5-芳基-4-(4-(5-甲基-1H-咪唑-4-基)哌啶-1-基)嘧啶类似物作为强效、高选择性且口服生物可利用的NHE-1抑制剂的合成及生物活性
Synthesis and biological activity of 5-aryl-4-(4-(5-methyl-1H-imidazol-4-yl)piperidin-1-yl)pyrimidine analogs as potent, highly selective, and orally bioavailable NHE-1 inhibitors.
作者信息
Atwal Karnail S, O'Neil Steven V, Ahmad Saleem, Doweyko Lidia, Kirby Mark, Dorso Charles R, Chandrasena Gamini, Chen Bang-Chi, Zhao Rulin, Zahler Robert
机构信息
Department of Discovery Chemistry, Bristol-Myers Squibb, Pharmaceutical Research Institute, PO Box 4000, Princeton, NJ 08543-5400, USA.
出版信息
Bioorg Med Chem Lett. 2006 Sep 15;16(18):4796-9. doi: 10.1016/j.bmcl.2006.06.077. Epub 2006 Jul 25.
A series of potent inhibitors of the sodium hydrogen exchanger-1 (NHE-1) is described. Structure-activity relationships identified the 3-methyl-4-fluoro analog 9t as a highly potent (IC50 = 0.0065 microM) and selective (NHE-2/NHE-1=1400) non-acylguanidine NHE-1 inhibitor. Pharmacokinetic studies showed that compound 9t has an oral bioavailability of 52% and a plasma half life of 1.5 h in rats. Because of its promising potency, selectivity, and a good pharmacokinetic profile, compound 9t was selected for further studies.
本文描述了一系列钠氢交换体-1（NHE-1）的强效抑制剂。构效关系研究确定3-甲基-4-氟类似物9t是一种高效（IC50 = 0.0065 microM）且具有选择性（NHE-2/NHE-1 = 1400）的非酰基胍类NHE-1抑制剂。药代动力学研究表明，化合物9t在大鼠体内的口服生物利用度为52%，血浆半衰期为1.5小时。由于其具有良好的效力、选择性和药代动力学特性，化合物9t被选作进一步研究对象。
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