Enzyme and receptor modulation
AssigneeGlaxoSmithKline Intellectual Property Development Limited
InventorsAlan Hornsby Davidson, Alan Hastings Drummond, Lindsey Ann Needham
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Abstract
Covalent conjugation of an alpha amino acid ester to a modulator of the activity of a target intracellular enzyme or receptor, wherein the ester group of the conjugate is hydrolysable by one or more intracellular carboxylesterase enzymes to the corresponding acid, leads to accumulation of the carboxylic acid hydrolysis product in the cell and enables improved or more prolonged enzyme or receptor modulation relative to the unconjugated modulator.
Claims16
A covalent conjugate of an alpha amino acid ester and a modulator of the activity of a target intracellular enzyme or receptor, wherein:
- the ester group of the conjugate Is hydrolysable by one or more intracellular carboxylesterase enzymes to the corresponding acid;
- and
- the alpha amino acid ester is conjugated to the modulator at a position remote from the binding Interface between the inhibitor and the target enzyme or receptor.
A covalent conjugate of an alpha amino acid ester and a modulator of the activity of a target Intracellular enzyme or receptor, wherein:
- the ester group of the conjugate is hydrolysable by one or more intracellular carboxylesterase enzymes to the corresponding acid;
- and
- the alpha amino add ester is conjugated to the modulator such that the binding mode of the conjugated modulator and the said corresponding add to the target enzyme or receptor is the same as that of the unconjugated modulator.
A method of increasing or prolonging the intracellular potency and/or residence time of modulator of the activity of a target intracellular enzyme or receptor comprising structural modification of the modulator by covalent attachment thereto of an alpha amino acid ester at a position remote from the binding interface between the inhibitor and the target enzyme or receptor, the ester group of the conjugate being hydrolysable by one or more intracellular carboxylesterase enzymes to the corresponding acid
A method of increasing or prolonging the intracellular potency and/or residence time of modulator of the activity of a target Intracellular enzyme or receptor comprising structural modification of the modulator by covalent attachment thereto of an alpha amino acid ester such that the binding mode of the conjugated modulator and the said corresponding add to the target enzyme or receptor is the same as that of the unconjugated modulator, the ester group of the conjugate being hydrolysable by one or more intracellular carboxylesterase enzymes to the corresponding acid.
A conjugate or method as claimed in any of the preceding claims wherein the modulator is one which binds non-covalently to the target intracellular enzyme or receptor.
A conjugate or method as claimed in any of the preceding claims wherein the alpha amino acid ester is covalently conjugated to the modulator through a linker radical.
A conjugate or method as claimed in any of the preceding claims wherein the alpha amino acid ester is conjugated to the modulator via the amino group of the amino acid ester.
A conjugate or method as claimed in any of the preceding claims wherein the ester is hydrolysable by cells containing one or more of the intracellular carboxylesterase enzymes hCE-1, hCE-2 and hCE-3 to the corresponding alpha amino acid.
A method of identifying a covalent conjugate of an alpha amino acid ester of a given modulator of the activity of a target Intracellular enzyme or receptor, said conjugate having increased or prolonged cellular potency relative to the given modulator, which method comprises:
- (iv) identifying a position or positions on a given modulator of the activity of a target intracellular enzyme or receptor, or on a plurality of given modulators of the activity of a target intracellular enzyme or receptor sharing the same binding mode for the target enzyme or receptor, said position or positions being remote from the binding interface between the modulators and the target enzyme or receptor;
- (iv) covalently modifying the modulator(s) by attachment of an alpha amino acid ester radical, or a range of different alpha amino acid ester radicals at one or more of the positions identified in (i);
- (iv) testing the alpha amino acid-conjugated modulator(s) prepared in (ii) to determine their activity against the target enzyme or receptor;
- and
- (iv) from data acquired in (iii), selecting one or more of the tested alpha amino acid ester-conjugated versions of the given modulator(s) which cause modulation of enzyme or receptor activity inside cells, are converted to and accumulate as the corresponding carboxylic acid inside cells, and which show increased or prolonged cellular potency.
Dependencies are inferred from the claim text.