Cyclopropanecarboxylic acid esters as potential prodrugs with enhanced hydrolytic stability

Article abstract of DOI:10.1021/ol702892e

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 °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.

Full text of DOI:10.1021/ol702892e

ORGANIC
LETTERS
2008
Vol. 10, No. 3
509-511
Cyclopropanecarboxylic Acid Esters as
Potential Prodrugs with Enhanced
Hydrolytic Stability
David M. Bender,† Jeffrey A. Peterson,† James R. McCarthy,*,† Hakan Gunaydin,‡
Yu Takano,‡ and K. N. Houk*,‡
Eli Lilly and Co., Lilly Corporate Center, Indianapolis, Indiana 46285, and
Department of Chemistry and Biochemistry, UniVersity of California,
Los Angeles, California 90095
mccarthy_james@lilly.com; houk@chem.ucla.edu
Received December 3, 2007
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 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.
Prodrugs with ester functionalities have the significant
potential to increase the oral availability of otherwise potent
orally unavailable therapeutics.1,2 For example, the antiviral
agent valacyclovir (Valtrex) is the L-valine ester of the parent
compound acyclovir. The ester has increased the oral
bioavailability of this drug by 5-fold relative to acyclovir
via recognition and active transport by the human peptide
transporter hPepT1.3 This type of prodrug strategy has also
been employed with nucleosides, and there are currently 20
such drugs reported in the literature.4,5 One such example is
Hoe-961, which is an orally active acetate prodrug of a novel
antiviral agent for the treatment of HSV.6
We have found that cyclopropanecarboxylic acid esters
can be used as prodrugs that can provide increased stability
in the acidic environment of the stomach and the alkaline
conditions present in the intestine. Increased stability should
result in better absorption of the intact prodrug into the
plasma. The cyclopropyl group has unique conjugating
properties that make it similar to a carbon-carbon double
bond in its interaction with adjacent π-electron systems.7 This
† Eli Lilly and Co.
‡ University of California.
(1) (a) March, J. AdVanced Organic Chemistry: Reactions, Mechanisms,
and Structure, 4th ed.; John Wiley & Sons: New York, 1992; pp 378-
383. (b) Kirby, A. J. In ComprehensiVe Chemical Kinetics; Bamford, T.,
Ed.; Elsevier Publishing Co.: Amsterdam/New York, 1972; Vol. 10, pp
57-207. (c) Euranto, E. K. In The Chemistry of Carboxylic Acids and
Esters; Patai, S., Ed.; Wiley: New York, 1969; pp 505-588.
(2) (a) Testa, B.; Mayer, J. M. Hydrolysis in Drug and Prodrug
Metabolism: Chemistry, Biochemistry, and Enzymology; Wiley-VCH
GmbH: Weinheim, Germany, 2003. (b) Beaumont, K.; Webster, R.;
Gardner, L.; Dack, K. Curr. Drug Metab. 2003, 4, 461-485. (c) Ettmayer,
P.; Amidon, G. L.; Clement, B.; Teata, B. J. Med. Chem. 2004, 47, 2393-
2404.
(4) Mackman, R. L.; Cihlar, T. Ann. Rep. Med. Chem. 2004, 39, 305-
321.
(5) (a) McCarthy, J. R.; Jarvi, E. T.; Matthews, D. P.; Edwards, M. L.;
Prakash, N. J.; Bowlin, T. L.; Mehdi, S.; Bey, P. J. Am. Chem. Soc. 1989,
111, 1127-1128. (b) McCarthy, J. R.; Matthews, D. P.; Stemerick, D. M.;
Huber, E. W.; Bey, P.; Lippert, B. J.; Snyder, R. D.; Sunkara, P. S. J. Am.
Chem. Soc. 1991, 113, 7439-7440.
(6) Smee, D. F.; Morrison, A. C.; Bailey, K. W.; Sidwell, R. W. 41st
Intersci. Conf. Antimicrob. Agents Chemother., Chicago, IL, Dec 16-19
2001, Abstract 1594.
(3) Weller, S.; Blum, M.; Douchette, M. Clin. Pharmacol. Ther. 1993,
54, 595-605.
10.1021/ol702892e CCC: $40.75
© 2008 American Chemical Society
Published on Web 01/09/2008

