强效、选择性且口服活性的腺苷A2A受体拮抗剂：吡唑并[4,3-e]-1,2,4-三唑并[1,5-c]嘧啶的芳基哌嗪衍生物。
Potent, selective, and orally active adenosine A2A receptor antagonists: arylpiperazine derivatives of pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidines.
作者信息
Neustadt Bernard R, Hao Jinsong, Lindo Neil, Greenlee William J, Stamford Andrew W, Tulshian Deen, Ongini Ennio, Hunter John, Monopoli Angela, Bertorelli Rosalia, Foster Carolyn, Arik Leyla, Lachowicz Jean, Ng Kwokei, Feng Kung-I
机构信息
Department of Chemical Research, , Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
出版信息
Bioorg Med Chem Lett. 2007 Mar 1;17(5):1376-80. doi: 10.1016/j.bmcl.2006.11.083. Epub 2006 Dec 3.
Antagonism of the adenosine A2A receptor offers great promise in the treatment of Parkinson's disease. Employing the known pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine A2A antagonist SCH 58261 as a starting point, we identified the potent and selective (vs. A1) antagonist 11h, orally active in the rat haloperidol-induced catalepsy model. We further optimized this lead to the methoxyethoxyethyl ether 12a (SCH 420814), which shows broad selectivity, good pharmacokinetic properties, and excellent in vivo activity.
腺苷A2A受体拮抗剂在帕金森病治疗中具有巨大潜力。以已知的吡唑并[4,3-e]-1,2,4-三唑并[1,5-c]嘧啶A2A拮抗剂SCH 58261为起点，我们鉴定出了强效且选择性（相对于A1）的拮抗剂11h，其在大鼠氟哌啶醇诱导的僵住症模型中具有口服活性。我们进一步将该先导化合物优化为甲氧基乙氧基乙基醚12a（SCH 420814），它具有广泛的选择性、良好的药代动力学性质以及出色的体内活性。
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