Fukami T, Nagase T, Fujita K, Hayama T, Niiyama K, Mase T, Nakajima S, Fukuroda T, Saeki T, Nishikibe M
New Drug Discovery Research Laboratories, Tsukuba Research Institute, Banyu Pharmaceutical Company, Ltd., Ibaraki, Japan.
J Med Chem. 1995 Oct 13;38(21):4309-24. doi: 10.1021/jm00021a021.
Analogues of the natural product endothelin A (ETA) receptor antagonists cyclo(-D-Trp1-D-Glu2-Ala3-D-Val4-Leu5-) (1) and cyclo(-D-Trp1-D-Glu2-Ala3-D-alloIle4-Leu5-) (2) were prepared and tested for inhibitory activity against [125I]endothelin (ET-1) binding to protein ETA receptors. The DDLDL chirality sequence of the natural products appeared to be critical for inhibitory activity because conversion of either D-Trp or D-Glu (or both) in 1 to the corresponding L-isomer(s) abolished this property. Systematic modifications at each position of the natural products clarified the structure-activity relationships and led to highly potent and selective ETA receptor antagonists. Most replacements of D-Trp1 and Leu5 with other amino acids caused a significant loss of inhibitory activity. In contrast, replacement of D-Glu2 with D-Asp2 enhanced the activity. With regard to the Ala3 position, all analogues with imino acids, independent of being cyclic or acyclic, showed higher affinities than did the amino acid analogues. In addition, most replacements with amino acids, which had various functional groups in their side chains, did not significantly modify ETA binding affinity. The D-Val4/D-alloIle4 position was very important for inhibitory activity, and a beta-position branched D-amino acid or a D-heteroarylglycine was preferable at this position. Among synthesized cyclic pentapeptides, compound 36 (BQ-518) was the most potent ETA receptor antagonist, with a pA2 of 8.1 against ET-1-induced vasoconstriction in isolated porcine coronary arteries. This compound also showed the greatest selectivity between ETA and ETB receptors (IC50 for human ETA = 1.2 nM, IC50 for human ETB = 55 microM). In contrast, compound 8 (BQ-123) is a highly soluble, potent, and selective ETA receptor antagonist (pA2 = 7.4, IC50 for human ETA = 8.3 nM, IC50 for human ETB = 61 microM). The sodium salt of 8 is practically freely soluble in saline. These compounds are useful tools for not only in vitro but also in vivo pharmacological studies.
制备了天然产物内皮素A（ETA）受体拮抗剂环（-D-色氨酸1-D-谷氨酸2-丙氨酸3-D-缬氨酸4-亮氨酸5-）（1）和环（-D-色氨酸1-D-谷氨酸2-丙氨酸3-D-别异亮氨酸4-亮氨酸5-）（2）的类似物，并测试了它们对[125I]内皮素（ET-1）与蛋白ETA受体结合的抑制活性。天然产物的DDLDL手性序列似乎对抑制活性至关重要，因为将1中的D-色氨酸或D-谷氨酸（或两者）转换为相应的L-异构体均会消除该特性。对天然产物每个位置进行系统修饰阐明了构效关系，并产生了高效且选择性的ETA受体拮抗剂。用其他氨基酸取代D-色氨酸1和亮氨酸5大多会导致抑制活性显著丧失。相反，用D-天冬氨酸2取代D-谷氨酸2增强了活性。关于丙氨酸3位置，所有含亚氨基酸的类似物，无论其为环状或非环状，均显示出比氨基酸类似物更高的亲和力。此外，用侧链具有各种官能团的氨基酸进行的大多数取代并未显著改变ETA结合亲和力。D-缬氨酸4/D-别异亮氨酸4位置对抑制活性非常重要，在此位置优选β位分支的D-氨基酸或D-杂芳基甘氨酸。在合成的环五肽中，化合物36（BQ-518）是最有效的ETA受体拮抗剂，在离体猪冠状动脉中对ET-1诱导的血管收缩的pA2为8.1。该化合物在ETA和ETB受体之间也表现出最大的选择性（人ETA的IC50 = 1.2 nM，人ETB的IC50 = 55 μM）。相比之下，化合物8（BQ-123）是一种高度可溶、有效且选择性的ETA受体拮抗剂（pA2 = 7.4，人ETA的IC50 = 8.3 nM，人ETB的IC50 = 61 μM）。8的钠盐在生理盐水中几乎可自由溶解。这些化合物不仅是体外药理学研究，也是体内药理学研究的有用工具。
