Nanomolar Potency and Metabolically Stable Inhibitors of Kidney Urea Transporter UT-B

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• 作者：Marc O. Anderson ; Jicheng Zhang ; Yan Liu ; Chenjuan Yao ; Puay-Wah Phuan ; A. S. Verkman
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：June 28, 2012
• 年：2012
• 卷：55
• 期：12
• 页码：5942-5950
• 全文大小：443K
• 年卷期：v.55,no.12(June 28, 2012)
• ISSN：1520-4804

文摘

Urea transporters, which include UT-B in kidney microvessels, are potential targets for development of drugs with a novel diuretic (鈥榰rearetic鈥? mechanism. We recently identified, by high-throughput screening, a triazolothienopyrimidine UT-B inhibitor, 1, that selectively and reversibly inhibited urea transport with IC₅₀ = 25.1 nM and reduced urinary concentration in mice (Yao et al. J. Am. Soc. Nephrol., in press). Here, we analyzed 273 commercially available analogues of 1 to establish a structure鈥揳ctivity series and synthesized a targeted library of 11 analogues to identify potent, metabolically stable UT-B inhibitors. The best compound, {3-[4-(1,1-difluoroethyl)benzenesulfonyl]thieno[2,3-e][1,2,3]triazolo[1,5-a]pyrimidin-5-yl}thiophen-2-ylmethylamine, 3k, had IC₅₀ of 23 and 15 nM for inhibition of urea transport by mouse and human UT-B, respectively, and 40-fold improved in vitro metabolic stability compared to 1. In mice, 3k accumulated in kidney and urine and reduced maximum urinary concentration. Triazolothienopyrimidines may be useful for therapy of diuretic-refractory edema in heart and liver failure.