Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
Bioorg Med Chem Lett. 2013 Jan 1;23(1):37-41. doi: 10.1016/j.bmcl.2012.11.046. Epub 2012 Nov 24.
Recent preclinical studies demonstrate a role for the prostaglandin E(2) (PGE(2)) subtype 1 (EP1) receptor in mediating, at least in part, the pathophysiology of hypertension and diabetes mellitus. A series of amide and N-acylsulfonamide analogs of a previously described picolinic acid-based human EP1 receptor antagonist (7) were prepared. Each analog had improved selectivity at the mouse EP1 receptor over the mouse thromboxane receptor (TP). A subset of analogs gained affinity for the mouse PGE(2) subtype 3 (EP3) receptor, another potential therapeutic target. One analog (17) possessed equal selectivity for EP1 and EP3, displayed a sufficient in vivo residence time in mice, and lacked the potential for acyl glucuronide formation common to compound 7. Treatment of mice with 17 significantly attenuated the vasopressor activity resulting from an acute infusion of EP1 and EP3 receptor agonists. Compound 17 represents a potentially novel therapeutic in the treatment of hypertension and diabetes mellitus.
最近的临床前研究表明，前列腺素 E（2）（PGE（2））亚型 1（EP1）受体在介导高血压和糖尿病的病理生理学方面起作用，至少在部分程度上起作用。一系列以前描述的基于吡啶甲酸的人 EP1 受体拮抗剂（7）的酰胺和 N-酰基磺酰胺类似物被制备。每个类似物在小鼠 EP1 受体上相对于小鼠血栓素受体（TP）具有改善的选择性。类似物的亚组获得了对小鼠前列腺素 E（2）亚型 3（EP3）受体的亲和力，这是另一个潜在的治疗靶点。一种类似物（17）对 EP1 和 EP3 具有同等的选择性，在小鼠体内具有足够的居留时间，并且缺乏化合物 7 常见的酰基葡萄糖醛酸形成的潜力。用 17 治疗小鼠可显著减弱由 EP1 和 EP3 受体激动剂急性输注引起的升压活性。化合物 17 代表了治疗高血压和糖尿病的潜在新型治疗药物。
