Jakob Shimshoni PhD Lecture

1. Pharmacokinetic-Based Design of
New CNS-Active Analogs of
Valproic Acid Derivatives with
Improved Potency and Low-
Toxicity
Jakob Avi ShimshoniJakob Avi Shimshoni
Supervisors: Prof. Meir Bialer & Prof. Boris YagenSupervisors: Prof. Meir Bialer & Prof. Boris Yagen

2. OutlineOutline
Common features of epilepsy and bipolar disorder
Part I
Epilepsy and antiepileptic drugsEpilepsy and antiepileptic drugs
 Valproic acid and its major side-effectsValproic acid and its major side-effects
Study objectives and resultsStudy objectives and results
Part II
Bipolar disorder and drug treatment thereofBipolar disorder and drug treatment thereof
 Molecular targets of mood-stabilizers and theirMolecular targets of mood-stabilizers and their
effect on growth cone behavioreffect on growth cone behavior
Study objectives and resultsStudy objectives and results

3. Common Features of Epilepsy & Bipolar
Disorder
 Both disorders respond to several identical drugs :
 Gradual progression in intensity and frequency of epileptic
seizures and manic-depressive episodes
 20-40% of bipolar and epileptic patients are resistant to
current drug-therapy
Amann et al, Epilepsia, 2005
N
C NH2O
Valproic AcidCarbamazepine Lamotrigine

4.  Common neurological condition occurring in
about 1% of the global population
 Characterized by periodic and unpredictable
occurrence of seizures, due to disordered,
synchronous firing of a population of brain
neurons
 Classification into partial seizure and generalized
seizure
Part I: Epilepsy

5. Antiepileptic Drugs (AEDs)
Old DrugsOld Drugs New DrugsNew Drugs
CarbamazepineCarbamazepine
PhenobarbitalPhenobarbital
PhenytoinPhenytoin
Valproic AcidValproic Acid
FelbamateFelbamate
GabapentinGabapentin
LamotrigineLamotrigine
LevetiracetamLevetiracetam
OxcarbazepineOxcarbazepine
PregabalinPregabalin
RufinamideRufinamide
StiripentolStiripentol
TiagabineTiagabine
TopiramateTopiramate
VigabatrinVigabatrin
ZonisamideZonisamide

6. Valproic Acid (VPA)
COOH
 Efficient in many types of epilepsy
 Migraine prophylaxis
 Bipolar disorder
 Major rare side effects:
hepatotoxicity & teratogenicity

7. VPA-Induced Fatal HepatotoxicityVPA-Induced Fatal Hepatotoxicity
Worldwide till 1999:Worldwide till 1999:
179 cases of fatal179 cases of fatal
hepatotoxicityhepatotoxicity
Risk Factors of Fatal Hepatic FailureRisk Factors of Fatal Hepatic Failure
Children under the age of two
Polytherapy
Metabolic disturbances and
liver disease
Chang et al, Drug Metab Rev, 2006Chang et al, Drug Metab Rev, 2006
COOH COOH
CYP2A6CYP2A6
CYP2C9CYP2C9
ββ-oxidation-oxidation ββ-oxidation-oxidation
COOHCOOH
VPAVPA
2-ene2-ene
VPAVPA
4-ene VPA4-ene VPA
2,4-diene2,4-diene
VPAVPA
CYP450CYP450
ffmm= 0.5-1%= 0.5-1%

8. COOH COOH
VPAVPA
2,2,3,3-tetramethylcyclopropane-
carboxylic acid (TMCA)
Quaternary Carbons & Acylurea containing
compounds & Hepatotoxicity
CONHCONH2
3,3-dimethylbutanoylurea (DBU)

9. VPA-Induced Teratogenicity
Finnell et al, Epilepsia, 2003; Sankar, Acta Neurol Scan, 2007Finnell et al, Epilepsia, 2003; Sankar, Acta Neurol Scan, 2007
 Major malformations associated VPA therapy:
abnormalities of the skeleton, CNS,
cardiovascular and urogenital system
Neural Tube Defects (NTD):
10-20 fold increased risk
Mechanism of VPA-Induced Teratogenicity
Inhibition of folate metabolism
HDAC-inhibition
Inhibition of neuroepithelial proliferation
Formation of cytotoxic, teratogenic metabolites:
2,4-diene-VPA, 4-ene-VPA

