CONJUGATES OF AN ALPHA, ALPHA-DISUBSTITUTUED GLYCINE ESTER AND A MODULATOR OF THE ACTIVITY OF A TARGET INTRACELLULAR ENZYME

摘要

Disclosed is a covalent conjugate of an alpha, alpha-disubstituted glycine ester and a modulator of the activity of a target intracellular enzyme, wherein: the ester group of the conjugate is hydrolysable by cells containing the intracellular carboxylesterase enzyme hCE-1 to the corresponding alpha amino acid and not by cells containing hCE-2 or hCE-3; the alpha, alpha-disubstituted glycine ester is conjugated to the modulator at a position remote from the binding interface between the inhibitor and the target enzyme; and the said alpha, alpha-disubstituted glycine ester being conjugated to the modulator via its alpha amino group such that the nitrogen of the said amino is not directly linked to a carbonyl moiety; whereby the amino acid conjugate which is the hydrolysis product of the alpha, alpha-disubstituted glycine ester conjugate retains the intracellular binding activity of the parent modulator with the target enzyme.