Collagenases substrate analogue inhibitors

INHIBITORS OF MAMMALIAN COLLAGENASES Non-substrate analogue inhibitors Substrate analogue inhibitors Phosphorus-based inhibitors Sulphur-based inhibitors Hydroxamate inhibitors tt-Carboxyalkyl inhibitors Miscellaneous inhibitors... 

A number of 7V-carboxyalkyl and A-phosphonoalkyl substituted substrate analogue inhibitors have been examined [161,204-208]. These derivatives contain both the acidic carboxylate (or phosphonate) and basic amine functionalities in the vicinity of the scissile bond. Thus, they are capable both of electrostatic interaction with the active site Zn(II) and hydrogen bonding interactions with other active site residues. They are, however, only moderately potent collagenase inhibitors Table 8.18). The stereochemistry at the carbon atom to which the carboxylate moiety is bonded markedly influences the inhibitory potency of these derivatives ((197) vs. (198)). The phosphonate analogues of this class of derivatives have also been evaluated Table 8.18), but are not substantially better inhibitors than the carboxyl-ates. 

Substrate analogues containing the mercaptan functionaUty have been extensively investigated as collagenase inhibitors, and some other sulphur-based functionalities have also been explored [1,161,172-185]. The mercap-tans tend to be very potent inhibitors of all of the MMP, presumably due to the strong interaction between the active site Zn(II) and the mercaptide anion. Unfortunately, these compounds tend to undergo inactivation by oxidative disulphide formation. However, the rate at which this occurs varies widely and depends on the structure of the inhibitor. The most common synthetic route to these derivatives again leads to a diastereomeric mixture. 

The hydroxamate functionality is an effective scissile bond surrogate in collagenase inhibitors [1,186-203], probably because of its ability to serve as a bidentate ligand for the active site Zn(II). N-terminal tri- and tetrapeptide hydroxamate substrate analogues are only moderately potent inhibitors Table 8.15). An intriguing observation with respect to possible binding modes is that the residues in subsites P and P2 can be replaced with their D-stereoisomer counterparts with essentially no loss of potency, as long as both are replaced with the D-isomers (compare (151), (152) and (153), and (154) vs. (157), in Table 8.15). 

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