10. VPA Constitutional Isomers, Amide
derivatives and Teratogenicity
Radatz et alRadatz et al, Epilepsy Res, 1998; Isoherranen et alIsoherranen et al, Epilepsia, 2002
VPA
ValpromideValpromide
COOH
COOH
Valnoctic Acid
CONH2COOH
Propylisopropyl acetic Acid

11. AEDs Containing Urea Moiety in Their
Structure
NH
H
N OO
H3C
O
NH
H
N
O
O
N
CO NH2
CH2CONHCONH2 CHCONHCONH2
C2H5
PhenobarbitalPhenobarbital PhenytoinPhenytoin CarbamazepineCarbamazepine
PhenacemidePhenacemide PheneturidePheneturide
CONHCONH2
TMCUTMCU

12. Study Objectives: Part I
 Design and synthesis of urea derivatives of VPA
constitutional isomers and homologs
 Evaluation of anticonvulsant activity, neurotoxicity
and teratogenicity of the above compounds
 PK study of the most potent and safe candidate among
the urea derivatives

13. Maximal
Electroshock
Seizures (MES)
Animal Models of Epilepsy
sc Metrazole
(scMet)
Identifies drugs effective
against generalized seizures;
seizure spread inhibition
Identifies drugs effective against
absence seizures; increase in seizure
threshold
Mice : Rotated rod
Rats : Positional sense test
6Hz psychomotor
seizure test
Identifies drugs effective against
therapy- resistant epilepsy
Neurotoxicity

14. Synthesis of Urea Derivatives of VPA
Constitutional Isomers
R1 C
O
OH
LDA, THF
R1 C
O-
O-
2Li+
R1 C
O
OH
R2
R1 C
O
Cl
R2
UREA, ACN R1 C
O
NHCONH2
R2
R-I
SOCl2
CONHCONH2
VPU
CONHCONH2
VCU
CONHCONH2
DIU
CONHCONH2
PIU
CONHCONH2
R-PIU
CONHCONH2
S-PIU
CONHCONH2
OCU
Shimshoni et alet al, J Med Chem, 2007
*

15. Shimshoni et alShimshoni et al, J Med Chem, 2007
Anticonvulsant Activity and Toxicity
CONHCONH2
PIU
CONHCONH2
VCU
CONHCONH2
DIU
∗ Significantly different from the corresponding amide (p<0.05); $ significantly different from the corresponding
enantiomer (p<0.05)
-->300>300>300OCU
3.26.51183718*
(S)-PIU
5.63.412422$
36$
(R)-PIU
2.15.9954516*
(R,S)-PIU
3.51.75616*
33*
DIU
6.949714*
24VCU
3.04.32327754VPU
1.21.6784646485VPA
PI
(scMet)
PI
(MES)
Neurotoxicity-TD50
(mg/kg)
scMet-ED50
(mg/kg)
MES-ED50
(mg/kg)
Compound
*CONH2
CONH2
CONH2

