2336
C. E. Burgos-Lepley et al. / Bioorg. Med. Chem. Lett. 16 (2006) 2333–2336
Table 3. Rat pharmacokinetic parameters for gabapentin 1 and
tetrazole 14b
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Schwarz, J. B.; Gibbons, S. E.; Graham, S. R.; Colbry,
N. L.; Guzzo, P. R.; Le, V.-D.; Vartanian, M. G.;
Kinsora, J. J.; Lotarski, S. M.; Li, Z.; Dickerson, M. R.;
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Parameter
Gabapentin 1
Tetrazole 14b
Bioavailability (%F)
Clearance (mL/min/kg)
76
85
6.0
1.5
8.6
0.65
10.6
1.0
Plasma half-life (t1/2
AUCa (lg h/mL)
Vdb (L/kg)
)
5.2
0.38
a Area under the concentration versus time curve.
b Volume of distribution.
9. (a) Stearns, B. A.; Anker, N.; Arruda, J. M.; Campbell, B.
T.; Chen, C.; Cramer, M.; Hu, T.; Jiang, X.; Park, K.;
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A
comparison of rat pharmacokinetic data for
compound 14b and gabapentin 1 is outlined in Table
3. Like gabapentin, compound 14b had good oral
bioavailability. However, the tetrazole 14b was more
rapidly cleared from plasma and as a consequence had
a shorter plasma half-life than gabapentin.
4. Conclusion
Bioisosteric replacements have been commonly used in
drug discovery to optimize drug-like properties such as
solubility, absorption, distribution, and/or clearance.
Attempts to introduce a traditional carboxylic acid
replacement to gabapentin 1 such as sulfinate, phosphi-
nate, or sulfonate were unsuccessful, in that binding of
these analogs to the a2-d protein was abolished. How-
ever, when a tetrazole group was employed as the
isostere, affinity for a2-d was retained, as demonstrated
by 14a. In addition, comparable efficacy against seizures
was observed in vivo for 14a and 14b compared to pre-
gabalin 2. However, when the acidic tetrazole proton
was replaced by N-Me (cf. 17), no binding to a2-d was
observed, underscoring the importance of the acidic
functionality for activity. Similarly, acyclic tetrazole 21
had approximately 16-fold weaker affinity for a2-d than
14b. Further characterization of compound 14b revealed
it had similar in vitro and in vivo potency, as well as
bioavailability when compared to gabapentin 1.
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