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Enzyme and receptor modulation

a technology of enzymes and receptors, applied in the field of enzymes and receptor modulation, can solve the problems of poor potency of modulators, and achieve the effect of prolonging and/or increasing activity

Inactive Publication Date: 2014-03-27
GLAXOSMITHKLINE INTPROP DEV LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

This approach enhances the potency and residence time of modulators by accumulating the hydrolyzed acid form within cells, compensating for lower intrinsic potency of the ester form and reducing systemic exposure and side effects.

Problems solved by technology

The potencies of the modulators are therefore poor despite their high binding affinities for the target enzyme or receptor.

Method used

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  • Enzyme and receptor modulation
  • Enzyme and receptor modulation
  • Enzyme and receptor modulation

Examples

Experimental program
Comparison scheme
Effect test

examples 1-6

[0100]The compounds 6-amino-5-(2,4-difluoro-benzoyl-1-phenyl-1H-pyridin-2-one (Compound I) and 6-amino-5-(2,4-difluoro-benzoyl-1-(2,5-difluorophenyl-1H-pyridin-2-one (Compound II):

are known inhibitors of the intracellular enzyme p38 MAP kinase (WO 03 / 076405). Examples 1, 3 and 5 below relate to the covalent conjugation of esterase motifs with di-substitution at the alpha carbon of the amino acid ester to these compounds, in a position remote from the binding interface between the inhibitor and the target enzyme (see the comments above concerning the binding mode of a model p38 MAP kinase inhibitor). Examples 2, 4 and 6 below relate to the carboxylic acid esterase hydrolysis products of Examples 1, 3 and 5 respectively.

Synthesis of Examples 1-6

Intermediate 1

4-Chlorophenyl 3-(2,4-difluorophenyl)-3-oxopropanimidothioate

[0101]

[0102]Intermediate 1 can be prepared using experimental procedures described in WO 2003076405.

Intermediate 2

{4-[6-Amino-5-(2,4-difluorobenzoyl)-2-oxopyridin-1(2H)y...

example 1

Cyclopentyl N-(2-{4-[6-amino-5-(2,4-difluorobenzoyl)-2-oxopyridin-1 (2H)-yl]phenyl}ethyl)-2-methylalaninate

[0141]

[0142]In this example compound of the invention, a dimethyl glycine cyclopentyl ester motif is covalently conjugated to the parent p38 MAP kinase inhibitor via the amino group of the dimethyl glycine cyclopentyl ester and through a —CH2CH2— linker radical.

[0143]The compound was synthesised using Intermediate 2 and Intermediate 3 as described below.

[0144]To a solution of Intermediate 2 (189 mg, 0514 mmol) in anhydrous THF (4 mL) were added cyclopentyl 2-methylalaninate hydrochloride (Intermediate 3) (160 mg, 0.77 mmol, 1.5 eq) and NaBH(OAc)3 (326 mg, 1.54 mmol, 3 eq). The mixture was stirred at room temperature for 16 hours, and then quenched with water (20 mL). The aqueous layer was extracted with EtOAc (3×20 mL), and the combined organic extracts washed with brine (40 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by pre...

example 2

N-(2-{4-[6-Amino-5-(2,4-difluorobenzoyl)-2-oxopyridin-1(2H)-yl]phenyl}ethyl)-2-methylalanine

[0146]

[0147]This Example relates to the carboxylic acid hydrolysis product of the compound of Example 1.

[0148]The compound was synthesised using Intermediate 2 and Intermediate 4 as described below in Scheme 6.

Stage 1—tert-Butyl N-(2-{4-[6-amino-5-(2,4-difluorobenzoyl)-2-oxopyridin-1(2H)-yl]phenyl}ethyl)-2-methylalaninate

[0149]To a solution of Intermediate 2 (180 mg, 0.489 mmol) in THF (3 mL) was added tert-butyl 2-methylalaninate (Intermediate 4) (117 mg, 0.73 mmol), stirred for 30 minutes, and then NaBH(OAc)3 (310 mg, 1.467 mmol). The reaction was stirred for 24 hours, diluted with EtOAc and the organic washed with sat NaHCO3, brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by preparative HPLC to provide the title compound (120 mg, 48% yield).

[0150]LC / MS: m / z 512 [M+H]+. 1H NMR (300 MHz, CDCl3) δ: 10.41 (1H, br s), 7.51-7.34 (4H, m), 7.28-7.26 (2H, m), 7.05-6.90 (2H...

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Abstract

Covalent conjugates of an α,α-disubstituted glycine 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 α,α-disubstituted glycine ester is conjugated to the modulator at a position remote from the binding interface between the inhibitor and the target enzyme or receptor pass into cells and the active acid hydrolysis product accumulates within the cells.

Description

[0001]This invention relates to a general method of increasing or prolonging the activity of a compound which modulates the activity of an intracellular enzyme or receptor by the covalent conjugation of an α,α-disubstituted glycine ester motif to the modulator. The invention also relates to modulators to which an α,α-disubstituted glycine ester motif has been covalently conjugated, and to a method for the identification of such conjugates having superior properties relative to the parent non-conjugated modulator. The invention further relates to the use of modulators containing α,α-disubstituted glycine ester motifs that allow the selective accumulation of amino acid conjugates inside cells of the monocyte-macrophage lineage.BACKGROUND TO THE INVENTION[0002]Many intracellular enzymes and receptors are targets for pharmaceutically useful drugs which modulate their activities by binding to their active sites. Examples appear in Table 1 below. To reach the target enzymes and receptors,...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07D213/73C12Q1/48
CPCC12Q1/485C07D213/73A61K47/542A61K31/4418A61P29/00A61P35/00A61P37/02A61P43/00A61K47/50A61K47/30
Inventor DRUMMOND, ALAN HASTINGSDAVIDSON, ALAN HORNSBYMOFFAT, DAVID FESTUS CHARLESDONALD, ALASTAIR DAVID GRAHAMDAVIES, STEPHEN JOHN
Owner GLAXOSMITHKLINE INTPROP DEV LTD
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