS 1067, MRS 1097, MRS 1222, L-249, 313, and L-268, 605 (all preclinical) represent new A(3)-receptor antagonists. GP 3269 (preclinical) is an adenosine kinase inhibitor with potential efficacy in septic shock, stroke, and pain. ARL 67085 (phase II) is an ATP bioisostere that is an antagonist of the P-2T receptor that is the first of new generation of antithrombotic agents. Systemic ATP has reached phase II trials as a novel approach to metastasis regression. The pyrimidine nucleotide, UTP (phase II) is being examined as P2Y(2) receptor agonist for the treatment of cystic fibrosis. (C) 1997 Wiley-Liss, Inc.