Ok Dong, Li Chunshi, Abbadie Catherine, Felix John P, Fisher Michael H, Garcia Maria L, Kaczorowski Gregory J, Lyons Kathryn A, Martin William J, Priest Birgit T, Smith McHardy M, Williams Brande S, Wyvratt Matthew J, Parsons William H
Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, NJ 07065, USA.
Bioorg Med Chem Lett. 2006 Mar 1;16(5):1358-61. doi: 10.1016/j.bmcl.2005.11.051. Epub 2005 Dec 5.
Novel cyclopentane-based 3-phenyl-1-hydroxypropyl compounds were evaluated for inhibitory activity against the peripheral nerve sodium channel Na(V)1.7 and off-target activity against the cardiac potassium channel hERG. The stereochemistry of the hydroxyl group and substitution on the phenyl rings with either fluorinated O-alkyl or alkyl groups were found to be critical for conferring potency against Na(V)1.7. A benchmark compound from this series displayed efficacy in rat models of inflammatory and neuropathic pain.
对新型环戊烷基3-苯基-1-羟丙基化合物进行了评估，以检测其对外周神经钠通道Na(V)1.7的抑制活性以及对心脏钾通道hERG的脱靶活性。发现羟基的立体化学以及苯环上用氟化O-烷基或烷基取代对于赋予对Na(V)1.7的效力至关重要。该系列中的一个基准化合物在炎症性和神经性疼痛的大鼠模型中显示出疗效。
