Prostaglandins & NSAIDs

Cheryl TajonOctober 13, 2008

Review Session: Exam 1Walter Holleran

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

Formation of Eicosanoids

1° pathway

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

Formation of Eicosanoids

1° pathway

C20:4 or 20:4∆5, 8, 11, 14

Essential fatty acids (EFA’s)

912

Cyclooxygenase (COX) mechanism

COX-2 PDB = 6COX

Cyclooxygenase (COX) mechanism

COX-2 PDB = 6COX

I

1 unsaturated bond

Saturated

I

1 unsaturated bond

Saturated

Bridged bicyclic system 2 fused rings

Bridged bicyclic system

ω-3 FA’s (like PGE3) are generated from eicosapentaenoic acid.

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

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

•Treats impotence•Given as an injection or urethral suppository

•Synthetic PGE1 analogue•Prevents NSAID-induced ulcers•C16 methyl increases stability and half-life

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

COX: “cyclic” pathway

Lipoxygenase: “linear” pathway; found in leukocytes; incorporates molecular oxygen into arachidonate (5-hydroperoxyeicosatetraenoate)

Chemoattractant for neutrophils

Arachidonic acid

lipoxygenase

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

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)

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

Prototype NSAIDs

CO2H

O

O

Aspirin

HO Ser

Enzyme

Acetylation

CO2H

OH

Salicylic acid

+O

O

Ser

Enzyme

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

acid

Critical single carbon bridge

•Ibuprofen•(S) is the active enantiomer.

•Less potent, more liver toxicity w/o -CH3 group

Aryl Propionic Acidsnaphthalene

isobutyl

Indole Acids

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

H2NO2S

NO

Valdecoxib

MeO2S

O

O

Refecoxib

H2NO2S

NN

CF3

Celecoxib

Selective COX-2 inhibitors:

Flurbiprofen

DuP 697

General structure for COX2 Selective NSAIDs

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

X X

S

F

SO2CH3

Br

DuP 697

NN

F

SO2CH3

CF3

SC 58125

F

SO2CH3

F

SO2CH3

SC 57666

Acetaminophen Toxicity

Leukotriene Synthesis

•Targeting FLAP will inhibit 5-lipoxygenase

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

Arachidonic acid

lipoxygenase

•Not much SAR

•Asthma•Can take orally

•Recently approved•Less effective than steroids

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

receptor.

Basic N

Linker; variability in X & Y

Usually methyl, but not always

1st generation antihistamines crossed blood-brain barrier.

Basic N

X

•Weakly or non-sedating•Don’t cross blood-brain barrier•Both compounds are metabolized by Cyt P450.

•Prodrug•No longer used

•Active drug•Not converted in the reverse fashion

All are competitive and bind with increased affinity for TNFα.Humira

Remicade

Enbrel

Important in gout; used in combination with methotrexate.

Purpose: to reduce binding of leukocytes to the endothelium