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FournieZaluski, MC ; Coric, P ; Thery, V ; Gonzalez, W ; Meudal, H ; Turcaud, S ; Michel, JB ; Roques, BP

Design of orally active dual inhibitors of neutral endopeptidase and angiotensin-converting enzyme with long duration of action

Journal of Medicinal Chemistry 39 (13) 2594-2608

par Administrateur - publié le

Abstract :

Mercaptoacyl dipeptides, containing a glycine Linked to a C-terminal 5-phenylproline, have been synthesized in order to obtain new highly efficient dual inhibitors of the two zinc metallopeptidases, neutral endopeptidase (NEP) and angiotensin-converting enzyme (ACE), which are involved in the control of blood pressure and fluid homeostasis. These compounds have been designed (i) to fit optimally the ACE pharmacophore previously described (Fournie-Zaluski, M. C. ; et al. J. Med. Chem. 1994, 37, 1070-1083), through interaction with the S-1, S-1’, and S-2’ subsites of this enzyme, (ii) and to interact with the S-1’ and S-2’ subsites of NEP with the 5-phenylproline moiety outside the catalytic domain (Coric, P. ; et al. J. Med. Chem. 1996, 39, 1210-1219). Replacement of Gly by Ala in these mercaptoacyl dipeptides induced an about 100-fold decreasein ACE inhibition.