N-[2-(Indan-1-yl)-3-mercapto-propionyl] amino acids as highly potent inhibitors of the three vasopeptidases (NEP, ACE, ECE): In vitro and In vivo activities.
We have previously reported the design of a lead compound 1a for the joint inhibition of neprilysin (NEP, EC 3.4.24.11), angiotensin converting enzyme (ACE, EC 3.4.15.1) and endothelin converting enzyme (ECE-1, EC 3.4.24.71), three metallopeptidases which are implicated in the regulation of fluid homeostasis and vascular tone. We report here the synthesis and biological activities of analogues derived from this lead with inhibitory potencies in the nanomolar range for the three enzymes. Compounds 8b and 15c are the most potent triple inhibitors described to date.
Département de Pharmacochimie Moléculaire et Structurale, U266 INSERM, UMR 8600 CNRS, UFR des Sciences Pharmaceutiques et Biologiques, 4, avenue de l'observatoire, 75270 Cedex 06, Paris, France.
Nicolas
N
Inguimbert
Hervé
H
Poras
Franck
F
Teffo
Françoise
F
Beslot
Mohamed
M
Selkti
Alain
A
Tomas
Elizabeth
E
Scalbert
Caroline
C
Bennejean
Pierre
P
Renard
Marie-Claude
MC
Fournié-Zaluski
Bernard-Pierre
BP
Roques
D000596:Amino Acids / Q000737:chemistry* / Q000494:pharmacology*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors; D000072396:Endothelin-Converting Enzymes; D007189:Indans / Q000737:chemistry* / Q000494:pharmacology*; D007275:Injections, Intravenous; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors*; D015260:Neprilysin / Q000037:antagonists & inhibitors; D019906:Nuclear Magnetic Resonance, Biomolecular; D011480:Protease Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013438:Sulfhydryl Compounds / Q000737:chemistry / Q000494:pharmacology; D013997:Time Factors
D000596:Amino Acids; D000806:Angiotensin-Converting Enzyme Inhibitors; D007189:Indans; D011480:Protease Inhibitors; D013438:Sulfhydryl Compounds; D016282:Aspartic Acid Endopeptidases; D008666:Metalloendopeptidases; D015260:Neprilysin; D000072396:Endothelin-Converting Enzymes