Salim Hadad

Pharmacokinetic Analysis and Antiepileptic Activity of Tetra-Methylcyclopropane Analogues of Valpromide

AbstractPurpose. The described structure pharmacokinetic pharmacodynamic relationships (SPPR) study explored the utilization of tetramethylcyclopropane analogues of valpromide (VPD), or tetra-methylcyclopropane carboxamide derivatives of valproic acid (VPA) as new antiepileptics. Methods. The study was carried out by investigating the pharmacokinetics in dogs and pharmacodynamics (anticonvulsant activity and neurotoxicity) of the following three cyclopropane analogues of VPD: 2,2,3,3-tetramethylcyclopropane carboxamide (TMCD), N-methyl TMCD (M-TMCD) and N-[(2,2,3,3-tetramethylcyclopropyl)carbonyl]-glycinamide (TMC-GLD). Results. The three investigated compounds showed a good anticonvulsant profile in mice and rats due to the fact that they were metabolically stable VPD analogues which were not biotransformed to their non-active acid, 2,2,3,3-tetramethylcyclopropane carboxylic acid (TMCA). M-TMCD was metabolized to TMCD and TMC-GLD underwent partial biotransformation to its glycine analogue N-[(2,2,3,3-tetramethylcyclopropyl)carbonyl]-glycine (TMC-GLN). Unlike TMC-GLN, the above mentioned amides had low clearance and a relatively long half life. Conclusions. In contrast to VPD which is biotransformed to VPA, the aforementioned cyclopropane derivatives were found to be stable to amide-acid biotransformation. TMCD and M-TMCD show that cyclic analogues of VPD, like its aliphatic isomers, must have either two substitutions at the β position to the carbonyl, such as in the case of TMCD, or a substitution in the α and in the β positions like in the VPD isomer, valnoctamide (VCD). This paper discusses the antiepileptic potential of tetramethylcyclopropane analogues of VPD which are in animal models more potent than VPA and may be non-teratogenic and non-hepatotoxic.

Pharmacokinetic Analysis and Antiepileptic Activity of N-Valproyl Derivatives of GABA and Glycine

AbstractPurpose. To explore the possibility of utilizing valproyl derivatives of GABA and glycine as new antiepileptics by using the structure pharmacokinetic-pharmacodynamic relationship (SPPR) approach. Methods. The pharmacokinetics and pharmacodynamics (anticonvulsant activity and neurotoxicity) of the following four conjugation products of valproic acid (VPA), glycine and GABA were investigated: valproyl glycine, valproyl glycinamide, valproyl GABA and valproyl gabamide. Results. Only valproyl glycinamide showed a good anticonvulsant profile in both mice and rats due to its better pharmacokinetic profile. Valproyl glycinamide was more potent than one of the major antiepileptic agents - VPA and showed a better margin between activity and neurotoxicity. Valproyl glycine and valproyl GABA were partially excreted unchanged in the urine (fe = 50% and 34%, respectively), while the urinary metabolites of the amide derivatives were valproyl glycine and valproyl GABA. Conclusions. The four investigated valproyl derivatives did not operate as chemical drug delivery systems (CDDS) of glycine or GABA, but acted rather as drugs on their own. The current study demonstrates the benefit of the SPPR approach in developing and selecting a potent antiepileptic compound in intact animals based not only on its intrinsic pharmacodynamic activity, but also on its better pharmacokinetic profile.

Can we develop improved derivatives of valproic acid

Valproic acid is one of the major antiepileptic drugs. In animal models, valproate showed less anticonvulsant potency than the other three established antiepileptic drugs: phenobarbital, phenytoin and carbamazepine. In addition, two major side-effects, teratogenicity and hepatotoxicity, have been associated with valproate Iherapy. Due to the above and the shortage of new antiepileptic drugs there is a substantial need to develop improved derivatives of valproate. This paper analyses three kinds of valproate derivatives: valpromide, the primary amide of valproate, and its analogues; monoester prodrugs of valproate and an active metabolite of valproate, 2-n-propyl-2-pentenoate. The comparative evaluation was carried out by pharmacokinetic and pharmacodynamic analyses in animals. From the data accumulated so far, we can conclude that 2-n-propyl-2-pentenoatc and/or a valpromide isomer, which does not undergo amide acid biotransformation and preferably is not an epoxide hydrolase inhibitor, may prove to be improved derivatives of the parent compound valproic acid.

