Discovery of Potent and Selective A2A Antagonists with Efficacy in Animal Models of Parkinson's Disease and Depression
Discovery of Potent and Selective A2A Antagonists with Efficacy in Animal Models of Parkinson's Disease and Depression
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DOI：
10.1021/acsmedchemlett.7b00175
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发表时间：
2017-08-01
影响因子：
4.2
通讯作者：
Mookhtiar, Kasim A.
中科院分区：
文献类型：
--
作者：
Basu, Sujay;Barawkar, Dinesh A.;Mookhtiar, Kasim A.
腺苷A(2A)受体拮抗剂是一种治疗帕金森病的非多巴胺能药物，目前正在研究中。早些时候，我们已经报道了7-甲氧基-4-吗啉-苯并噻唑衍生物作为A(2A)ADAR拮抗剂的治疗潜力。在这里，我们描述了一系列新的[1，2，4]三唑并[5，1-f]紫红素-2-酮衍生物，它们对A(2A)受体具有功能性拮抗作用，对A(1)、A(2B)和A(3)受体具有高度的选择性。来自这种新支架的化合物导致了高度有效的、选择性的、稳定的和适度的脑渗透化合物33的发现。化合物33具有良好的体内外药代动力学性质。化合物33在两种常用的帕金森病模型(氟哌啶醇诱导的大鼠癫痫模型和6-OHDA损伤的大鼠模型)和抑郁症(TST和FST小鼠模型)上显示出强大的口服效果。
Adenosine A(2A) receptor (A(2A)AdoR) antagonism is a non-dopaminergic approach to Parkinsons disease treatment that is under development. Earlier we had reported the therapeutic potential of 7-methoxy-4-morpholino-benzothiazole derivatives as A(2A)AdoR antagonists. We herein described a novel series of [1,2,4]triazolo[5,1-f]purin-2-one derivatives that displays functional antagonism of the A(2A) receptor with a high degree of selectivity over A(1), A(2B), and A(3) receptors. Compounds from this new scaffold resulted in the discovery of highly potent, selective, stable, and moderate brain penetrating compound 33. Compound 33 endowed with satisfactory in vitro and in vivo pharmacokinetics properties. Compound 33 demonstrated robust oral efficacies in two commonly used models of Parkinsons disease (haloperidol-induced catalepsy and 6-OHDA lesioned rat models) and depression (TST and FST mice models).