NSAIDs & Gout MedChem

What drugs are non-selective COX inhibitors (NSAIDs)?

Aspirin, ketoprofen, ibuprofen, flurbiprofen, ketorlac, naproxen, diclofenac, indomethacin, acetaminophen

What drugs are COX-2 preferential inhibitors?

Meloxicam, diclofenac

What drug is a COX-2 selective inhibitor?

Celecoxib

What does PGD2 cause?

Inflammation

What does PGE2 cause?

Fever

What prostacyclin (PGI2) cause?

Inhibits platelet activation

Vasodilation

What does thromboxane (TxA2) cause?

Promotes platelet activation

Vasoconstriction

What types of interactions are most likely between arachidonic acid and COX1/COX2?

Ionic interactions due to carboxylic acid

Hydrophobic interactions due to long fatty acid chains

What are examples of basic amino acids?

Histidine, lysine, arginine

What are examples of hydrophobic amino acids?

Valine, leucine, isoleucine, methionine, proline

What NSAID chiral center does not epimerize and why?

Naproxen due to the electron-donating methoxy functional group

Describe conformational restriction in diclofenac

Ortho-Cl group sterically clashes with phenyl group of phenylacetic acid

How can a bond rotation in diclofenac prevent steric clashing?

Rotation about the C-N bond orients lower aromatic ring perpendicular to phenyl group

Improves binding affinity

What is the oral dosage of diclofenac?

50 mg BID/TID

Describe conformational restriction in fenoprofen

Multiple energetically favored binding conformations in solution

Only one conformation is favored by the COX active site

Sampling of conformations to find the right "fit"

What is the dosage of fenoprofen?

400-600 mg TID/QID

Describe conformational restriction in indomethacin

Ortho-H sterically clashes with methyl group on indole ring

How can a bond rotation in indomethacin mitigate steric clashing?

Rotation about indicated C-C bond orients benzene ring perpendicular to the indole ring

Improves binding affinity

What is the dosage of indomethacin?

Once daily

What functional group contained in meloxicam mimics carboxylic acid?

Enol (alkene + alcohol)

What interactions are present between celecoxib and COX-2 at the allosteric pocket?

Hydrogen bonding interactions between sulfonamide and Arg, His, Tyr

Hydrophobic interactions between phenyl and Val

Describe the biosynthesis of uric acid from purine catabolism

Adenine is turned into hypoxanthine by adenine deaminase

Xanthine oxidase turns hypoxanthine to xanthine and xanthine to uric acid

Uric acid can transform to and from urate

Uricase transforms urate to allantoin, which can then become glyoxylic acid + urea

What properties contribute to the poor solubility and promote crystalization of uric acid?

Intermolecular hydrogen bonding and pi stacking

Tautomerization of uric acid

What does uric acid anion transporter 1 (URAT1) inhibition prevent?

Uric acid reabsorption in proximal tubules

What is the MOA of probenecid?

Contains a carboxylic acid that mimics negatively-charged urate

Inhibits URAT1 and prevents urate reabsorption

What are DDIs of probenecid?

ANIONIC drugs excreted through OAT1

Probenecid also inhibits OAT1

What is the MOA of allopurinol?

Contains pyrazole that mimics the imidazole ring of hypoxanthine/xanthine

Displays 15-20x higher affinity for xanthine oxidase (XO) than xanthine

What reaction does allopurinol undergo?

Oxidation by xanthine oxidase to become an active metabolite with longer half-life

Both allopurinol and and its oxidized metabolite inhibit XO

What is the MOA of pegloticase?

A recombinant porcine-like uricase that promotes uric acid elimination by converting it to allantoin

What is pegloticase linked to?

Covalently linked to polyethylene glycol (PEG)

What are the benefits to pegloticase being covalently linked to PEG?

Evades immunogenic response

Evades proteolysis

Reduces renal clearance by increasing MW