Conformationally constrained analogues of endogenous tripeptide inhibitorsof zinc metalloproteinases

Two diastereomeric furan-2-carbonylamino-3-oxohexahydroindolizino[8,7-b]ind ole carboxylates, highly constrained analogues of endogenous pyroglutamyl t ripeptide inhibitors of snake venom endopeptidases, have been prepared as p otential inhibitors of adamalysin II and matrix metalloproteinases. They pr oved to be inactive against adamalysin II and weak inhibitors of gelatinase A, gelatinase B, stromelysin 1 and human neutrophyl collagenase. Evaluatio n of the mode of binding of the (2R,5S,11bR) isomer in the active site of a damalysin II suggests that the decrease of potency may be due to the reorie ntation of the acylamino chain in three of the heterocyclic nucleus, to a s hort contact at the entrance of the S-1' hydrophobic cleft and to the loss of flexibility of the tetracyclic nucleus in the P-1', P-2' region of the i nhibitor, which prevents optimal arrangement in the S-1' specificity subsit e. (C) 2001 Editions scientifiques et medicales Elsevier SAS.