Bradbury R H, Bath C, Butlin R J, Dennis M, Heys C, Hunt S J, James R, Mortlock A A, Sumner N F, Tang E K, Telford B, Whiting E, Wilson C
Cardiovascular and Musculoskeletal Department, ZENECA Pharmaceuticals, Macelesfield, Cheshire, U.K.
J Med Chem. 1997 Mar 14;40(6):996-1004. doi: 10.1021/jm9604585.
Use of automated synthesis led to the discovery of several 6-membered nitrogen heterocycles as replacements for the N-isoxazolyl substituent present in the 1-naphthalenesulfonamides endothelin-A (ETA) antagonist 5-(dimethylamino)-N-(3,4-dimethyl-5-isoxazolyl)-1-naphthalenesu lfo namides (BMS 182874). In each of these heterocycles, a small substituent such as halogen para to the position of attachment to the sulfonamide nitrogen atom was found to be advantageous for ETA receptor affinity. Of these heterocycles, 2-pyrazines offered the greatest scope for improving receptor affinity. Optimization of the substituents at the 3- and 5-positions in the pyrazine ring led to potent, ETA-selective compounds such as 5-(dimethylamino)-N-(5-chloro-3-methoxy-2-pyrazinyl)-1- naphthalenesulfonamides (7m, ETA pIC50 8.1). When dosed orally at 10 mg/kg to conscious, normotensive rats infused with big ET-1, compounds such as 7m showed significant inhibition of the pressor response with a duration of effect lasting for the 5-h course of the experiment.
使用自动化合成方法发现了几种六元氮杂环，可作为1-萘磺酰胺类内皮素A（ETA）拮抗剂5-（二甲氨基）-N-（3,4-二甲基-5-异恶唑基）-1-萘磺酰胺（BMS 182874）中存在 的N-异恶唑基取代基的替代物。在这些杂环中的每一种中，发现与磺酰胺氮原子连接位置对位的小取代基（如卤素）有利于ETA受体亲和力。在这些杂环中，2-吡嗪为提高受体亲和力提供了最大的空间。对吡嗪环3位和5位的取代基进行优化，得到了强效的、ETA选择性化合物，如5-（二甲氨基）-N-（5-氯-3-甲氧基-2-吡嗪基）-1-萘磺酰胺（7m，ETA的pIC50为8.1）。当以10mg/kg的剂量口服给予输注大ET-1的清醒正常血压大鼠时，7m等化合物显示出对升压反应的显著抑制作用，其作用持续时间长达实验的5小时过程。
