| 摘要 |
<p>Inhibitors of the Zn+2-metalloendopeptidases, enkephalinase, angiotensin-converting enzyme, and collagenase are provided. The enkephalinase inhibitors of the invention are useful as analgesics or antihypertensives. The angiotensin-converting enzyme inhibitors of the invention are useful as antihypertensives. The collagenase inhibitors of the invention are useful in treating diseases, such as corneal ulceration, periodontal disease, and arthritis, which involve undesirable activity of bacterial or mammalian collagenases. The inhibitors of the invention are peptide or peptide-ester derivatives of the dipeptide analogs of the formula X¿1?-(CR3R4)z-(CR5R6)x-CHR9-CO2H wherein X1- is a functional group, such as (N=C) (CH2) (C=0)-, from which a Zn?+2¿ metalloendopeptidase, at its active site, is capable of abstracting a proton to yield and activated functional group capable of forming a stable, covalent bond with a residue in the active site; z is 0 or 1, wherein, when z is 0, the group -(CR¿3?R4)z-(CR5R6)x- is not in the compound and the group X1-is bonded directly to the group -(CHR9)-; x is 0 if z is 0 or is 0 or 1 if z is 1, wherein, when x is 0 and z is 1, the group -(CR5R6)x- is not in the compound and the group -(CR3R4)- is bonded directly to the group -(CHR9)-; R2, R3, R4, R5, and R6 are independently hydrogen or alkyl of 1 to 3 carbon atoms; and R9 is benzyl, alkyl of 1 to 5 carbon atoms, or hydrogen. Among the dipeptide analogs derivatized with peptides or peptide esters in accordance with the invention is 2-benzyl-5-cyano-4-oxopentanoic acid, which the invention provides substantially free of its 3- benzyl regioisomer.</p> |