Pharmacokinetic Analysis of the Structural Requirements for Forming “Stable” Analogues of Valpromide

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.

Pharmacokinetic analysis and antiepileptic activity of two new isomers of N-valproyl glycinamide.

Valproyl glycinamide (TV 1901‐VPGD) is a new antiepileptic drug, which is currently undergoing clinical trials. The present study explored the pharmacokinetics and pharmacodynamics (anticonvulsant activity and neurotoxicity) of two new isomers of valproyl glycinamide: valnoctyl glycinamide (VCGD) and diisopropylacetyl (DIGD). Both VCGD and DIGD showed anticonvulsant activity and a safety margin in mice similar to those of VPGD. Following iv administration (556 mg) to six dogs, VCGD had a clearance (Cl) value of 3·8±1·1 L h−1 (mean±SD), a volume of distribution (Vss) of 15±2 L, and a half‐life (t1/2) of 1·9±0·3 h. DIGD had Cl, Vss, and t1/2 values of 10±0·8 L h−1, 19±3 L, and 1·6±0·2 h, respectively. Neither VCGD nor DIGD operated as chemical drug delivery systems (CDDSs) of glycine, valnoctic acid, or diisopropyl acetic acid and both showed antiepileptic profiles different from that of valproic acid (VPA). Both glycinamides were biotransformed to their glycine analogues with similar fractions metabolized ( fm): 59±5% (VCGD) and 62±15% (DIGD). The two glycine metabolites, valnoctyl glycine (VCGA) and diisopropylacetyl glycine (DIGA), were also administered to the same dogs in order to calculate the above fm values.

FC27 comparative pharmacokinetic and pharmacodynamic analysis of phthaloyl glycine derivatives with potential antiepileptic activity

Glycine, in addition to GABA, is one of the most important neurotransmitter amino acids. The described structure pharmacokinetic pharmacodynamic relationships (SPPR) study explored the possibility of utilizing phthaloyl derivatives of glycine as new antiepileptics. This was carried out by investigating the pharmacokinetics and pharmacodynamics (anticonvulsant activity and neurotoxicity) of the following four phthalimide derivatives: phthaloyl glycine, phthaloyl glycinamide, N,N-diethyl phthaloyl glycinamide and N,N-diisopropyl phthaloyl glycinamide. Phthaloyl glycine did not demonstrate anticonvulsant activity, possibly because of its poor pharmacokinetics, high clearance, low volume of distribution and short half life. The three glycinamide derivatives showed anticonvulsant activity and had better pharmacokinetic profiles, longer half life and mean residence time, than phthaloyl glycine. Phthaloyl glycinamide was more potent than one of the major antiepileptic agents— valproic acid and showed a better margin between activity and neurotoxicity. The four investigated phthaloyl glycine derivatives did not operate as chemical drug delivery systems (CDDS) of glycine, but acted rather as drugs on their own. Phthaloyl glycine was excreted unchanged in the urine while the urinary metabolites of the glycinamide derivatives were phthaloyl glycine and phthaloyl glycinamide. In this analogous series of phthalimide derivatives, minor chemical changes affected dramatically the compounds’ pharmacokinetics. The current study demonstrates the benefit of the SPPR approach in developing and selecting a potent antiepileptic compound in intact animals based not only on its intrinsic pharmacodynamic activity, but also on its better pharmacokinetic profile.

Selective intracomplex reaction of pendant groups in a purine-pyrimidines base pair

Abstract Evidence is presented suggesting that hydrogen-bonded base pairing and/or aryl stacking interactions between derivatives of guanine (9-[(4-aminobutyloxy)-methyl]guanine) and cytosine (1-([(2-benzyloxy)ethoxy]methyl)cytosine) lead to enhanced intracomplex chemical reaction between the corresponding amino and ester groups. On the basis of analysis of the kinetic data it is concluded that a chain length of four methylene groups (4-amino- butyloxy as compared to 2-aminoethoxy or 6-aminohexyloxy) on the guanine is necessary to achieve the appropriate geometry for intracomplex reaction. Support for the reaction scheme is provided by the absence of reaction between the guanine derivative and a corresponding ester derivative of thymine, not expected to associate.