PROSTAGLANDINS & NSAIDS

CH.SUMALATHA
M.PHARM(Ph.D)
Assistant Professor
Department of Pharmaceutical Chemistry
 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

Lehninger Principles of Biochemistry, 3rd Edition, Nelson, D. and Cox, M., p.378
 12 9

Essential
fatty acids
(EFA’s)
Cyclooxygenase (COX) mechanism

COX-2
PDB = 6COX
Cyclooxygenase (COX) mechanism

COX-2
PDB = 6COX
 1 unsaturated
bond

Saturated

I
 1 unsaturated
bond

Saturated

Bridged
Bridged bicyclic
bicyclic system
system I 2 fused rings
ω-3 FA’s (like PGE3)
are generated from
eicosapentaenoic
acid.

•Treats impotence
•Given as an injection or
urethral suppository
•Synthetic PGE1 analogue
•Prevents NSAID-induced
ulcers
•C16 methyl increases
stability and half-life

•PGI2 analogue
•Induces uterine •Treats hypertension
contractions •Disadvantage: requires
•Prepares cervix for labor & a central line
delivery •Short half-life (3-5 min)
•Induces abortion (1st & 2nd
trimester)
 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)
 Prototype NSAIDs
• Inhibits by acetylating a serine residue in the
active site.

CO2H CO2H
O OH O Ser
HO Ser Acetylation +
O
O

Aspirin Enzyme Salicylic acid Enzyme

•However, NSAIDs can also inhibit synthesis of

beneficial prostaglandins in GI tract and kidney.
 Critical single
carbon bridge

•Ibuprofen
•(S) is the active
enantiomer.
acid
•Less potent, more
liver toxicity w/o -CH3
group
Aryl Propionic Acids
naphthalene
isobutyl
Indole Acids
 COX has two isozymes.
• Both carry out the same reactions, but
COX-1 COX-2

Active under normal Normally dormant; when

healthy conditions activated produces excess
inflammatory
prostaglandins

Selective COX-2 inhibitors:

H2NO2S MeO2S H2NO2S

N
O N CF3
O
N
O

Valdecoxib Refecoxib Celecoxib

Flurbiprofen

DuP 697
 General structure for COX2 Selective
NSAIDs
• Consist of a central ring with 1,2-biaryl
substitution X X

SO2CH3 SO2CH3
SO2CH3 SO2CH3
F F
F F
N
N
S
Br CF3

DuP 697 SC 58125 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.
 Usually methyl, but not always

Basic N

Linker; variability in X & Y

1st generation antihistamines

crossed blood-brain barrier.
Basic N

•Weakly or non-sedating
•Don’t cross blood-brain
barrier
•Both compounds are
X 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
Humira TNFα.

Remicade

Enbrel
Important in gout; used in combination with
methotrexate.

Purpose: to reduce
binding of
leukocytes to the
endothelium