Kalla Rao V, Zablocki Jeff, Tabrizi Mojgan Aghazadeh, Baraldi Pier Giovanni
Department of Medicinal Chemistry, CV Therapeutics Inc., Palo Alto, CA 94304, USA.
Handb Exp Pharmacol. 2009(193):99-122. doi: 10.1007/978-3-540-89615-9_4.
A selective, high-affinity A(2B) adenosine receptor (AR) antagonist will be useful as a pharmacological tool to help determine the role of the A(2B)AR in inflammatory diseases and angiogenic diseases. Based on early A(2B)AR-selective ligands with nonoptimal pharmaceutical properties, such as 15 (MRS 1754: K(i)(hA(2B)) = 2 nM; K(i)(hA(1)) = 403 nM; K(i)(hA(2A)) = 503 NM, and K(i)(hA(3)) = 570 nM), several groups have discovered second-generation A(2B)AR ligands that are suitable for development. Scientists at CV Therapeutics have discovered the selective, high-affinity A(2B)AR antagonist 22, 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). Compound 22 has demonstrated favorable pharmacokinetic (PK) properties (T(1/2) = 4 h and F > 35% rat), and it is a functional antagonist at the A(2B)AR(K (B) = 6 nM). In a mouse model of asthma, compound 22 demonstrated a dose-dependent efficacy supporting the role of the A(2B)AR in asthma. In two Phase I clinical trails, 22 (CVT-6883) was found to be safe, well tolerated, and suitable for once-daily dosing. Baraldi et al. have independently discovered a selective, high-affinity A(2B)AR antagonist, 30 (MRE2029F20), 8-(5-pyrazolyl)-xanthine (K(i)(hA(2B)) = 5.5 nM; K(i)(hA(1)) = 200 nM; K(i)(hA(2A), A(3)) > 1,000, that has been selected for development in conjunction with King Pharmaceuticals. Compound 30 has been demonstrated to be a functional antagonist of the A(2B)AR, and it has been radiolabeled for use in pharmacological studies. A third compound, 58 (LAS-38096), is a 2-aminopyrimidine derivative (discovered by the Almirall group) that has high A(2B)AR 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 58 has been moved into preclinical safety testing. A fourth selective, high-affinity A(2B)AR antagonist, 54 (OSIP339391 K(i))(hA(2B)) = 0.5 nM; K(i))(hA(1)) = 37 nM; K(i))(hA(2A)) = 328; and K(i))(hA(3)) = 450 nm) was discovered by the OSI group. The three highly selective, high-affinity A(2B)AR antagonists that have been selected for development should prove useful in subsequent clinical trials that will establish the role of the A(2B)ARs in various disease states.
一种选择性、高亲和力的A(2B)腺苷受体（AR）拮抗剂将作为一种药理学工具，有助于确定A(2B)AR在炎症性疾病和血管生成性疾病中的作用。基于早期具有非最佳药学性质的A(2B)AR选择性配体，如15（MRS 1754：K(i)(hA(2B)) = 2 nM；K(i)(hA(1)) = 403 nM；K(i)(hA(2A)) = 503 nM，以及K(i)(hA(3)) = 570 nM），几个研究小组发现了适合开发的第二代A(2B)AR配体。CV Therapeutics的科学家发现了选择性、高亲和力的A(2B)AR拮抗剂22，一种8-(4-吡唑基)-黄嘌呤衍生物（CVT-6883，K(i)(hA(2B)) = 22 nM；K(i)(hA(1)) = 1,940 nM；K(i)(hA(2A)) = 3,280 nM；以及K(i)(hA(3)) = 1,070 nM）。化合物22已显示出良好的药代动力学（PK）性质（T(1/2) = 4小时，大鼠体内F > 35%），并且它是A(2B)AR的功能性拮抗剂（K(B) = 6 nM）。在哮喘小鼠模型中，化合物22显示出剂量依赖性疗效，支持A(2B)AR在哮喘中的作用。在两项I期临床试验中，发现22（CVT-6883）安全、耐受性良好且适合每日一次给药。Baraldi等人独立发现了一种选择性、高亲和力的A(2B)AR拮抗剂30（MRE2029F20），8-(5-吡唑基)-黄嘌呤（K(i)(hA(2B)) = 5.5 nM；K(i)(hA(1)) = 200 nM；K(i)(hA(2A), A(3)) > 1,000 nM），该化合物已被选中与King Pharmaceuticals联合开发。化合物30已被证明是A(2B)AR的功能性拮抗剂，并且已被放射性标记用于药理学研究。第三种化合物58（LAS-38096）是一种2-氨基嘧啶衍生物（由Almirall小组发现），具有高A(2B)AR亲和力和选择性（K(i)(hA(2B)) = 17 nM；K(i)(hA(1)) > 1,000 nM；K(i)(hA(2A)) > 2,500 nM；以及K(i)(hA(3)) > 1,000 nM），并且58已进入临床前安全性测试。第四种选择性、高亲和力的A(2B)AR拮抗剂54（OSIP339391 K(i)(hA(2B)) = 0.5 nM；K(i)(hA(1)) = 37 nM；K(i)(hA(2A)) = 328 nM；以及K(i)(hA(3)) = 450 nM）由OSI小组发现。已被选中进行开发的这三种高选择性、高亲和力的A(2B)AR拮抗剂在随后的临床试验中应会证明有用，这些试验将确定A(2B)AR在各种疾病状态中的作用。