16. Shimshoni et alShimshoni et al, J Med Chem, 2007
Anticonvulsant Activity and Toxicity
CONHCONH2
PIU
CONHCONH2
VCU
CONHCONH2
DIU
-->300>300>300OCU
3.26.5118 (82-154)37 (32-45)18* (10-29)(S)-PIU
5.63.4124 (93-182)22$ (14-32)36$ (25-52)(R)-PIU
2.15.995 (71-124)45 (35-61)16* (11-23)(R,S)-PIU
3.51.756 (45-66)16* (10-24)33* (18-51)DIU
6.9497 (75-122)14* (11-18)24 (16-35)VCU
3.04.3232 (193-365)77 (55-107)54 (38-66)VPU
1.21.6784 (503-1176)646 (466-869)485 (324-677)VPA
PI
(scMet)
PI
(MES)
Neurotoxicity
(TD50 mg/kg)
scMet
(ED50 mg/kg)
MES
(ED50 mg/kg)
Compound
-->300>300>300OCU
3.26.5118 (82-154)37 (32-45)18* (10-29)(S)-PIU
5.63.4124 (93-182)22$ (14-32)36$ (25-52)(R)-PIU
2.15.995 (71-124)45 (35-61)16* (11-23)(R,S)-PIU
3.51.756 (45-66)16* (10-24)33* (18-51)DIU
6.9497 (75-122)14* (11-18)24 (16-35)VCU
3.04.3232 (193-365)77 (55-107)54 (38-66)VPU
1.21.6784 (503-1176)646 (466-869)485 (324-677)VPA
PI
(scMet)
PI
(MES)
Neurotoxicity
(TD50 mg/kg)
scMet
(ED50 mg/kg)
MES
(ED50 mg/kg)
Compound
∗ Significantly different from the corresponding amide (p<0.05); $ significantly different from the corresponding
enantiomer (p<0.05)

17. 75 (54-93) (PI<4)46*
(36-59) (PI<6.5)(S)-PIU
56#
(28-75) (PI=2.1)43 (30-60) (PI=2.7)(R)-PIU
71 (58-79) (PI<1.4)42 ( 39-45) (PI<2.4)(R,S)-PIU
49*
(45-59) (PI<2)43*
( 31-53) (PI<2.3)DIU
48*
(43-51) (PI<2.1)21*
(17-25) (PI<4.7)VCU
105 (83-139) (PI<0)58 (49-71) (PI<1.7)VPU
310 (258-335) (PI=1.3)126 (95-152) (PI=3.2)VPA
6Hz-ED50
at 44mA (mg/kg)
6Hz-ED50
at 32mA (mg/kg)
Compound
Anticonvulsant Activity and Toxicity
Shimshoni et alShimshoni et al, J Med Chem, 2007
∗ Significantly different from the corresponding amide (p<0.05); $ significantly different from the corresponding
enantiomer (p<0.05)
CONHCONH2
VCU
CONHCONH2
DIU
CONHCONH2
S-PIU

18. 108919Levetiracetam
75 (PI<4)46*
(PI<6.5)(S)-PIU
56#
(PI=2.1)43 (PI=2.7)(R)-PIU
71 (PI<1.4)42 (PI<2.4)(R,S)-PIU
49*
(PI<2)43*
(PI<2.3)DIU
48*
(PI<2.1)21*
(PI<4.7)VCU
105 (PI<0)58 (PI<1.7)VPU
310 (PI=1.3)126 (PI=3.2)VPA
ED50
at 44mA
(mg/kg)
ED50
at 32mA
(mg/kg)
Compound
Anticonvulsant Activity in Mice 6Hz Model
Shimshoni et alShimshoni et al, J Med Chem, 2007
∗ Significantly different from the corresponding amide (p<0.05); $ significantly different from the corresponding
enantiomer (p<0.05)
CONHCONH2
VCU
CONHCONH2
DIU
CONHCONH2
S-PIU
CONH2 CONH2
CONH2

19. 5.52.2143 (102-173)26 (23-28)64 (55-74)DBU
3.6<PI<6-300<TD50
<50083 (60-116)>250IVU
7.63.3228 (196-264)30 (17-46)69 (35-150)PVU
1.21.6784 (503-1176)646 (466-869)485 (324-677)VPA
PI
(scMet)
PI
(MES)
Neurotoxicity-TD50
(mg/kg)
scMet- ED50
(mg/kg)
MES-ED50
(mg/kg)
Drug
Anticonvulsant Activity and Toxicity of VPU
Homologs
Shimshoni et alShimshoni et al, submitted to Epilepsia, 2008
CONHCONH2
CONHCONH2
CONHCONH2
COOH
-398(356-445)-244(192-306)Toxicity
1.3310(258-335)1.8133(108-172)6Hz (44mA)
3.2126 (95-152)380 (55-104)6Hz (32mA)
PI
(VPA)
ED50 or TD50
(mg/kg)
VPA
PI
(DBU)
ED50 or TD50
(mg/kg)
DBU
Test
-398(356-445)-244(192-306)Toxicity
1.3310(258-335)1.8133(108-172)6Hz (44mA)
3.2126 (95-152)380 (55-104)6Hz (32mA)
PI
(VPA)
ED50 or TD50
(mg/kg)
VPA
PI
(DBU)
ED50 or TD50
(mg/kg)
DBU
Test

