Ksander G M, de Jesus R, Yuan A, Ghai R D, Trapani A, McMartin C, Bohacek R
Research Department, Novartis Pharmaceuticals Corporation, Summit, New Jersey 07901, USA.
J Med Chem. 1997 Feb 14;40(4):495-505. doi: 10.1021/jm960582o.
The design and preparation of ortho-substituted benzofused macrocyclic lactams are described. The benzofused macrocyclic lactams were designed as neutral endopeptidase 24.11 (NEP) inhibitors. Docking studies were carried out in a model of thermolysin (TLN) using the MACROMODEL and QXP modeling programs to select suitable ring sizes. These studies predicted that the 11-, 12-, and 13-membered ring macrocyclic lactams would be active in both enzymes TLN and NEP. Good predictability of experimental results, within this series, of binding to thermolysin and to a lesser extent to NEP was observed. A visual comparison, docked at the active site of TLN, is presented for thiorphan, a 10-membered ring macrocycle and an 11-membered ring benzofused macrocyclic lactam. Potent inhibition of both NEP and thermolysin was obtained. The 11-membered ring macrocycle 25a is the most potent inhibitor from this series of compounds (TLN IC50 = 68 nM; NEP IC50 = 0.9 nM). The effects of prodrug 44b administered at 10 mg/kg po on plasma atrial natriuretic peptide (ANP) levels in conscious rats was greater than 200% over a 4 h period.
描述了邻位取代的苯并稠合大环内酰胺的设计与制备。苯并稠合大环内酰胺被设计为中性内肽酶24.11（NEP）抑制剂。使用MACROMODEL和QXP建模程序在嗜热菌蛋白酶（TLN）模型中进行对接研究，以选择合适的环大小。这些研究预测11元、12元和13元环的大环内酰胺在TLN和NEP这两种酶中均具有活性。在该系列中，观察到与嗜热菌蛋白酶结合的实验结果具有良好的可预测性，而与NEP结合的可预测性稍差。展示了在TLN活性位点对接的硫肽、一个10元环大环和一个11元环苯并稠合大环内酰胺的直观比较。获得了对NEP和嗜热菌蛋白酶的强效抑制。11元环大环化合物25a是该系列化合物中最有效的抑制剂（TLN的IC50 = 68 nM；NEP的IC50 = 0.9 nM）。以10 mg/kg口服给予前药44b，在4小时内对清醒大鼠血浆心钠素（ANP）水平的影响超过200%。
