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(12) Hauck, R.-S., Elmazar, M. M. A., Plum, C., and Nau, H. (1992)
The enantioselective teratogenicity of 2-n-propyl-4-pentynoic acid
(4-yn-VPA) is due to stereoselective intrinsic activity and not
differences in pharmacokinetics. Toxicol. Lett. 60, 145-153.
(13) Andrews, J . E., Ebron-McCoy, M., Bojic, U., Nau, H., and Kavlock,
R. J .. (1995) Validation of an in vitro teratology system using
chiral substances: Stereoselective teratogenicity of 4-yn-valproic
acid in cultured mouse embryos. Toxicol. Appl. Pharmacol. 132,
310-316.
(14) Elmazar, M. M. A., Hauck, R.-S., and Nau, H. (1993) Anticon-
vulsant and neurotoxic activities of twelve analogues of valproic
acid. J . Pharm. Sci. 82, 1255-1258.
(15) Palaty, J ., and Abbott, S. (1995) Structure-activity relationships
of unsaturated analogues of valproic acid. J . Med. Chem. 38,
3398-3406.
(16) Nau, H., and Scott, W. J . (1986) Weak acids may act as teratogens
by accumulating in the basic milieu of the early mammalian
embryo. Nature 323, 276-278.
(17) Wegner, Ch., and Nau, H. (1992) Alteration of embryonic folate
metabolism by valproic acid during organogenesis: Implications
for mechanism of teratogenesis. Neurology 42 (Suppl. 5), 17-24.
(18) Fisher, E., Wittfoht, W., and Nau, H. (1992) Quantitative deter-
mination of valproic acid and 14 metabolites in serum and urine
by gas chromatography/mass spectrometry. Biomed. Chromatogr.
6, 24-29.
noted that the sedative activity is influenced more
specifically by the spatial arrangements of the molecules
than the anticonvulsant activity. This could mean that
sedation caused by this class of compounds is not solely
dictated by unspecific interactions. On the other hand,
it could well be that neither log P values nor a partition
system (RM) always correctly represent lipophilicity in a
biological system. Perhaps a correlation of anticonvul-
sant potency and neurotoxicity with other lipophilicity
descriptors should be tried with this class of carboxylic
acids. In the present series of compounds, the most
favorable ratio between desirable pharmacological effect
and unwanted side effect is obtained for substances with
methyl-branching in position 4 and C log P values of
around 2.6.
Other differences in the activities of the substances
tested may be due to pharmacokinetics, a subject which
is presently under investigation. Furthermore, studies
on structure-activity relationships should also be carried
out in regard to the hepatotoxic potential of these new
analogues (31, 32).
(19) Still, W. C., Kahn, M., and Mitra, A. (1978) Rapid chromato-
graphic technique for preparative separations with moderate
resolution. J . Org. Chem. 43, 2923-2925.
(20) Fischer, E., Holzapfel, J ., and Gewinner v., H. (1912) U¨ ber optisch-
aktive Dialkyl-essigsa¨uren (On optically active dialkylacetic
acids). Chem. Ber. 45, 247-257.
(21) Meerwein, H. (1919) U¨ ber die wechselnde Affinita¨tsbeanspru-
chung aliphatischer Radikale (Fu¨nfte Mitteilung u¨ber Pinakoli-
numlagerungen) (On the changing affinities of aliphatic radicals
(5th report on pinacoline rearrangement)). Liebigs Ann. Chem.
419, 121-175.
(22) Tiffenau, M. (1923) Sur quelques nouveaux acides dialcoylbarbi-
turiques disssyme´triques. I. Se´rie e´thylalcoyle´e (On some new
asymmetric dialkylbarbituric acids. I. Ethylalkyl series). Bull.
Soc. Chim. Fr. 33, 183-188.
(23) Cerbai, G., Turbanti, L., Tellini, N., Fabrizi, P., and Dell’Omodarme,
G. (1871) Derivati acetilenici ad attivitia antispastica Nota
IIsAminoesteri dell’acido propilpropargilacetico (Acetylenic de-
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of propyl-propargylacetic acids). Farmaco, Ed. Sci. 27, 217-234.
(24) Moura Campos de, M., and Amaral do, L. (1965) Neighboring
group participation in addition reactions. VI. Lactonization of
4-pentenoic acid by iodine. Arch. Pharm. 298, 92-100.
(25) Darzens, G. (1926) Me´thode de pre´paration de vale´rolactones R
substitue´e (A method for preparation of R-substituted valerolac-
tones). Comp.rend.hebd.se´a.acad.sie´. 183, 111.
Ack n ow led gm en t. This work was supported by a
grant from the Alexander von Humboldt-Stiftung to
M.M.A.E., and by a grant from the BgVV Berlin (ZE-
BET), by American Biogenetic Sciences, and by the
European Commission (Biotech Programme BIO2-CT93-
0471).
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