20. 5.52.21432664DBU
3.6<PI<6-300<TD50
<50083>250IVU
7.63.32283069PVU
1.21.6784646485VPA
PI
(scMet)
PI
(MES)
Neurotoxicity-TD50
(mg/kg)
scMet- ED50
(mg/kg)
MES-ED50
(mg/kg)
Drug
Anticonvulsant Activity and Toxicity of VPU
Homologs
Shimshoni et alShimshoni et al, submitted to Epilepsia, 2008
CONHCONH2
CONHCONH2
CONHCONH2
COOH
Toxicity 244 - 398 -
6Hz (44mA) 133 1.8 310 1.3
6Hz (32mA) 80 3 126 3.2
Test DBU’s ED50
or TD50
(mg/kg)
PI (DBU) VPA’s ED50
or TD50
(mg/kg)
PI (VPA)

21. 1.513312301 (1,8)VPA
0.812410205 (1.1)(S)-PIU
5.7*
12310335 (1.8)(S)-PIU
01049205 (1.1)(R)-PIU
15.4*#
529335 (1.8)(R)-PIU
2.77510205 (1.1)VCU
0.911510167(0.9)VPU
13.7*8010261(1.8)VPU
29.1*
14113452 (2.7)VPA
01881525% CELControl
Exencephaly
%
No. of Live
Fetuses
No. LittersDose
mg/kg
(mmol/kg)
Treatment Groupa
Teratogenicity of Acylurea Isomers of VPU in
SWV Mice
Shimshoni et alShimshoni et al, J Med Chem, 2007
∗ Significantly different from control (p<0.05); # significantly different from the corresponding
enantiomer (p<0.05)

22. 0.615612502 (2.7)DBU
19810671 (3.6)DBU
0.618013520 (3.6)PVU
013512520 (3.6)IVU
29.1*
14113452 (2.7)VPA
01881525% CELControl
Exencephaly
%
No. of Live
Fetuses
No. of
Litters
Dose
mg/kg
(mmol/kg)
Treatment Group
Shimshoni et alShimshoni et al, submitted to Epilepsia, 2008
Teratogenicity of Acylurea Homologs of VPU in
SWV Mice
∗ Significantly different from control (p<0.05)

23. PK Profile of DBU in Rats (10mg/kg, i.v.)
CL (L/h•kg) 0.12 0.24 0.36
Vss (L/kg) 0.78 0.87 0.86
t1/2 (h) 4.5 4.0 1.6
MRT (h) 6.5 3.5 2.5
fe (%) 2.4 1.8 6.3
DBU VPA TMCU
Shimshoni et alShimshoni et al, submitted to Epilepsia, 2008
0.0
5.0
10.0
15.0
20.0
25.0
0 5 10 15 20 25
Time (h)
PlasmaConc.(mgL)
CONHCONH2

24. ->19>500>10026 (14-42)
1.21.6784 (503-1176)646 (466-869)485 (324-677)VPA
PI
scMet
PI
MES
Tox
(TD50
, mg/kg)
scMet
(ED50
, mg/kg)
MES
(ED50
, mg/kg)
Drug
CONH SO2NH2
Anticonvulsant Activity and
Teratogenicity of N-TMCD-Sulfonamide
Shimshoni et al, submitted to Bioorg & Med Chem, 2008
Drug Dose, mg/kg Live Fetuses Embryolethality NTD (%)
(mmol/kg) (%)
Control - 111 3.3 0
VPA 600 (3.6) 67 25.7* 22
N-TMCD- 1067 (3.6) 107 6.1 0
Sulfonamide