can provide increased stability to hydrolytic conditions with-
out the disadvantages of benzoate esters.2b While the hy-
drolysis and transport properties of cyclopropyl esters of â
adrenergic receptor blockers have been reported, the utility
of these compounds as prodrugs is based on the higher per-
meability of the esters as compared to the parent molecules.8
We have found that esters of cyclopropanecarboxylic acid
demonstrate a substantial increase in stability under both
acid- and base-catalyzed hydrolytic conditions relative to
related esters. The increase in the stability of some cyclo-
propanecarboxylic acid esters under the physiological condi-
tions were reported earlier by Bodor.9 Table 1 shows the
than cyclopentanecarboxylic acid ester, 5a. The contrast is
even greater for the cyclobutane analogue 4a, where the t1/2
is only 14.1 h in 0.1 N HCl and 16.0 h in pH 10 buffer.
While the benzoate ester 7a is less stable in pH 10 buffer
than the cyclopropanecarboxylic acid ester 1a (t1/2 ) 55.4 h
vs 78.7 h, respectively), it is more stable in 0.1 N HCl. The
cyclohexanecarboxylate ester 6a is slightly more stable than
1a in pH 10 buffer (87 h vs 78.7 h). Comparing the more
sterically hindered pivalic acid ester 8a, with 1-methyl-
cyclopropanecarboxylic acid benzyl ester 10a, the cyclopro-
pane ester is more than twice as stable in acid (t1/2 ) 267.5
h vs 125.7 h) and 1.3 times more stable in pH 10 buffer.
This trend holds for amino acid derivatives 11a vs 12a as
well. Both amino acids are stable under acidic conditions,
but the cyclopropane analog 11a is almost six times more
stable (t1/2 ) 7.8 h vs 43.1 h) in pH 10 buffer.
Table 1. Half-lives for the Hydrolysis of Esters
The advantage of the increased stability of cyclopropane
derivatives of amino acid esters under hydrolytic conditions
for the design of a suitable prodrug is highlighted by
comparing the stability of valacyclovir 13 with the cyclo-
propane analog 14 (Table 2). At 40 °C, the half-life of the
Table 2. Hydrolysis Rates of 13 and Cyclopropane Derivative
14
cyclopropane amino acid ester at pH 6 is >300 h while the
value for valacyclovir is 69.7 h. This trend holds at pH 8
and pH 10 as well. The enhancement in chemical stability
is very important in terms of drug development potential.
Anand and co-workers10 note that acyclovir would be a
suitable drug for the treatment of herpes simplex keratitis,
the leading cause of blindness in the United States,10 but
the corneal permeability is very low. Valacyclovir has much
better permeability, but the half-life in aqueous buffer is
unsatisfactory for an ophthalmic solution. This issue could
be overcome with the cyclopropane prodrug 14, where the
half-life in pH 6 buffer at 5 °C is 352 days.11
We hypothesize that hyperconjugative stabilization of
cyclopropanecarboxylic acid esters is responsible for the
increased hydrolytic stability of these esters. In order to
quantitate the stabilization of cyclopropanecarboxylic acid
esters compared to other esters, the isodesmic reactions
shown in Table 3 were computed at the CBS-QB3 level.
Cyclopropanecarboxylic acid esters are stabilized by about
half-lives determined here for benzyl cyclopropanecarboxy-
late esters 1a, 10a, and 11a in 0.1 N HCl and pH 10 buffers
at 40 °C compared to several other related esters. Benzyl
cyclopropanecarboxylate 1a is substantially (six times) more
stable than the open-chain isopropyl analogue 3a in 0.1 N
HCl at 40 °C (t1/2 ) 180.2 h vs 32.1 h) and almost twice as
stable in pH 10 buffer (t1/2 ) 78.7 h vs 40.0 h). This
cyclopropanecarboxylic acid ester is similarly more stable
(7) (a) de Meijere, A. Angew. Chem., Int. Ed. 1970, 18, 809-826. (b)
Fuchs, R.; Bloomfield, J. J. J. Org. Chem. 1963, 28, 910-912. (c) Wiberg,
K. B.; Hadad, C. M.; Rablen, P. R.; Cioslowski, J. J. Am. Chem. Soc. 1992,
114, 8644-8654.
(8) Hovgaard, L.; Brondsted, H.; Buur, A.; Bundgaaard, H. Pharm. Res.
1995, 12, 387-392.
(9) . Bodor, N. J. Med. Chem. 1980, 23, 474-480.
(10) Anand, B. S.; Nashed, Y. E.; Mitra, A. K. Curr. Eye Res. 2003, 26,
151-163.
(11) Extrapolated from the Arrhenius plot; see the Supporting Informa-
tion.
510
Org. Lett., Vol. 10, No. 3, 2008

