Affiliation: | 1. Institut des Biomolécules Max Mousseron, Université Montpellier, CNRS, ENSCM, Faculté de Pharmacie, 34000 Montpellier, France Avara Pharmaceutical Services, Boucherville, QC, J4B 7 K8 Canada;2. Institut des Biomolécules Max Mousseron, Université Montpellier, CNRS, ENSCM, Faculté de Pharmacie, 34000 Montpellier, France Asymptote Project Management, 1 rue Edisson, 69500 Bron, France;3. Institut des Biomolécules Max Mousseron, Université Montpellier, CNRS, ENSCM, Faculté de Pharmacie, 34000 Montpellier, France;4. Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques UMR8601, CNRS, Université Paris-Descartes, 45 rue des Saints Pères, 75270 Paris Cedex 06, France;5. Centre Biocommunication en Cardio-métabolique, Université Montpellier, Faculté de Pharmacie, 34000 Montpellier, France;6. Institut des Biomolécules Max Mousseron, Université Montpellier, CNRS, ENSCM, Faculté de Pharmacie, 34000 Montpellier, France Current address: BioCIS, UMR 8076, CNRS, Université Paris Sud, Université Paris-Saclay, 92296 Châtenay-Malabry, France |
Abstract: | More than 160 arginine analogues modified on the C-terminus via either an amide bond or a heterocyclic moiety (1,2,4-oxadiazole, 1,3,4-oxadiazole and 1,2,4-triazole) were prepared as potential inhibitors of NO synthases (NOS). A methodology involving formation of a thiocitrulline intermediate linked through its side-chain on a solid support followed by modification of its carboxylate group was developed. Finally, the side-chain thiourea group was either let unchanged, S-alkylated (Me, Et) or guanidinylated (Me, Et) to yield respectively after TFA treatment the corresponding thiocitrulline, S-Me/Et-isothiocitrulline and N-Me/Et-arginine substrate analogues. They all were tested against three recombinant NOS isoforms. Several compounds containing a S-Et- or a S-Me-Itc moiety and mainly belonging to both the dipeptide-like and 1,2,4-oxadiazole series were shown to inhibit nNOS and iNOS with IC50 in the 1–50 μM range. Spectral studies confirmed that these new compounds interacted at the heme active site. The more active compounds were found to inhibit intra-cellular iNOS expressed in RAW264.7 and INS-1 cells with similar efficiency than the reference compounds L-NIL and SEIT. |