NSAIDS – Aspirin, Ibuprofen, Celebrex and Beyond.

NSAIDS – Aspirin, Ibuprofen, Celebrex and Beyond

Prostaglandins have several differenct biological functions, one of which isto stimulate inflammation. The biological synthesis of prostaglandinsincludes several steps, starting with arachidonic acid:

arachidonic acidprostaglandin

synthase

PGH2

(a peroxide)prostaglandin

Prostaglandins

Aspirin, or O-acetyl-salicylic acid, has two carbonyl functional groups.Which of those is more electrophilic or “activated”?

O CH3

OCOOH

Prostaglandin synthase is composed of two enzymes. One of theenzymes, CycloOXygenase (COX), has a serine hydroxyl group thatis necessary for enzyme activity. In the presence of aspirin, the hydroxylgroup of cyclooxygenase becomes “acylated”. Aspirin is termed anon-reversible inhibitor, because it covalently modifies the active siteof the enzyme and the enzyme is not functional while that covalentmodification exists. Draw the electron pushing for that process.

That process is called “transesterification”. Note that the enzyme isnow unable to catalyze the formation of prostaglandins. If prostaglandinsare not synthesized, inflammation and associated pain does not occur.

Aspirin

Ibuprofen

COOHO CH3

OCOOH

aspirin ibuprofen

Note that ibuprofen (Advil, Motrin, Nuprin) lacks the ester functional group present in aspirin. Since that ester functional group was involved in the chemistry between aspirin and the COX enzyme, we might expect that ibuprofen has a different mode of action…

• Ibuprofen mimics arachadonic acidand fits into the active site of theCOX enzyme. While ibuprofen isin the active site, arachadonic acidcannot enter and prostagladinsynthesis is inhibited. This isreversible inhibition.

Because of patent rights, legal issues and monetaryconsiderations, scientists are constantly searching for new, more effective medications.

MeO

COOH

Naproxen (in Aleve)

Several different forms of the CycloOXygenase enzyme exist. COX-1And COX-2 are the best understood. The structures of COX-1 andCOX-2 are similar, but these enzymes serve markedly different functions.

Arachidonic AcidCOX-1

COX-2

“housekeeping” prostaglandins

• platelets (for blood clotting)• prostaglandin E2 (for kidney function)• prostaglandin I2 (for stomach lining)

“inflammatory”prostaglandins

Scientists reasoned that if we could find compoundsthat are highly selective for the active site of COX-2, butare unable to bind to COX-1, we could manage pain/inflammation without affecting other “housekeeping”functions.

O

O

SO2CH3

NN

CF3

SO2NH2

COX-2 inhibitors

Vioxx Celebrex

These drugs were hailed as “super aspirins”… they are nowoff the general market because of negative side effects.

4 May 2000

Soon after the crystal structure in 2000, scientists proposed the structure of a molecule (APHS) which was calculated to fit perfectly into the active site, thus effectively shutting down the inflammatory/pain response.

• What mode of action would APHS be predicted to have?

• Is it wise to mask inflammation/pain?

• The mode of action of Tylenol is not yet understood ….

O

O

S