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cokinetic profile of these last two inhibitors was not suitable for
further evaluation as a result of facile amide hydrolysis in vivo.
The combination of P2 Pro with an unsubstituted cyclopropyl ni-
trile in P1 (Table 7, entries 40 and 41) gave inhibitors significantly
less potent than the thienyl alanine analog 17 (Table 4). Incorpora-
tion of the phenyl cyclopropyl group did not result in the expected
increase in potency (entry 42). However, some intrinsic potency
was gained by homologation of the phenyl into a benzyl substituted
cyclopropane (entries 43 and 44). Attempts to further improve the
potency of these P2 Pro dipeptide nitriles met with limited success.
In addition, these derivatives (e.g., 43, isomer B) showed no
improvement of their pharmacokinetic profiles.
In conclusion, we have designed a series of dipeptide nitriles as
potent and selective inhibitors of Cat C. The presence of a sulfur
atom in P2 appears to be involved in a favorable binding interac-
tion in the active site. Incorporation of a cyclopropyl group in P1
significantly improves the stability of the dipeptides towards the
action of hydrolases present in blood. Identification of 23 as a po-
tent and selective inhibitor of Cat C allowed us to demonstrate
in vivo the possibility to modulate the processing of other serine
proteases through the inhibition of Cat C.19 Additional optimiza-
tion will be required in order to identify a candidate suitable for
development.
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