title: Selective, high affinity A(2B) adenosine receptor antagonists: N-1 monosubstituted 8-(pyrazol-4-yl)xanthines.
abstract: 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.
authors.affiliation: Department of Bioorganic Chemistry, CV Therapeutics Inc., 3172 Porter Drive, Palo Alto, CA 94304, USA.
authors.forename: Rao V
authors.initials: RV
authors.lastname: Kalla
authors.forename: Elfatih
authors.initials: E
authors.lastname: Elzein
authors.forename: Thao
authors.initials: T
authors.lastname: Perry
authors.forename: Xiaofen
authors.initials: X
authors.lastname: Li
authors.forename: Art
authors.initials: A
authors.lastname: Gimbel
authors.forename: Ming
authors.initials: M
authors.lastname: Yang
authors.forename: Dewan
authors.initials: D
authors.lastname: Zeng
authors.forename: Jeff
authors.initials: J
authors.lastname: Zablocki
mesh_terms: 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*
chemical_list: D058917:Adenosine A2 Receptor Antagonists; D011720:Pyrazoles; D043704:Receptor, Adenosine A2B; D014970:Xanthines; D014498:Uracil