Technology Opportunities

Commercial Advantages:

An individual stereoisomer of valnoctamide (VCD - I) or propylisopropyl acetamide (PID- II), has the potential to become better and superior to the commercially available racemic VCD (a mixture of four stereoisomers). The same is applicable to propylisopropyl acetamide (PID II). A VCD or PID individual stereoisomer will be more potent than racemic VCD, will be non-teratogenic and will lack epoxide hydrolase inhibition which is associated with the therapy of VCD therapy, its isomer valpromide (VPD - III) and valproic acid (VPA - IV).

General Background:

Racemic VCD (I) is an over-the counter (OTC) tranquilizer which has been available clinically for three decades in several European countries. Recently, interest in VCD (I) and its isomer PID (II) was revived due to the observation that these compounds possess marked anticonvulsant activity in classical animal models during the preclinical antiepileptic screening (1). Such a finding was not surprising since VCD is an isomer of the antiepileptic agent VPD (III) - the primary amide of a major antiepileptic drug VPA (IV).
VCD, PID and VPD in mice or rats (1) are 3-20 times more potent than VPA as antiepileptics. In addition, VPD and VCD, unlike VPA, have not been found to be teratogenic in mice since they contain a carboxamido moiety instead of a free carboxylic acid (2,3). However, in humans VPD acts as a prodrug of VPA and therefore, its superiority over VPA in animal models does not have clinical implications (4).

Unlike VPD, VCD acts as a drug on its own in both animal and man, and undergoes in humans only slow and very minor biotransformation to its corresponding (less active) acid, valnoctic acid (VCA). Similarly to VCD, in dogs, PID does not undergo metabolic hydrolysis to its corresponding acid, propylisopropyl acetic acid (PIA) (5). Based on its anticonvulsant potency, commercial availability as an anxiolytic agent, metabolic stability and lack of teratogenicity, VCD was viewed as having the potential to become a new antiepileptic drug. It was found however, that VCD is an inhibitor of an important detoxifying enzyme epoxide hydrolase (6). This discovery is a major drawback to the application of the racemic VCD as a new antiepileptic drug. Preliminary results indicated that racemic PID in active concentrations is also capable of inhibiting the enzyme epoxide hydrolase.

Since PID and VCD have one and two chiral centers, respectively, they are a mixture of one and two pairs of enantiomers, respectively (Figure 1). Thus, there is a good possibility that the pharmacokinetics and pharmacodynamics of the individual stereoisomers as well as their side effects including epoxide hydrolase inhibition, are stereoselective. Pharmacokinetic stereoselectivity alone, could lead to pharmacodynamic stereoselectivity which would have considerable clinical implications for further development of VCD and/or PID.

Current status:

Based on this background, a new stereoselctive gas chromatography-mass spectrometry (GC-MS) assay has been developed which allows for the specific and sensitive quantification of four VCD and two PID stereoisomers. This assay of the quantification of VCD in the four VCD stereoisomers was recently employed in a pharmacokinetic study of healthy subjects and epileptic patients (7). The results of this study indeed showed that the pharmacokinetics of VCD is stereoselective (7).

The differences in the pharmacokinetics of the individual VCD stereoisomers increase the likelihood that differences also exist in their antiepileptic and anxiolytic activity as well as in the side effects associated with (racemic) VCD therapy, and specifically in epoxide hydrolase inhibition (6). The same might be true for PID individual stereoisomers.

We recently synthesized the two PID enantiomers (R)-PID and (S)-PID and two VCD stereoisomers: (2R,3S)-VCD and (2S,3S)-VCD and established their absolute configuration by X-ray analysis. The pharmacodynamic analysis of the individual PID and VCD stereoisomers, including epoxide hydrolase inhibition and teratogenicity, are currently in progress. Synthesis of (2S, 3R)-VCD and (2R, 3R)-VCD are close to completion. These individual VCD stereoisomers will be used for further pharmacological and toxicological testing.

A patent on this subject has been filed worldwide.

Future Plans:

To conduct a series of acute and subacute toxicological studies on the most promising stereoisomers of VCD and PID which are mandatory before clinical phase I.

Application & Potential Market:

Pharmaceuticals.

CONH₂ CONH₂

valnoctamide-VCD (I) propylisopropyl acetamide-PID (II)

CONH₂ COOH

valpromide (III) valproic acid (IV)

CONH₂ CONH₂

(2S,3S)-VCD (2R,3R)-VCD

CONH₂ CONH₂

(2S,3R)-VCD (2R,3S)-VCD

CONH₂ CONH₂

(2R)-PID (2S)-PID

Figure 1. Structure of VCD (4 stereoisomers), PID (2 enantiomers) VPD and VPA

References:

1) Bialer M., Haj-Yehia A., Badir K. and Hadad S. Can we develop improved derivatives of valproic acid? Pharm. World Sci. 16:2-6 (1994).

2) Radatz M., Ehlers K., Yagen B., Bialer M. and Nau H. Valnoctamide, valpromide and valnoctic acid are much less teratogenic in mice than valproic acid. Epilepsy Res. In press (1998).

3) Nau H. and Hendrickx A.G. Valproic acid teratogenesis. ISI Atlas Sci. Pharmacol. 1:52-56 (1987).

4) Bialer M. Clinical pharmacology of valpromide. Clin. Pharmacokinet. 20:114-122 (1991).

5) Haj-Yehia A. and Bialer M. Structure-pharmacokinetic relationships in a series of valpromide isomers with antiepileptic activity. Pharm. Res. 6:238-244 (1989).

6) Pisani F., Haj-Yehia A., Fazio F., Artesi C., Oteri G., Perucca E., Koertz D., Levy R.H. and Bialer M. Carbamazepine-valnoctamide interaction in epileptic patients: in vitro/in vivo correlation. Epilepsia 34:954-959 (1993).

7) Barel S., Yagen B., Schurig V., Soback S., Pisani F., Perucca E. and Bialer M. Stereoselctive pharmacokinetic analysis of valnoctamide in healthy subjects and epileptic patients. Clin. Pharmacol Ther. 61:442-449 (1997).