Development of rasagiline, a selective MAOB inhibitor, for the treatment of Parkinsons Disease

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Development of rasagiline, a selective MAO-B
inhibitor, for the treatment of Parkinsons
Disease

• John PM Finberg
• Pharmacology Dept,
• Rappaport Faculty of Medicine,
• Technion, Haifa, Israel

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The Royal London Hospital
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James Parkinson, 1755-1824 Medical studies,
London Hospital 1775 1817 The Shaking
Palsy "Involuntary tremulous motion, with
lessened muscular power, in parts not in action
and even when supported with a propensity to
bend the trunk forward and to pass from a
walking to a running pace the senses and
intellect being uninjured."
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Substantia nigra ????? ?????
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Normal s.n.
Parkinsons s.n.
Lewy body (L)
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???? ????????

• ???? ?? ???????? ???????????? (?????? ???????)
  ????? ?????
• ???? ?????? ????? ?????? ???? ??????? ?????? ????
  L-DOPA ???????? ???? ?????? ???????????
• ??????? ????? ????? ???? ?? ??? ?????? ????????
  ??????? (MAO)
• ?????? ?? MAO ???? ???? ?????? ???? ????????

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Generalised structure of a neuron
Cell body (perikaryon)
dendrites
axon
nucleus
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(No Transcript)
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DAT
Storage vesicle
VMAT
DA
DA
L-DOPA
MAO (Monoamine oxidase)
DA
Tyrosine
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????? MAO ?????? ????? ????????

• ?????? MAO ???? ???? ??-????? MAO-A ?-MAO-B
• ??????? ???? ??????? ???? ??????
• ?? ???? ???? ????? ???????? ??????? ?? MAO-A ???
  ?????? ?????? ???? ???? ??? ??????? ???????????
  ?????
• ?????? ?? MAO-B ?????? ????? ????? ????? ????????
  ???? ???????? ?????? ????????

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????? MAO ?????? ????? ????????

• ???? ?-MAO-B ?????? ????? ???? 1970 ?? ??? Knoll
  ???????? ????? selegiline
• Selegiline ????? ???? ?-methamphetamine, ?????
  ???? ???? ?????????
• Rasagiline ???? ????? ???? ?????? ?????? ?????
  ????? ?? ??? Youdim and Finberg ????? ?-MAO
  AGN-1135

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Propargyl group
Hepatic metabolism CYP-2B6, 3A4, 2A6
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R
S-
Binda C et al (2004) J Med Chem 471767
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(No Transcript)
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Binda C et al (2004) J Med Chem 471767
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flavin
Binda C et al (2004) J Med Chem 471767
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Rasagiline a MAO-B inhibitor with superior
neuroprotective properties
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Drug development

• Discovery of active compound
• Patent application
• Preclinical development
• Clinical trial
• Marketing

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STAGES IN DEVELOPMENT OF A NEW DRUG
Classical method Molecular method Many new
compounds Isolate molecular target and design
drug based on structure/activity Animal
or tissue activity screening Active
compound Developmental pharmacology Animal
Toxicology
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STAGES IN DEVELOPMENT OF A NEW DRUG

• Clinical Trial
• Stage 1 First time given to humans
• Stage 2 First time given to patients
• Stage 3 Major clinical trial, 500-5000
  patients, double blind if possible. Following
  this stage, submit New Drug Application (NDA)
• Stage 4 Controlled marketing