| Popis: |
The rational design and synthesis of a series of peptidyl carbamates incorporating a derivatized ornithyl or lysyl residue at the P3 or P4 subsite is described. The derivatized residues were chosen as mimics of desmonsine cross-links ubiquitously found in mature elastin. The alteration of specific residues of the peptidyl carbamate, in addition to the realization of a stereospecific synthesis, required utilization of two convergent synthetic approaches. When tested for inhibitory activity against the serine dependent enzymes, human leukocyte elastase, porcine pancreatic elastase, trypsin, chymotrypsin, as well as acetyl cholinesterase, the compounds were found to be specific inhibitors of the elastases. Thus the series was found to exhibit inhibitor dissociation constants as low as 0.2 × 10−6M and 3.0 × 10−6M for human leukocyte and porcine pancreatic elastase, respectively. Michaelis-Menten kinetics demonstrated active site inhibition. Placement of Nδ-Bz-L-Orn at P4 withp-nitrophenol at P1’(23a) ... |
