Cyclopropanecarboxylic acid esters as potential prodrugs with enhanced hydrolytic stability.
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.
Bender
David M
DM
Eli Lilly and Co., Lilly Corporate Center, Indianapolis, Indiana 46285, USA.
Peterson
Jeffrey A
JA
McCarthy
James R
JR
Gunaydin
Hakan
H
Takano
Yu
Y
Houk
K N
KN
D000212:Acyclovir / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D000998:Antiviral Agents / Q000737:chemistry* / Q000494:pharmacology; D003521:Cyclopropanes / Q000737:chemistry* / Q000494:pharmacology; D004952:Esters; D006868:Hydrolysis; D015394:Molecular Structure; D011355:Prodrugs / Q000737:chemistry* / Q000494:pharmacology; D000077483:Valacyclovir; D014633:Valine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology
D000998:Antiviral Agents; D003521:Cyclopropanes; D004952:Esters; D011355:Prodrugs; C015766:cyclopropanecarboxylic acid; C030797:cyclopropane; D014633:Valine; D000077483:Valacyclovir; D000212:Acyclovir