Kalla Rao V, Elzein Elfatih, Perry Thao, Li Xiaofen, Gimbel Art, Yang Ming, Zeng Dewan, Zablocki Jeff
Department of Bioorganic Chemistry, CV Therapeutics Inc., 3172 Porter Drive, Palo Alto, CA 94304, USA.
Bioorg Med Chem Lett. 2008 Feb 15;18(4):1397-401. doi: 10.1016/j.bmcl.2008.01.008. Epub 2008 Jan 8.
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.
已经合成了一系列N-1单取代的8-吡唑基黄嘌呤，并评估了它们对腺苷受体（AdoRs）的亲和力。我们发现了两种化合物18（CVT-7124）和28（CVT-6694），它们对A(2B)腺苷受体表现出良好的亲和力（K(i)分别为6 nM和7 nM），并且对人A(1)、A(2A)和A(3)腺苷受体具有更高的选择性（分别大于1000倍、大于830倍和大于1500倍；分别大于850倍、大于700倍和大于1280倍）。已证明CVT-6694可阻断支气管平滑肌细胞（BSMC）中白细胞介素-6和单核细胞趋化蛋白-1的释放，这一过程被认为是由A(2B)腺苷受体的激活所促进的。
