Tasker A S, Sorensen B K, Jae H S, Winn M, von Geldern T W, Dixon D B, Chiou W J, Dayton B D, Calzadila S, Hernandez L, Marsh K C, WuWong J R, Opgenorth T J
Pharmaceutical Products Division, Abbott Laboratories, Abbott Park, Illinois 60064, USA.
J Med Chem. 1997 Jan 31;40(3):322-30. doi: 10.1021/jm960077r.
The benzodioxole ((methylenedioxy)benzene) group is present in a number of endothelin (ET) receptor antagonists thus far reported. As part of our own endothelin antagonist program we have developed (2R*,3R*,4S*)-1-(N,N-dibutylacetamido)-4-(1,3-benzodioxol-5- yl)-2-(4-methoxyphenyl)pyrrolidine-3-carboxylic acid (A-127722). This is a potent antagonist, binding to the ETA and ETB receptor subtypes with affinities (IC50) of 0.4 and 520 nM, respectively, and also contains the aforementioned benzodioxole. While this compound was seemingly optimized at its N-terminus, no effort had been directed toward understanding the contributions to binding affinity or receptor subtype selectivity conferred by the benzodioxole. Substitution by 1- or 2-naphthyl yielded weak antagonists. Oxygenated benzenes, such as p-anisyl, were potent compounds with IC50s in the low-nanomolar range. Simple deletion of either of the two oxygen atoms (dihydrobenzofurans) yielded extremely potent agents, possessing subnanomolar affinity for the ETA receptor. Additionally, the compounds showed enhanced selectivity, binding to the ETB receptor subtype in the micromolar range. This paper describes the development of this novel class of compounds.
苯并二氧杂环戊烯（亚甲二氧基苯）基团存在于迄今为止报道的多种内皮素（ET）受体拮抗剂中。作为我们自身内皮素拮抗剂项目的一部分，我们已研发出（2R*，3R*，4S*）-1-（N，N-二丁基乙酰氨基）-4-（1，3-苯并二氧杂环戊烯-5-基）-2-（4-甲氧基苯基）吡咯烷-3-羧酸（A-127722）。这是一种强效拮抗剂，对ETA和ETB受体亚型的亲和力（IC50）分别为0.4和520 nM，并且也含有上述苯并二氧杂环戊烯。虽然该化合物在其N端似乎已得到优化，但尚未致力于了解苯并二氧杂环戊烯对结合亲和力或受体亚型选择性的贡献。用1-或2-萘基取代产生了弱拮抗剂。含氧苯，如对甲氧基苯基，是IC50在低纳摩尔范围内的强效化合物。简单地去除两个氧原子中的任何一个（二氢苯并呋喃）产生了极具活性的药物，对ETA受体具有亚纳摩尔亲和力。此外，这些化合物表现出增强的选择性，在微摩尔范围内与ETB受体亚型结合。本文描述了这类新型化合物的研发情况。
