Department of Bioorganic Chemistry, CV Therapeutics Inc., 3172 Porter Drive, Palo Alto, CA, 94304, USA,
Purinergic Signal. 2009 Mar;5(1):21-9. doi: 10.1007/s11302-008-9119-x. Epub 2008 Jun 21.
The selective, high affinity A(2B) adenosine receptor (AdoR) antagonists that were synthesized by several research groups should aid in determining the role of the A(2B) AdoR in inflammatory diseases like asthma or rheumatoid arthritis (RA) and angiogenic diseases like diabetic retinopathy or cancer. CV Therapeutics scientists discovered the selective, high affinity A(2B) AdoR antagonist 10, a 8-(4-pyrazolyl)-xanthine derivative [CVT-6883, K(i)(hA(2B)) = 22 nM; K(i)(hA(1)) = 1,940 nM; K(i)(hA(2A)) = 3,280; and K(i)(hA(3)) = 1,070 nM] that has favorable pharmacokinetic (PK) properties (t (1/2) = 4 h and F > 35% rat). Compound 10 demonstrated functional antagonism at the A(2B) AdoR (K(B) = 6 nM) and efficacy in a mouse model of asthma. In two phase 1 clinical trials, CVT-6883 was found to be safe, well tolerated, and suitable for once daily dosing. A second compound 20, 8-(5-pyrazolyl)-xanthine, has been nominated for development from Baraldi's group in conjunction with King Pharmaceuticals that has favorable A(2B) AdoR affinity and selectivity [K(i)(hA(2B)) = 5.5 nM; K(i)(hA(1)) > 1,000 nM; K(i)(hA(2A)) > 1,000; and K(i)(hA(3)) > 1,000 nM], and it has been demonstrated to be a functional antagonist. A third compound 32, a 2-aminopyrimidine, from the Almirall group has high A(2B) AdoR affinity and selectivity [K(i)(hA(2B)) = 17 nM; K(i)(hA(1)) > 1,000 nM; K(i)(hA(2A)) > 2,500; and K(i)(hA(3)) > 1,000 nM], and 32 has been moved into preclinical safety testing. Since three highly selective, high affinity A(2B) AdoR antagonists have been nominated for development with 10 (CVT-6883) being the furthest along in the development process, the role of the A(2B) AdoR in various disease states will soon be established.
已经有几个研究小组合成了具有选择性和高亲和力的 A(2B) 腺苷受体（AdoR）拮抗剂，这将有助于确定 A(2B)AdoR 在哮喘或类风湿性关节炎（RA）等炎症性疾病以及糖尿病性视网膜病变或癌症等血管生成性疾病中的作用。CV Therapeutics 的科学家发现了选择性高亲和力的 A(2B)AdoR 拮抗剂 10，这是一种 8-(4-吡唑基)-黄嘌呤衍生物[CVT-6883，Ki(hA(2B))=22 nM；Ki(hA(1))=1,940 nM；Ki(hA(2A))=3,280；Ki(hA(3))=1,070 nM]，具有良好的药代动力学（PK）特性（t(1/2)=4 h，F>35%大鼠）。化合物 10 在 A(2B)AdoR 上表现出功能拮抗作用（K(B)=6 nM），并在哮喘的小鼠模型中具有疗效。在两项 1 期临床试验中，CVT-6883 被发现安全、耐受性良好，适合每日一次给药。第二种化合物 20，8-(5-吡唑基)-黄嘌呤，已被提名由 Baraldi 小组与 King 制药公司共同开发，该化合物具有良好的 A(2B)AdoR 亲和力和选择性[Ki(hA(2B))=5.5 nM；Ki(hA(1))>1,000 nM；Ki(hA(2A))>1,000；Ki(hA(3))>1,000 nM]，并已被证明是一种功能性拮抗剂。第三种化合物 32，一种来自 Almirall 小组的 2-氨基嘧啶，具有高 A(2B)AdoR 亲和力和选择性[Ki(hA(2B))=17 nM；Ki(hA(1))>1,000 nM；Ki(hA(2A))>2,500 nM；Ki(hA(3))>1,000 nM]，并且 32 已进入临床前安全性测试。由于已经有三种高度选择性和高亲和力的 A(2B)AdoR 拮抗剂被提名开发，其中 10（CVT-6883）在开发过程中走得最远，因此 A(2B)AdoR 在各种疾病状态中的作用将很快得到确定。
