Exam 2: Lecture 3, NSAIDs Med Chem

Question 1

All naturally occurring PGs contain this substitution pattern…..

Answer 1

15a hydroxyl group and trans double bond at C -13

unless dble bond occurs at C-8/C-12, side chains are trans

Question 2

PGs are classified by capital letters depending….

Answer 2

on nature and stereochemistry of the oxygen substituent at the 9/11 positions

Question 3

number of double bonds in side chains corresponds with…

Answer 3

subscript

Question 4

Enzyme involved in deactivation of prostaglandins

Answer 4

Prostaglandin-15-hydroxy dehydrogenase

Question 5

COX-1 is responsible for…

Answer 5

production of PGs that are involved in protection of gastric mucosa, maintenance of kidney function

Question 6

COX-2 is responsible for…

Answer 6

production of PGs at inflammatory sites

Question 7

COX-3 is responsible for…

Answer 7

selectively inhibited by antipyretic/analgesic drugs

recent discovery, possible site of Tylenol action

Question 8

Difference in COX-1 and COX-2 site

Answer 8

isoleucine in COX-1 and Valine in COX-2, results in bigger and more flexible channel in COX-2

Question 9

SAR Para-amino phenol derivatives (Tylenol)

Answer 9

Sub at nitrogen reduces basicity, decrease activity unless subsistent is metabolically labile

Amides derived from aromatic acids are less active or inactive

Etherification of phenolic function with methyl or propyl groups produces derivatives with greater side effects than with ethyl

Question 10

MOA Acetaminopehn

Answer 10

interfere with pyrogenic factors possibly through COX-3

Depletion of glutathione, cofactor for PGE

AM404 potent activator of ion channel TRPV1 and has effect n CB1. Both receptors involved in pain and thermoregulatory pathywa

Question 11

Hepatotoxicity of Acetaminophen

Answer 11

Hepatic necrosis develops at lower doses in some heavy drinkers to higher levels CYP2E1/CYP3A4 so less drug required to have negative effect

Question 12

Other effects of Salicylates?

Answer 12

uricosuric properties
inhibition of platelet aggregation
protective against Col0n cancer

Question 13

MOA Salicylates

Answer 13

inhibition of COX lead to inhibit of biosynthesis of prostaglandins

Question 14

SAR Salicylates

Answer 14

GI side effects associated with carboxylic acid

acidity of COOH decrease, analgesic stay same but inflammatory effect decrease

removing phenolic group, or more meta/para = lose activity

sub of halogen atoms on ring increase potency and toxicity

sub of aromatic ring at 5 position increase anti-inflam activity

Question 15

Salicylates metabolism

Answer 15

10% excreted as free acid

75% conj with glycine to produce salicylic acid

15% conj with glucuronic acid to form glucuronide ether/ester

Question 16

SAR Arylalkanoic acids (indomethacin)

Answer 16

anti inflame activity increase as acidity of carboxylic group increase

amide analogs inactive

N of indole ring not essential

cis confirmation of 5 position preferred

Question 17

Metabolism of indomethacin

Answer 17

N-Deacetylation
O-demethylation
Glucuronidation

Question 18

Sulindac

Answer 18

longterm treatment RA,etc

prodrug, 8 times more effective aspirin

less CNS/GI effect but other undesirable side effects like poor water solubility resulting in crystalluria

highly bound to drum proteins bc acidic

Question 19

SAR Sulindac

Answer 19

Replace methoxy group by fluro group enhances analgesic effects

Z-isomer more portent than E-isomer

Decreased water solubility alleviated by replacing CL with sulfonyl group

Question 20

SAR Sulindac

Answer 20

Replace methoxy group by flour group enhances analgesic effects

Z-isomer more portent than E-isomer

Decreased water solubility alleviated by replacing CL with sulfinyl group

Question 21

Diclofenac sodium

Answer 21

inhibition of COX system
inhibition of lipoxygenase
inhibition of AA release and stim of its reuptake - reduction AA availability

free acid highly bound to serum proteins

50/60% dose bioavailability due to extensive hepatic metabolism

long-term use predispose to peptic ulcer, prescribed Arthrotec = combo with misoprostol

Question 22

Etodolac

Answer 22

New class of NSAIDs

inhibit COX without affecting LOX system

Question 23

Nabumetone

Answer 23

non acidic, does not produce sig primary insult and is ineffectual inhibit of PG cyclooxyrgenase in gastric mucosa so producing min secondary insult….

better for GI essentially

Question 24

Nabumetone

Answer 24

non acidic, dose not produce sig primary insult and is ineffectual inhibit of PG cyclooxyrgenase in gastric mucosa so producing min secondary insult….

better for GI essentially

Question 25

Ibuprofen

Answer 25

marketed as racemic drug, activity is in S+ isomer tho.

Absence of a methyl = reduce anti-inflame and more toxic

Question 26

SAR Naproxen

Answer 26

a methyl group improv potency
S more potent isomer
replacing Carboxyl grp with functional groups able to be metabolized to carboxyl function = retention activity