Functional Group Replacement

Ester - Carboxylic ester functionality is metabolically labile in vivo due to the ubiquitous presence of esterases throughout the body. This liability commonly prevents ester-containing compounds from being used as oral drugs unless the compounds were designed as "soft drugs" to achieve a desirable short duration of action. Oxazoles and oxadiazoles commonly serve as bioisosteric replacements of ester moieties with increased stability to hydrolytic degradation. (4-6),


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In the development of the cyclin-dependent kinase 2 (CDK2) inhibitors as anticancer agents, 2-amino-5-thio-substituted thiazole 1 was identified during high throughput screening with good selectivity against protein kinases A and C (7). Despite its potent CDK2 inhibitory activity, compound 1 lacks cellular activity in cell proliferation assays due to hydrolysis of the ethyl ester to the corresponding carboxylic acid that is completely devoid of CDK2 inhibitory activity. Attempts to increase the cellular stability of 1 by replacing the ethyl ester with a bioisostere oxazole moiety led to compound 2 which is metabolically stable against esterases, maintains the selectivity and shows increased CDK2 inhibitory potency, as well as potent antiproliferative activity in cancer cell lines.

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