Prostaglandins

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Prostaglandins NSAIDs

• Cheryl Tajon
• October 13, 2008
• Review Session Exam 1
• Walter Holleran

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Formation of Eicosanoids
1 pathway
Lehninger Principles of Biochemistry, 3rd
Edition, Nelson, D. and Cox, M., p.378
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Formation of Eicosanoids

1 pathway
C204 or 204?5, 8, 11, 14
Lehninger Principles of Biochemistry, 3rd
Edition, Nelson, D. and Cox, M., p.378
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Essential fatty acids (EFAs)
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Cyclooxygenase (COX) mechanism
COX-2 PDB 6COX
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Cyclooxygenase (COX) mechanism
COX-2 PDB 6COX
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1 unsaturated bond
Saturated
I
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1 unsaturated bond
Saturated
Bridged bicyclic system
Bridged bicyclic system
I
2 fused rings
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?-3 FAs (like PGE3) are generated from
eicosapentaenoic acid.
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• Synthetic PGE1 analogue
• Prevents NSAID-induced ulcers
• C16 methyl increases stability and half-life

• Treats impotence
• Given as an injection or urethral suppository

• PGI2 analogue
• Treats hypertension
• Disadvantage requires
• a central line
• Short half-life (3-5 min)

• Induces uterine contractions
• Prepares cervix for labor delivery
• Induces abortion (1st 2nd trimester)

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Arachidonic acid
COX
Present in blood platelets
Thromboxanes induce constriction of blood vessels
and platelet aggregation (blood clotting). Low
doses of aspirin, taken regularly, reduce the
probability of heart attacks and
strokes. Lehningher Principles of Biochemistry,
3rd Ed., p.785
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COX cyclic pathway Lipoxygenase linear
pathway found in leukocytes incorporates
molecular oxygen into arachidonate
(5-hydroperoxyeicosatetraenoate)
Chemoattractant for neutrophils
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Arachidonic acid
lipoxygenase
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What conditions are NSAIDs used?

• 1o treat inflammation, mild to moderate pain,
  fever
• Specific uses headaches, arthritis, sports
  injuries, menstrual cramps
• Included in cold/allergy preparations

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Molecular target for NSAIDs

• COX is a homodimer.
• Active sites for COX1 2 are different.
• COX2 has an extended binding pocket that can be
  utilized for selectivity.
• All COX inhibitors, regardless of selectivity,
  bind in the arachidonic acid binding site.

TiPS Nov 1999 (vol. 20)
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Prototype NSAIDs

• Inhibits by acetylating a serine residue in the
  active site.

• However, NSAIDs can also inhibit synthesis of
  beneficial prostaglandins in GI tract and kidney.

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Critical single carbon bridge

• Ibuprofen
• (S) is the active enantiomer.
• Less potent, more liver toxicity w/o -CH3 group

acid
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Aryl Propionic Acids
naphthalene
isobutyl
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Indole Acids
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COX has two isozymes.

• Both carry out the same reactions, but

COX-1 Active under normal healthy conditions
COX-2 Normally dormant when activated produces
excess inflammatory prostaglandins
Selective COX-2 inhibitors
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Flurbiprofen
DuP 697
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General structure for COX2 Selective NSAIDs

• Consist of a central ring with 1,2-biaryl
  substitution

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Acetaminophen Toxicity
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Leukotriene Synthesis

• Targeting FLAP will inhibit 5-lipoxygenase

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• Inhibits synthesis of leukotrienes
• Approved 10yrs ago for asthma

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Arachidonic acid
lipoxygenase

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• Not much SAR

• Asthma
• Can take orally

• Recently approved
• Less effective than steroids

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• Present at physiological pH.
• Develop antagonists of this species against H1
  receptor.

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Usually methyl, but not always
Basic N
Linker variability in X Y
1st generation antihistamines crossed blood-brain
barrier.
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Basic N

• Weakly or non-sedating
• Dont cross blood-brain barrier
• Both compounds are metabolized by Cyt P450.

X
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• Prodrug
• No longer used

• Active drug
• Not converted in the reverse fashion

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All are competitive and bind with increased
affinity for TNFa.
Humira
Remicade
Enbrel
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Important in gout used in combination with
methotrexate.
Purpose to reduce binding of leukocytes to the
endothelium
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