In vivo properties of thiol inhibitors of the three vasopeptidases NEP, ACE and ECE are improved by introduction of a 7-azatryptophan in P2' position.
Three zinc metallopeptidases are implicated in the regulation of fluid homeostasis and vascular tone and represent interesting targets for the treatment of chronic heart failure. We have previously reported the synthesis of a triple inhibitor able to simultaneously inhibit 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) with nanomolar potency towards NEP and ACE and a lesser affinity for ECE. Here, we report the optimization and biological activities of analogs derived from lead compound 1 (2S)-2-[(2R)-2-((1S)-5-bromo-indan-1-yl)-3-mercapto-propionylamino]-3- (1H-indol-3-yl)-propionic acid by a structural approach. Among several inhibitors, compound 21, (2S)-2-[(2R)-2-((1S)-5-bromo-indan-1-yl)-3-mercapto-propionylamino]-3-(1H-pyrrolo[2,3-b]pyridin-3-yl)-propionic acid was selected by taking into account its good molecular adaptation with the recently published structures of the three vasopeptidases. This optimization procedure led to an improved pharmacologic activity when compared with 1.
Département de Pharmacochimie moléculaire et Structurale, U266 INSERM-FRE 2463 CNRS, UFR des Sciences Pharmaceutiques et Biologiques, 4 avenue de l'observatoire, 75270 Paris, Cedex 06, France.
N
N
Inguimbert
H
H
Poras
H
H
Dhotel
F
F
Beslot
E
E
Scalbert
C
C
Bennejean
P
P
Renard
M-C
MC
Fournié-Zaluski
B-P
BP
Roques
D000409:Alanine / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors*; D000072396:Endothelin-Converting Enzymes; D007189:Indans / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D008297:Male; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors / Q000378:metabolism; D015394:Molecular Structure; D015260:Neprilysin / Q000037:antagonists & inhibitors*; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship; D013438:Sulfhydryl Compounds / Q000737:chemistry; D014364:Tryptophan / Q000031:analogs & derivatives* / Q000737:chemistry; D014652:Vascular Diseases / Q000628:therapy
C492091:2-(2-(5-bromoindan-1-yl)-3-mercaptopropionylamino)-3-(1H-pyrrolo(2,3-b)pyridin-3-yl)propionic acid; D000806:Angiotensin-Converting Enzyme Inhibitors; D007189:Indans; D011480:Protease Inhibitors; D013438:Sulfhydryl Compounds; C006657:7-azatryptophan; D014364:Tryptophan; D007703:Peptidyl-Dipeptidase A; D016282:Aspartic Acid Endopeptidases; D008666:Metalloendopeptidases; D015260:Neprilysin; D000072396:Endothelin-Converting Enzymes; D000409:Alanine