configurational space of the TIP4P water molecules was
explored with a MC sampling where equilibration runs of
2.5 M configurations were followed by production runs of
4 M configurations.12
Table 3. Energies of Stabilization upon Replacement of H by
R and Relative Energies of the gem-Diol Intermediates with
Respect to Reactants and a Water Molecule
These TSs were re-optimized at the B3LYP/6-31+G(d)
level with CPCM solvation corrections by constraining the
TS distances to those obtained from FEP calculations. These
B3LYP/6-31+G(d) free energies are given in Table 4. The
R
∆H(CBS-QB3) ∆H(B3LYP) ∆H(B3LYP-gem-diol)
cyclopropyl
methyl
-12.6
-10.2
-9.2
-10.1
-10.4
-10.0
-10.9
-11.6
-9.2
-7.5
-8.9
-8.8
-8.2
-9.4
13.8
11.1
11.1
10.2
10.7
10.9
14.3
Table 4. Activation Free Energies for Reactions of 1b and
4b-7b
isopropyl
cyclobutyl
cyclopentyl
cyclohexyl
phenyl
substrate
TS1-B3LYP
intermediate
TS2-B3LYP
1b
4b
5b
6b
7b
24.0
23.1
24.2
24.7
21.3
19.0
17.6
18.8
19.4
16.0
27.2
23.2
24.9
24.6
23.9
2 kcal/mol more than other alkyl esters; this must arise by
hyperconjugative donation from the cyclopropane group into
the π*CO orbital. This is interrupted in the tetrahedral
intermediate formed in the acid- and base-promoted hydroly-
sis reactions. This is consistent with the calculations on
conjugation in cyclopropanecarboxylic acid ester derivatives.7b
Stabilization has been attributed to the electrostatic stabiliza-
tion of the carbonyl bond by the cyclopropyl group as well.7c
The activation free energies for base-promoted hydrolysis
of cyclic esters 1b and 4b-7b were investigated with a
combination of QM/MM/MC free energy perturbation (FEP)
calculations and B3LYP/6-31+G(d) calculations.12 Transition
states (TS) TS1 and TS2 (Figure 1) were located with the
root-mean-square error between B3LYP/6-31+G(d) com-
puted activation free energies for substrates 1b and 4b-7b
and experimental activation free energies for substrates 1a
and 4a-7a was 0.8 kcal/mol. Substrate 1b is the most stable
substrate, which is also consistent with the result of the
isodesmic reactions. Since the increase in the activation free
energy for substrates 1b and 4b-7b does not correlate with
the size of the substituents, steric effects are not expected to
be responsible for the slow hydrolysis of 1b. The stability
of ester 1b results from the larger activation free energy for
the base-promoted hydrolysis, since the TS lacks the hyper-
conjugative stabilization. This same principle applies to the
acid-catalyzed hydrolysis.
In summary, the significant stability of cyclopropane esters
can be attributed to a hyperconjugative stabilization particular
to this group. The utility of the stabilization is currently being
studied in the design of prodrug esters that can be beneficial
for delivering active drugs in man.
Figure 1. Schematic diagram of the competing reaction pathways.
Acknowledgment. We thank Dr. Robert W. Armstrong
(Eli Lilly and Co.) and Dr. Jon A. Erickson (Eli Lilly and
Co.) for useful discussions regarding this work. K.N.H.
thanks the National Science Foundation for financial support,
and Y.T. thanks the JSPS for a fellowship.
FEP calculations in a box of 750 TIP4P water molecules
from which one water molecule was removed for each heavy
atom in the solutes to make space for the solutes. The QM
region was described with the semiempirical PDDG/PM3
method, and the reaction coordinate was explored with 0.02
Å increments starting from 5 Å separated reactants. The
Supporting Information Available: Experimental pro-
cedures for compounds, descriptions of computational meth-
ods, and coordinates of computed structures. This material
is available free of charge via the Internet at http://pubs.acs.org.
(12) Gunaydin, H.; Acevedo, O.; Jorgensen, W. L.; Houk, K. N. J. Chem.
Theory Comput. 2007, 3, 1028-1035.
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