25. Conclusions: Part I
• Urea derivatives of VPA constitutional isomers exhibited potent
and broad anticonvulsant activity
• PIU exhibited enantioselective activity (S-PIU was more potent in
the MES, whereas R-PIU was more potent in the scMet and 6Hz
tests)
• Even at doses 3 times larger than their ED50 values, PIU, VCU
and VPU were non teratogenic
• PIU enantiomers demonstrated enantioselective teratogenicity (R-
PIU was more teratogenic than S-PIU)

26. 5. Homologs of VPU with 2-3 carbon atoms less, but
containing quaternary carbon (DBU and PVU) retain
high anticonvulsant activity and are non-teratogenic
6. Based on the pharmacokinetic study in rats, DBU’s
half-life was in a similar magnitude as VPA
7. VCU, PIU and DBU have the potential to become
antiepileptic drugs second generation to VPA
Conclusions: Part I

27. Part II: Bipolar Disorder (BD)
 BD is common, affecting approximately 1-2% of the
population
 BD is characterized by unpredictable swings in mood
from mania to depression
 Manic episodes emerge gradually and last as long as
several months to years when untreated
 Frequent age of onset: 20-30 years
Belmaker, N Engl J Med, 2004

28. Clinical Features
depressed, miserableelevated, labileMood
retardation or agitation,
poverty of movements
disinhibition, excessive
spending
Behavior
fatigueinsomnia, weight lossPhysical
guilt, unworthinessgrandiose, self confidentIdeation
lacking energy, apathyexcessive, increased
psychomotor activity
Energy
slow, monotonousfast, flight of ideasTalk
DepressionMania
Belmaker, N Engl J Med, 2004

29. FDA Approved Drug Treatments for BD
ManiaMania MaintenanceMaintenance
AntipsychoticsAntipsychotics
LithiumLithium
CarbamazepineCarbamazepine
Valproic AcidValproic Acid
LithiumLithium
LamotrigineLamotrigine
OlanzapineOlanzapine
AripiprazoleAripiprazole
((atypical antipsychotic)
DepressionDepression
Olanzapine (3mg)Olanzapine (3mg) +
Fluoxetine (25mg)Fluoxetine (25mg)
(Symbyax®)(Symbyax®)
Ketter et al, Psychopharm Bull, 2006

30. Berridge et al, Cell, 1989; Silverstone et al, Bipolar Disorder, 2005
diacylglycerol
PLC
Inositol
IP IP2
Inositol synthaseIno-1
Glucose-6-
phosphate
IMPase
BD & the Inositol Depletion Theory
Mania:
Inositol
Depression:
Inositol
VPA
Li+

31. Neurites elongate by growth at their distal end called the growth cone
Growth cones integrates external signals and translate them into
changes in the rate and direction of growth
The Effect of Mood Stabilizers on Growth
Cone Behavior
Harwood et al, Clin Neuroscience Res, 2004

32. The Effect of Mood Stabilizers on Growth
Cone Behavior
VPA, CBZ & Li+
Common mechanism :growth cone spreading via inositol depletion
Antipsychotics and Antidepressant have no growth cone spreading effect
The spread of growth cones provides a cell-based assay that may be
utilized as a screening approach for mood stabilizing properties
Williams et al, Nature, 2002
Inositol

33. Study Objectives: Part II
 Evaluate the effect of VPA constitutional
isomers, cyclopropyl analogs for mood
stabilizing properties
 Evaluate the inositol depleting activity of the
aforementioned compounds

34. VPA Constitutional Isomers, Cyclopropyl
Analogs & their Corresponding Amide
Shimshoni et al, Mol Pharmacol, 2007
COOH
COOH
COOH COOH COOH
COOH CONH2 CONHCH3 CONHCONH2
COOH
CONH2 CONH2 CONH2 CONH2
VPA
4-ene-VPA 4-yne-VPA
PIA DIA VCA
VPD PID DID VCD
TMCA TMCD MTMCD TMCU

