DRUG DEVELOPMENT Search for New Drugs

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DRUG DEVELOPMENTSearch for New Drugs
D. MOLECULAR MODIFICATION
Use SAR to develop a LEAD Compound
Advantages of this approach?

• greater number of compounds

• fine-tune desirable properties

Lead Drug

• determination of pharmacophore

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MOLECULAR MODIFICATION Benzodiazepines
Chlordiazepoxide Diazepam
Oxazepam (Librax) (Valium)
(generic)
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MOLECULAR MODIFICATION Benzodiazepines
Flurazepam Clorazepate
Clonazepam (Dalmane) (Tranxene)
(Rivotril)
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MOLECULAR MODIFICATION Benzodiazepines
Lorazepam Alprazolam
Temazepam (Ativan)
(Xanax) (Restoril)
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MOLECULAR MODIFICATION Benzodiazepines
Triazolam (Halcion)

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MOLECULAR MODIFICATIONSGeneral Processes
MOLECULAR SIMPLIFICATION

• Natural products are the lead

• Partial replica of lead

e.g. physostigmine morphine
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MOLECULAR SIMPLIFICATIONAntiacetylcholinesteras
es
acetylcholinesterase
Acetylcholine
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MOLECULAR SIMPLIFICATIONAntiacetylcholinesteras
es
Physostigmine (discontinued 1998)
Neostigmine (Prostigmin)
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MOLECULAR SIMPLIFICATIONAntiacetylcholinesteras
es
Pyridostigmine (Mestinon)
Edrophonium (Enlon)
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MOLECULAR SIMPLIFICATIONNarcotic Analgesics
Levorphanol (discontinued 2002)
Morphine
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MOLECULAR SIMPLIFICATIONNarcotic Analgesics
Levorphanol
Pentazocine ( Talwin )
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MOLECULAR SIMPLIFICATIONNarcotic Analgesics
Pentazocine ( Talwin )
Meperidine ( Demerol )
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MOLECULAR SIMPLIFICATIONNarcotic Analgesics
Sufentanil ( Sufenta )
Opiate Pharmacophore
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MOLECULAR SIMPLIFICATIONNarcotic Analgesics
Methadone ( Metadol )
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MOLECULAR ASSOCIATION
More complex analogs of lead

• Molecular Addition

• Molecular Hybridization

• Molecular Replication

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MOLECULAR ADDITION

• Weak association
• of different molecules

e.g. methenamine mandelate dimenhydrinate
....

....
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MOLECULAR ADDITION
Methenamine mandelate (Mandelamine)
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MOLECULAR ADDITION
Dimenhydrinate (Gravol)
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MOLECULAR HYBRIDIZATION
Covalent association of different molecules
e.g. nifenazone fenethylline dual
action antibiotics hybrid drugs

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MOLECULAR HYBRIDIZATION
Nifenazone
Fenethylline
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MOLECULAR HYBRIDIZATION
Dual Action Antibiotic
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MOLECULAR HYBRIDIZATION

Ethacrynic acid
Nifedipine
Hybrid Drug
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MOLECULAR REPLICATION
Covalent association of identical molecules
e.g. dapsone d-tubocurarine
doxacurium atracurium cisatracurium

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MOLECULAR REPLICATION
Dapsone (Avlosulfon)
d-Tubocurarine
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MOLECULAR REPLICATION
Succinylcholine
Doxacurium (Nuromax)
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MOLECULAR REPLICATION
Cisatracurium (Nimbex)
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MOLECULAR REPLICATION
bis Prednisolone phosphate
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MOLECULAR REPLICATION
Forbisen
Dibozane