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首页> 外文期刊>Journal of Medicinal Chemistry >Design and synthesis of potent, selective inhibitors of endothelin-converting enzyme.
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Design and synthesis of potent, selective inhibitors of endothelin-converting enzyme.

机译：设计和合成有效的，选择性的内皮素转化酶抑制剂。

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Endothelin-1 is the most potent peptidic vasoconstrictor discovered to date. The final step of posttranslational processing of this peptide is the conversion of its precursor by endothelin-converting enzyme-1 (ECE-1), a metalloprotease which displays high amino acid sequence identity with neutral endopeptidase 24.11 (NEP) especially at the catalytic center. A series of potent and selective arylacetylene-containing ECE-1 inhibitors have been prepared. (S, S)-3-Cyclohexyl-2-[[5-(2, 4-difluorophenyl)-2-[(phosphonomethyl)amino]pent-4-ynoyl]amino] propio nic acid (47), an arylacetylene amino phosphonate dipeptide, was found to inhibit ECE-1 and NEP with IC50 values of 14 nM and 2 microM, respectively. Similarly, (S)-[[1-[(2-biphenyl-4-ylethyl)carbamoyl]-4-(2-fluorophenyl)but-3- yny l]amino]methyl]phosphonic acid (56), an arylacetylene amino phosphonate amide, had IC50's of 33 nM and 6.5 microM for ECE-1 and NEP, respectively. Slight modification of the aryl moiety was found to have dramatic effects on ECE-1/NEP selectivity. The 2-fluoro dipeptide analogue, (S, S)-2-[[5-(2-fluorophenyl)-2-[(phosphonomethyl)amino]pent-4-ynoyl]+ ++amin o]-4-methylpentanoic acid (40), showed a 72-fold selectivity for ECE-1 over NEP, while the 3-fluoro dipeptide analogue, (S, S)-2-[[5-(3-fluorophenyl)-2-[(phosphonomethyl)amino]pent-4-ynoyl]+ ++amin o]-4-methylpentanoic acid (22), was equipotent for ECE-1 and NEP. Several of these inhibitors were shown to be potent in blocking ET-1 production in vivo as demonstrated by the big ET-1-induced pressor response in rats. These potent inhibitors are the most selective for ECE-1 reported to date and are envisaged to have a variety of therapeutic applications.
机译：内皮素-1是迄今为止发现的最有效的肽血管收缩剂。该肽的翻译后加工的最后一步是内皮素转化酶-1（ECE-1）对其前体的转化，该酶是一种金属蛋白酶，与中性内肽酶24.11（NEP）表现出很高的氨基酸序列同一性，尤其是在催化中心。已经制备了一系列有效的和选择性的含芳基乙炔的ECE-1抑制剂。 （S，S）-3-环己基-2-[[5-（2,4-二氟苯基）-2-[（膦酰基甲基）氨基]戊-4-戊酰基]氨基]丙酸（47），芳基乙炔基氨基发现膦酸二肽可抑制ECE-1和NEP，IC50值分别为14 nM和2 microM。类似地，（S）-[[[[1-[（2-联苯基-4-基乙基）氨基甲酰基] -4-（2-氟苯基）丁-3-yny [氨基]甲基]膦酸（56），芳基乙炔基氨基膦酰胺，对ECE-1和NEP的IC50分别为33 nM和6.5 microM。发现芳基部分的轻微修饰对ECE-1 / NEP选择性具有显着影响。 2-氟二肽类似物，（S，S）-2-[[5-（2-氟苯基）-2-[（膦酰基甲基）氨基]戊-4-炔基] +++氨基[] o] -4-甲基戊酸（40）对ECE-1的选择性比NEP高72倍，而3-氟二肽类似物（S，S）-2-[[5-（3-氟苯基）-2-[（膦酰基甲基）氨基]戊-4-炔基] +++氨基[omin] -4-甲基戊酸（22）等价于ECE-1和NEP。这些抑制剂中的几种已显示出在体内阻断ET-1产生的作用，如大ET-1诱导的大鼠升压反应所证明的。这些有效的抑制剂对迄今为止报道的ECE-1具有最高的选择性，并被认为具有多种治疗应用。

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