35. Growth Cone-Based Assay: Dorsal Root Ganglion
(DRG)
DRG are composed of several thousand cell bodies of
somatosensory neurons
Rat DRG showing neuron outgrowth
(x20)

36. a. Control
0
10
20
30
40
50
60
0-50
50-100
100-150
150-200
200-250
250-300
300-350
350-400
400-450
450-500
500-550
550-600
600-650
650-700
700+
b. 3mM VPA ***
0
10
20
30
40
50
60
0-50
50-100
100-150
150-200
200-250
250-300
300-350
350-400
400-450
450-500
500-550
550-600
600-650
650-700
700+
c. 2mM LiCl **
0
10
20
30
40
50
60
0-50
50-100
100-150
150-200
200-250
250-300
300-350
350-400
400-450
450-500
500-550
550-600
600-650
650-700
700+
d.1mM PIA *
0
10
20
30
40
50
60
0-50
50-100
100-150
150-200
200-250
250-300
300-350
350-400
400-450
450-500
500-550
550-600
600-650
650-700
700+
e. 0.5mM PIA *
0
10
20
30
40
50
60
0-50
50-100
100-150
150-200
200-250
250-300
300-350
350-400
400-450
450-500
500-550
550-600
600-650
650-700
700+
f. 1mM PIA+2mM
Inositol
0
10
20
30
40
50
60
0-50
50-100
100-150
150-200
200-250
250-300
300-350
350-400
400-450
450-500
500-550
550-600
600-650
650-700
700+
g. 1mM DIA ***
0
10
20
30
40
50
60
0-50
50-100
100-150
150-200
200-250
250-300
300-350
350-400
400-450
450-500
500-550
550-600
600-650
650-700
700+
h. 1mM DIA+2mM
Inositol
0
10
20
30
40
50
60
0-50
50-100
100-150
150-200
200-250
250-300
300-350
350-400
400-450
450-500
500-550
550-600
600-650
650-700
700+
i. 0.5mM DIA
0
10
20
30
40
50
60
0-50
50-100
100-150
150-200
200-250
250-300
300-350
350-400
400-450
450-500
500-550
550-600
600-650
650-700
700+
Spread (um2
) Spread (um2
) Spread (um2
)
Shimshoni et al, Mol Pharmacol, 2007
Growth Cone Spreading Effect of Aliphatic VPA
Constitutional Isomers
%
%
%

37. b. 3mM TMCD
0
10
20
30
40
50
60
0-50
50-100
100-150
150-200
200-250
250-300
300-350
350-400
400-450
450-500
500-550
550-600
600-650
650-700
700+
d. 0.5mM MTMCD *
0
10
20
30
40
50
60
0-50
50-100
100-150
150-200
200-250
250-300
300-350
350-400
400-450
450-500
500-550
550-600
600-650
650-700
700+
e. 1mM MTMCD *
0
10
20
30
40
50
60
0-50
50-100
100-150
150-200
200-250
250-300
300-350
350-400
400-450
450-500
500-550
550-600
600-650
650-700
700+
f. 1mM MTMCD+2mM Inositol
0
10
20
30
40
50
60
0-50
50-100
100-150
150-200
200-250
250-300
300-350
350-400
400-450
450-500
500-550
550-600
600-650
650-700
700+
Growth Cone Spreading Effect of VPD
Constitutional Isomers, Cyclic VPA Analogs &
their Amides
Shimshoni et al, Mol Pharmacol, 2007
Spread (um2
) Spread (um2
) Spread (um2
)
%
%
c. 3mM VPD
0
10
20
30
40
50
60
0-50
50-100
100-150
150-200
200-250
250-300
300-350
350-400
400-450
450-500
500-550
550-600
600-650
650-700
700+
a. Control
0
10
20
30
40
50
60
0-50
50-100
100-150
150-200
200-250
250-300
300-350
350-400
400-450
450-500
500-550
550-600
600-650
650-700
700+

