Cyclopropanecarboxylic acid esters as potential prodrugs with enhanced hydrolytic stability |
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Authors: | Bender David M Peterson Jeffrey A McCarthy James R Gunaydin Hakan Takano Yu Houk K N |
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Institution: | Eli Lilly and Co., Lilly Corporate Center, Indianapolis, Indiana 46285, USA. |
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Abstract: | Esters of cyclopropanecarboxylic acid demonstrate a substantial increase in stability under both acid- and base-catalyzed hydrolytic conditions. Comparison of the stability of valacyclovir 13 with the cyclopropane analogue 14 shows that at 40 degrees C and pH 6 the half-life of 14 is >300 h while the value for 13 is 69.7 h. CBS-QB3 calculations on isodesmic reactions for transfer of groups from an alkane to an ester show that a cyclopropyl group provides hyperconjugative stabilization. |
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