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 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.
Olimpieri
Francesca
F
Dipartimento di Chimica, Materiali, e Ingegneria Chimica Giulio Natta, 20131 Milano, Italy.
Tambaro
Simone
S
Fustero
Santos
S
Lazzari
Paolo
P
Sanchez-Roselló
Maria
M
Pani
Luca
L
Volonterio
Alessandro
A
Zanda
Matteo
M
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D005461:Fluorine / Q000737:chemistry*; D006801:Humans; D015260:Neprilysin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010455:Peptides / Q000737:chemistry; D007703:Peptidyl-Dipeptidase A / Q000737:chemistry* / Q000378:metabolism; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013438:Sulfhydryl Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
D000806:Angiotensin-Converting Enzyme Inhibitors; D010455:Peptides; D011480:Protease Inhibitors; D013438:Sulfhydryl Compounds; D005461:Fluorine; D007703:Peptidyl-Dipeptidase A; D015260:Neprilysin