TY - JOUR
T1 - Pharmacokinetic Analysis of the Structural Requirements for Forming “Stable” Analogues of Valpromide
AU - Haj-Yehia, Abdulla
AU - Hadad, Salim
AU - Bialer, Meir
PY - 1992/8
Y1 - 1992/8
N2 - The following valpromide (VPD) analogues were synthesized and their structure-pharmacokinetic relationships explored: 3-ethyl pentanamide (EPD), methylneopentylacetamide (MND), 1-methyl cyclohexanecarboxamide (MCD), cycloheptanecarboxamide (CHD), and t-butylacetamide (TBD). Two aliphatic (EPD and MND) and two cyclic amides (MCD and CHD) underwent complete or partial conversion to their corresponding acids. The only amide found in this study to be “stable” to the amide-acid biotransformation was TBD. It also had the lowest clearance and the longest half-life and mean residence time. Unlike the other investigated amides, TBD contained two substitutions of two methyl moieties at the β position of its chemical structure. A “stable” valpromide analogue must have either two substitutions at the β position, such as in the case of TBD, or a substitution in the α and β positions, such as in the case of the VPD isomer valnoctamide (VCD). This paper discusses the antiepileptic potential of stable VPD analogues which may be more potent and less teratogenic than their biotransformed isomers.
AB - The following valpromide (VPD) analogues were synthesized and their structure-pharmacokinetic relationships explored: 3-ethyl pentanamide (EPD), methylneopentylacetamide (MND), 1-methyl cyclohexanecarboxamide (MCD), cycloheptanecarboxamide (CHD), and t-butylacetamide (TBD). Two aliphatic (EPD and MND) and two cyclic amides (MCD and CHD) underwent complete or partial conversion to their corresponding acids. The only amide found in this study to be “stable” to the amide-acid biotransformation was TBD. It also had the lowest clearance and the longest half-life and mean residence time. Unlike the other investigated amides, TBD contained two substitutions of two methyl moieties at the β position of its chemical structure. A “stable” valpromide analogue must have either two substitutions at the β position, such as in the case of TBD, or a substitution in the α and β positions, such as in the case of the VPD isomer valnoctamide (VCD). This paper discusses the antiepileptic potential of stable VPD analogues which may be more potent and less teratogenic than their biotransformed isomers.
KW - pharmacokinetics
KW - stable analogues
KW - structural requirements
KW - valpromide
UR - http://www.scopus.com/inward/record.url?scp=0026733527&partnerID=8YFLogxK
U2 - 10.1023/A:1015862613315
DO - 10.1023/A:1015862613315
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C2 - 1409378
AN - SCOPUS:0026733527
SN - 0724-8741
VL - 9
SP - 1058
EP - 1063
JO - Pharmaceutical Research
JF - Pharmaceutical Research
IS - 8
ER -