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

A novel family of peptidomimetics incorporating fluoroalkyl groups, mainly a trifluoromethyl, in α-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.

Graphical abstractA series of novel peptidomimetics incorporating fluoroalkyl groups have been synthesized in solution and in solid phase. These compounds were found to be dual ACE/NEP inhibitors in the nanomolar range.Figure optionsDownload full-size imageDownload as PowerPoint slide