Filipski Kevin J, Sammons Matthew F, Bhattacharya Samit K, Panteleev Jane, Brown Janice A, Loria Paula M, Boehm Markus, Smith Aaron C, Shavnya Andre, Conn Edward L, Song Kun, Weng Yan, Facemire Carie, Jüppner Harald, Clerin Valerie
Pfizer Worldwide Research & Development, 1 Portland Street, Cambridge, Massachusetts 02139, United States.
Pfizer Worldwide Research & Development, 558 Eastern Point Road, Groton, Connecticut 06340, United States.
ACS Med Chem Lett. 2018 Apr 12;9(5):440-445. doi: 10.1021/acsmedchemlett.8b00013. eCollection 2018 May 10.
Sodium-phosphate cotransporter 2a, or NaPi2a (SLC34A1), is a solute-carrier (SLC) transporter located in the kidney proximal tubule that reabsorbs glomerular-filtered phosphate. Inhibition of NaPi2a may enhance urinary phosphate excretion and correct maladaptive mineral and hormonal derangements associated with increased cardiovascular risk in chronic kidney disease-mineral and bone disorder (CKD-MBD). To date, only nonselective NaPi inhibitors have been described. Herein, we detail the discovery of the first series of selective NaPi2a inhibitors, resulting from optimization of a high-throughput screening hit. The oral PK profile of inhibitor PF-06869206 () in rodents allows for the exploration of the pharmacology of selective NaPi2a inhibition.
钠-磷酸盐共转运蛋白2a，即NaPi2a（SLC34A1），是一种溶质载体（SLC）转运蛋白，位于肾近端小管，负责重吸收肾小球滤过的磷酸盐。抑制NaPi2a可能会增加尿磷排泄，并纠正慢性肾脏病-矿物质和骨异常（CKD-MBD）中与心血管风险增加相关的适应性不良的矿物质和激素紊乱情况。迄今为止，仅描述了非选择性的NaPi抑制剂。在此，我们详细介绍了首个选择性NaPi2a抑制剂系列的发现，这是通过对高通量筛选得到的活性化合物进行优化而产生的。抑制剂PF-06869206（）在啮齿动物中的口服药代动力学特征，有助于探索选择性抑制NaPi2a的药理学特性。
