Jakob.Ph D Lecture Final Version

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Jakob.Ph D Lecture Final Version

  1. 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. 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. 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. 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. 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. 6. Valproic Acid (VPA) COOH  Efficient in many types of epilepsy  Migraine prophylaxis  Bipolar disorder  Major rare side effects: hepatotoxicity & teratogenicity
  7. 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. 8. COOH COOH VPAVPA 2,2,3,3-tetramethylcyclopropane- carboxylic acid (TMCA) Quaternary Carbons & Acylurea containing compounds & Hepatotoxicity CONHCONH2 3,3-dimethylbutanoylurea (DBU)
  9. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 40. Screening for HDAC and GSK3 Modulators Shimshoni et al, Mol Pharmacol, 2007 β-Catenin HDACsVPA GSK3Li+ Enhanced Gene Expression Relative light units
  41. 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. 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. 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

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