Selective, high affinity A(2B) adenosine receptor antagonists: N-1 monosubstituted 8-(pyrazol-4-yl)xanthines.
A series of N-1 monosubstituted 8-pyrazolyl xanthines have been synthesized and evaluated for their affinity for the adenosine receptors (AdoRs). We have discovered two compounds 18 (CVT-7124) and 28 (CVT-6694) that display good affinity for the A(2B) AdoR (K(i)=6 nM and 7 nM, respectively) and greater selectivity for the human A(1), A(2A), and A(3) AdoRs (>1000-, >830-, and >1500-fold; >850-, >700-, and >1280-fold, respectively). CVT-6694 has been shown to block the release of interleukin-6 and monocyte chemotactic protein-1 from bronchial smooth muscle cells (BSMC), a process believed to be promoted by activation of A(2B) AdoR.
Kalla
Rao V
RV
Department of Bioorganic Chemistry, CV Therapeutics Inc., 3172 Porter Drive, Palo Alto, CA 94304, USA.
Elzein
Elfatih
E
Perry
Thao
T
Li
Xiaofen
X
Gimbel
Art
A
Yang
Ming
M
Zeng
Dewan
D
Zablocki
Jeff
J
D058917:Adenosine A2 Receptor Antagonists; D000818:Animals; D001667:Binding, Competitive; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D006801:Humans; D007700:Kinetics; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D043704:Receptor, Adenosine A2B / Q000378:metabolism; D013379:Substrate Specificity; D014498:Uracil / Q000031:analogs & derivatives / Q000737:chemistry; D014970:Xanthines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
D058917:Adenosine A2 Receptor Antagonists; D011720:Pyrazoles; D043704:Receptor, Adenosine A2B; D014970:Xanthines; D014498:Uracil