Department of Pharmacy, National University of Singapore, 3 Science Drive 2, Singapore 117543, Singapore.
Pharmaceutical Chemistry Division, School of Advance Science, Vellore Institute of Technology University, Vellore 632014, Tamilnadu, India.
Eur J Med Chem. 2015 Mar 6;92:784-98. doi: 10.1016/j.ejmech.2015.01.046. Epub 2015 Jan 22.
An efficient synthetic procedure was adopted to synthesize a series of new molecules containing the pyrazolo[3,4-d]pyrimidine (PP) scaffold, which have been evaluated as promising human adenosine receptor (AR) antagonists. The effect of substitutions at the N(2), C(4) and C(6) positions of PPs on the affinity and selectivity towards the adenosine receptors were explored. Most of the pyrazolo[3,4-d]pyrimidine-4-carboxylates displayed from moderate to good affinity at the human A3AR (hA3AR), as indicated by the low micromolar range of Ki values (Ki hA3AR = 0.7-34 μM). In particular, compounds 60 and 62 displayed good affinity at the hA3AR (60, Ki hA3AR = 2.2 μM and 62, Ki hA3AR = 2.9 μM) and selectivity towards the other AR subtypes (60, >46-fold selective and 62, >34-fold selective, respectively). In view of these results, these novel PP analogues were docked both in the crystallographic structure of the hA2AAR and in a homology model of the hA3AR in order to support the structure activity relationship (SAR) analysis. These preliminary results demonstrated that pyrazolo[3,4-d]pyrimidine can be considered a promising scaffold to obtain new molecules with potent hA3AR antagonist activity.
采用了一种有效的合成方法来合成一系列含有吡唑并[3,4-d]嘧啶（PP）骨架的新分子，这些分子已被评估为有希望的人腺苷受体（AR）拮抗剂。研究了在 PPs 的 N(2)、C(4)和 C(6)位置取代对腺苷受体亲和力和选择性的影响。大多数吡唑并[3,4-d]嘧啶-4-羧酸酯在人 A3AR（hA3AR）上表现出从中等到良好的亲和力，其 Ki 值（Ki hA3AR = 0.7-34 μM）处于低微摩尔范围内。特别是化合物 60 和 62 在 hA3AR 上具有良好的亲和力（60，Ki hA3AR = 2.2 μM 和 62，Ki hA3AR = 2.9 μM），并且对其他 AR 亚型具有选择性（60，> 46 倍选择性，62，> 34 倍选择性）。鉴于这些结果，这些新型 PP 类似物在 hA2AAR 的晶体结构和 hA3AR 的同源模型中进行了对接，以支持结构活性关系（SAR）分析。这些初步结果表明，吡唑并[3,4-d]嘧啶可以被认为是获得具有强效 hA3AR 拮抗剂活性的新分子的有前途的支架。
