SAR of Anticonvulsant Drugs

SAR of Anticonvulsant Drugs

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  Structural Activity RelationshipOf Some Anticonvulsant Drugs - By: Chhabi Acharya Matina Awale VIth Sem, B. Pharmacy Hope Int’l College
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  We will discussabout: Structural activity relationship of: 1.Hydantoin 2.Barbiturates 3.Benzodiazepines 4.Valproic Acid 5.Succinimides
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  1. Hydantoins • Phenylethylhydation R1= H R2 = C2H5 R3 = C6H5 • Phenytoin R1 = H R2 = R3 = C6H5 • Mephenytoin R1 = CH3 R2 = C2H5 R3 = C6H5 • Ethotoin R1 = C2H5 R5 = H R5 = C6H5 Hydantoin
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  Contd.. • A phenylor other aromatic substituents at C5 is essential for the activity. • Alkyl substituents at position 5 may contribute to sedation, a property absent in phenytoin. Hydantoin Hydantoin
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  • Among otherhydantoins, like spirohydantoins, thiohydantoins, dithiohydantoins, and 1, 3- disubstituted hydantoins, some exhibit activity against chemically induced convulsions. • While remaining are ineffective against electroshock induced convulsions. Contd.. Hydantoin
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  2. Barbiturates • Phenobarbitone R1= H R2 = C2H5 R3 = C6H5 • Mephobarbitone R1 = CH3 R2 = C2H5 R3 = C6H5 • Metharbital R1 = CH3 R2 = C2H5 R3 = C2H5
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  Contd.. • Optimum activityis observed when one of the substituents at C5 is phenyl. • The 5, 5-diphenyl derivatives have less activity than phenobarbitone. • N2 and N3 substituents, in some cases also results in an increased activity. • 5, 5-dibenzyl barbituric acid causes convulsions.
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  3. Benzodiazepines • Diazepam R1= CH3 R2 = H R3 = Cl • Nitrazepam R1 = H R2 = H R3 = NO2 • Clonazepam R1 = H R2 = Cl R3 = NO2
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  Contd.. • The electronwithdrawing atom or group at position 7 increases the anti-epileptic activity while electron donating substituents at 7, 8 or 9 positions decrease it. • A phenyl group at position 5 is necessary for activity. But only halogen substituents are allowed in the ortho position.
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  Contd.. • The electronwithdrawing groups at ortho or diortho positions at 5-phenyl increase the activity while any substituents on meta or para position at 5-phenyl decreases the activity. • Methyl substitution at position 1 confirms high activity.
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  4. Valproic Acid •Among other relatives of valproic acid, 3, 3, 4-trimethylpentanoic acid is also as active as valproic acid. • The anticonvulsant activity increases with increased chain length. • Introduction of a double bond decreases the activity.
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  5. Succinimides • Phensuximide R1= C6H5 R2 = H R3 = CH3 • Methsuximide R1 = C6H5 R2 = R 3 = CH3 • Ethosuximide R = C2H5 R2 = CH3 R3=H
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  Contd.. • Methsuximide and phensuximidehave phenyl substituents which makes them active against electrically induced convulsion. • N-Methylation decreases activity against electroshock seizures and impart more activity against chemically induced convulsion.
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  Recent Development • AWD131-138: Chemically, AWD 131-138 is 1-(Cchloropheny1) Cmorpholino imidazolin-2-one • This compound is currently in Phase I clinical development. • It possesses a broad spectrum of anticonvulsant activity as well as anxiolytic action. • Its mechanism of action is by blockade of the voltage activated Ca2+ channel in a dose- dependent manner.
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  Contd.. • Retigabine: Chemically,retigabine is ethyl N-(2-amino-4-(4-fluorobenz 1 amino)phenylcarbamate • It is structurally unrelated to currently marketed anticonvulsant agents. • It shows a unique mode of action by increasing K+ conductance in neuronal cells. • Phase I and II studies have shown good tolerability and efficacy trials are ongoing.
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  Contd.. • Rufinamide • Remacemide •Pregabalin • NPS 1776 • NW 1015 • Harkoseride • Canaxolone • Serotolide
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  References • Burger’s MedicinalChemistry and Drug Discovery, Volume Vi, Nervous System Agent • Foye’s Principle Of Medicinal Chemistry. • Kadam – Bothara, Principle of Medicinal Chemistry, Nirali Prakashan • Structure from: http://commons.wikimedia.org Edited with chemdraw