MedChem - anti-inflammatory drugs

What is the role of prostanoids?

Signals for inflammation

How are prostanoids synthesised?

• Physical, chemical or inflammatory stimuli stimulate phospholipase A2

• Phospholipase a2 makes arachidonic acid

• COX makes arachidonic acid into 2 molecules of prostaglandin g2

• Prostaglandin g2 converted to prostaglandin h2 via prostaglandin G/H synthase 2

• Made into different prostaglandins dependant on different tissues e.g., prostacyclin, thromboxane a2, prostaglandin d2, prostaglandin e2

What do corticosteroids prevent the release of?

Arachidonic acid

Where do NSAIDs block?

COX enzyme

What is the structure of arachidonic acid?

Long chain fatty acid in Z configuration, comprised of double bonds

What happens to the 6 membered ring from PGH2 when converted to prostaglandins?

Becomes 5-membered ring

Why is thrombocane a2 a short-lived compound?

Has 2 oxygens covalently bonded to one another so very easily cleaved

Where is COX-1 expressed?

Expressed in all tissues - mostly in stomach

What is the role of COX-2 in the stomach?

Involved in mucosal defence and repair

What regulates the expression of COX-1?

Hormonal signalling involved in maintaining physiological homeostasis

When is COX-2 expressed?

In response to adverse stimuli e.g., inflammation

What amino acid is key to COX-1 activity?

Serine 530

What is the advantage of the side pocket of COX-2 for drugs?

Allows drugs to be selective for COX-1 or 2 as they can it into side pocket where val523 and arg513 are

What can be a downside of COX-1 selective drugs?

Increase risk of GIT damage if very COX-1 selective even if managing GIT inflammation

What is the increased risk with COX-2 selective inhibitors?

Increase risk of bleeds, thrombosis etc

What is the MOA of aspirin?

Acetylates S530 in COX-1 and COX-2 catalytic site by transesterification and inhibits key step in prostanoid biosynthesis

What are some examples of propanoic acid derivative NSAIDs?

Ibuprofen, naproxen

What is the structure of ibuprofen?

Chiral centre - S enantiomer is 1000x more active, contains COOH group

What is the general structure of all non-selective COX inhibitors?

Carboxylic acid group and other features mimic arachidonic acid structure

What is the structure of naproxen?

Contains napthlene group - needs glutathione to detoxify when removed, 2 benzene groups occupy same space as arachidonic acids double bonds

What is the most active stereoisomer of the profens?

S enantiomer

What are some examples of ethanoic acid derivative NSAIDs?

Indomethacin, diclofenac, sulindac

What is the structure of indomethacin?

BIcyclic ring system, chloride group means very lipophilic molecule

How does diclofenac work?

Inhibits COX and lip oxygenate pathways and inhibits release and promotes reuptake of arachidonic acid

What halogen does diclofenac containing meaning it is very lipophilic and makes the benzene ring meta directing?

Chloride

Why does sulindac produce less GI side effects?

Prodrug and needs systematic activation inside the body

What amino acid do NSAIDs try to block?

Serine 530

Where do propionic acid derivatives get stuck?

Trapped at neck of entrance site due to r120

What part of diclofenac forms bonds with the COX-2 active site?

COOH

What is an advantage of piroxicam?

No COOH so should decrease GI disturbances

What small molecule is needed for piroxicam to carry out its activity in the active site?

Water

What functional groups are present in piroxicam?

Acidic ketoenol group that changes formation

What are some examples of selective COX-2 inhibitors?

Celecoxib, etoricoxib

What is the binding of celecoxib/etoricoxib like in the COX-2 active site?

Block S530 group again, has a trifluoromethyl group point down, sulfonamide binds into side pocket and has strong interactions

What is methotrexate an analogue of?

Folic acid

What functional group is replaced from the OH in folic acid to methotrexate?

NH2 group

How does methotrexate work?

Inhibits dihydrofolate reductase and ATIC which reduces purine and pyrimidine biosynthesis, meaning more availability of adenosine which creates an anti-inflammatory response

What is the role of adenosine when there is an increased amount from methotrexate?

Suppresses inflammation

How does leflunomide work?

Reversible inhibitor of dihydroorotate dehydrogenase and inhibits production of uridine monophosphate, reducing RNA and DNA synthesis which reduces T-Cell activation and reduces inflammation

What can be some drawbacks to leflunomide?

Liver damage and hypertension, teratogenic

How does tofacitinib work?

JAK3 inhibitor which exerts immunosuppresion by inhibiting JAK-STAT signalling pathway

When is tofacitinib used?

When patient not responded well to biologics

What part of sulfasalazine is cleaved in the gut to make sulfapyridine and 5-ASA?

N=N double bond

What type of drug is sulfasalazine?

Prodrug

What is the role of 5-ASA?

Induces apoptosis, activates PPAR-gamma and expression, ROS scavenger

What is the role of sulfasalazine in RA?

Not fully understood but leads to increased endogenous adenosine

How does azathioprine work?

Anti-inflammatory and immunosuppressant - suppresses purine biosynthesis and reduces cell proliferation

What causes gout?

Deposition of crystalline uric acid - leads to pain and inflammation

What is the key enzyme to target which directly inhibits uric acid?

Xanthine oxidase

What is the properties of colchicine?

Naturally occurring NSAID that doesn’t induce fluid retention, looks sort of sexy

What is the structure of allopurinol?

Similar to hypoxanthine, Nitrogen slightly different makes it very powerful

What drugs used to treat gout inhibit xanthine oxidase?

Allopurinol, febuxostat