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

• Published in: The journal of peptide research 2004-02, Vol.63 (2), p.99-107
• Main Authors: Inguimbert, N., Poras, H., Dhotel, H., Beslot, F., Scalbert, E., Bennejean, C., Renard, P., Fournié-Zaluski, M.-C., Roques, B.-P.
• Format: Article
• Language: English
• Subjects: Alanine - analogs & derivatives; Alanine - chemical synthesis; Alanine - chemistry; Alanine - pharmacology; angiotensin-converting enzyme; Angiotensin-Converting Enzyme Inhibitors - chemistry; Angiotensin-Converting Enzyme Inhibitors - pharmacology; Animals; Aspartic Acid Endopeptidases - antagonists & inhibitors; endothelin-converting enzyme; Endothelin-Converting Enzymes; hypertension; Indans - chemical synthesis; Indans - chemistry; Indans - pharmacology; inhibitor; Male; Metalloendopeptidases - antagonists & inhibitors; Metalloendopeptidases - metabolism; Molecular Structure; neprilysin; Neprilysin - antagonists & inhibitors; Peptidyl-Dipeptidase A - metabolism; Protease Inhibitors - chemical synthesis; Protease Inhibitors - chemistry; Protease Inhibitors - pharmacology; Rats; Rats, Wistar; Structure-Activity Relationship; Sulfhydryl Compounds - chemistry; Tryptophan - analogs & derivatives; Tryptophan - chemistry; Vascular Diseases - therapy; vasopeptidase; zinc metallopeptidase
• ISSN: 1397-002X; 1399-3011
• DOI: 10.1111/j.1399-3011.2003.00121.x

:  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.