Evaluating prodrug strategies for esterase-triggered release of alcohols.

Abstract:

:Prodrugs are effective tools in overcoming drawbacks typically associated with drug formulation and delivery. Those employing esterase-triggered functional groups are frequently utilized to mask polar carboxylic acids and phenols, increasing drug-like properties such as lipophilicity. Herein we detail a comprehensive assessment for strategies that effectively release hydroxy and phenolic moieties in the presence of an esterase. Matrix metalloproteinases (MMPs) serve as our proof-of-concept target. Three distinct ester-responsive protecting groups are incorporated into MMP proinhibitors containing hydroxy moieties. Analytical evaluation of the proinhibitors demonstrates that the use of a benzyl ether group appended to the esterase trigger leads to considerably faster kinetics of conversion and enhanced aqueous stability when compared with more conventional approaches where the trigger is directly attached to the inhibitor. Biological assays confirm that all protecting groups effectively cleave in the presence of esterase to generate the active inhibitor. The superior reaction-based prodrug strategies presented here should serve as a platform for esterase-responsive prodrug design in the future.

journal_name

ChemMedChem

journal_title

ChemMedChem

authors

Perez C,Daniel KB,Cohen SM

doi

10.1002/cmdc.201300255

subject

Has Abstract

pub_date

2013-10-01 00:00:00

pages

1662-7

issue

10

eissn

1860-7179

issn

1860-7187

journal_volume

8

pub_type

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