38. b. 3mM VPA ***
0
10
20
30
40
50
60
0-50
50-100
100-150
150-200
200-250
250-300
300-350
350-400
400-450
450-500
500-550
550-600
600-650
650-700
700+
a. Control
0
10
20
30
40
50
60
0-50
50-100
100-150
150-200
200-250
250-300
300-350
350-400
400-450
450-500
500-550
550-600
600-650
650-700
700+
c. 3mM VPD
0
10
20
30
40
50
60
0-50
50-100
100-150
150-200
200-250
250-300
300-350
350-400
400-450
450-500
500-550
550-600
600-650
650-700
700+
d. 3mM DID
0
10
20
30
40
50
60
0-50
50-100
100-150
150-200
200-250
250-300
300-350
350-400
400-450
450-500
500-550
550-600
600-650
650-700
700+
e. 3mM PID
0102030405060
0-50
50-100
100-150
150-200
200-250
250-300
300-350
350-400
400-450
450-500
500-550
550-600
600-650
650-700
700+
f. 3mM VCD
0102030405060
0-50
50-100
100-150
150-200
200-250
250-300
300-350
350-400
400-450
450-500
500-550
550-600
600-650
650-700
700+
%
Shimshoni et al, Mol Pharmacol, 2007
Spread (um2
) Spread (um2
) Spread (um2
)
Growth Cone Spreading Effect of VPD
Constitutional Isomers
%

39. Effect of VPA Derivatives & Analogs on
InsP3 Levels
Shimshoni et al, Mol Pharmacol, 2007
InsP3 depletion in D. discoideum
0
40
80
120
160Control
VPA
Lithium
TM
CD
PIA
PID
InsP3levels(%ofcontrol)
* *
*

40. Screening for HDAC and GSK3 Modulators
Shimshoni et al, Mol Pharmacol, 2007
β-Catenin
HDACsVPA
GSK3Li+
Enhanced
Gene
Expression
Relative light units

41. Conclusions : Part II
1. PIA and DIA, the constitutional isomers of VPA, as
well as the amide of cyclic VPA analog, MTMCD are
more effective than VPA in increasing growth cone
spreading via inositol depletion mechanism
2. Anticonvulsant potency and growth cone spreading
effect of the above compounds are poorly correlated,
suggesting a different mechanisms of their action
3. PIA, DIA and MTMCD have a potential as new
antibipolar drugs

42. 1. Shimshoni JA, Dalton EM, Jenkins A, Eyal S, Ewan K, Williams RSB, Pessah
N, Yagen B, Harwood AJ, Bialer M. The effects of CNS-active valproic acid
constitutional isomers, cyclopropyl analogues and amide derivatives on neuronal
growth cone behaviour. Mol Pharmacol, 2007, 71: 884-92
2. Shimshoni JA, Bialer M, Wlodarczyk B, Finnell RH, Yagen B. Potent
anticonvulsant urea derivatives of constitutional isomers of valproic acid. J Med
Chem, 2007, 50: 6419-6427
3. Shimshoni JA, Bialer M, Yagen B. Synthesis and anticonvulsant activity of
aromatic tetramethylcyclopropanecarboxamide aromatic derivatives. Submitted
to Bioorg & Med Chem, 2008
4. Shimshoni JA, Yagen B, Pessah N, Wlodarczyk, Finnell, Bialer M.
Anticonvulsant profile and teratogenicity of 3,3-dimethylbutanoylurea: a
potential for a second generation drug to valproic acid. Submitted to Epilepsia,
2008
List of Publications

43. Acknowledgements
Prof. Meir Bialer & Prof. Boris YagenProf. Meir Bialer & Prof. Boris Yagen
Prof. Adrian HarwoodProf. Adrian Harwood
Dr Ken EwanDr Ken Ewan
Dr Robin WilliamsDr Robin Williams
Miss Emma DaltonMiss Emma Dalton
Dan KaufmannDan Kaufmann
Dorit MimrodDorit Mimrod
Neta PessahNeta Pessah
Naama HenNaama Hen
Idit AchachIdit Achach
Cardiff University Texas University
Prof. Richard H. FinnellProf. Richard H. Finnell
Dr Bogdan WlodarczykDr Bogdan Wlodarczyk
Lab Members