新型部分氟化硫醇双效ACE/NEP抑制剂的合成与酶活性评估

Synthesis and enzymatic evaluation of novel partially fluorinated thiol dual ACE/NEP inhibitors.

作者信息

Olimpieri Francesca, Tambaro Simone, Fustero Santos, Lazzari Paolo, Sanchez-Roselló Maria, Pani Luca, Volonterio Alessandro, Zanda Matteo

机构信息

Dipartimento di Chimica, Materiali, e Ingegneria Chimica Giulio Natta, 20131 Milano, Italy.

出版信息

Bioorg Med Chem Lett. 2009 Aug 15;19(16):4715-9. doi: 10.1016/j.bmcl.2009.06.064. Epub 2009 Jun 21.

DOI:10.1016/j.bmcl.2009.06.064

PMID:19596577

Abstract

A novel family of peptidomimetics incorporating fluoroalkyl groups, mainly a trifluoromethyl, in alpha-position to a zinc(II)-binding thiol function, was synthesized in solution as well as in solid-phase. These compounds showed inhibitory potency in the nanomolar range against both angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP), whereas no inhibition of endothelin-converting enzyme-1 (ECE-1) was observed. The trifluoromethyl-derivatives were more potent than the parent unfluorinated analogues in the case of ACE, and less potent in the case of NEP.

摘要

合成了一类新型拟肽，其在与锌（II）结合的硫醇官能团的α位引入了氟代烷基，主要是三氟甲基，合成方法包括溶液法和固相法。这些化合物对血管紧张素转换酶（ACE）和中性内肽酶（NEP）均显示出纳摩尔级别的抑制活性，而未观察到对内皮素转换酶-1（ECE-1）的抑制作用。在ACE的情况下，三氟甲基衍生物比未氟化的母体类似物更具活性，而在NEP的情况下则活性较低。