A2B 腺苷受体配体的最新进展。
Recent developments in A2B adenosine receptor ligands.
作者信息
Kalla Rao V, Zablocki Jeff, Tabrizi Mojgan Aghazadeh, Baraldi Pier Giovanni
机构信息
Department of Medicinal Chemistry, CV Therapeutics Inc., Palo Alto, CA 94304, USA.
出版信息
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。
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