Med Chem part 3 Flashcards
explain WHY acetaminophen does not possess anti inflammatory and only antipyretic/analgesic activity
acetaminophen works by inhibiting Peroxidase activity, preventing the regeneration of the Tyr385 free radical to keep the prostaglandin synthesis cycle moving
HOWEVER, it can only do this in areas of LOW reactive oxygen species, and ROS is high in areas of inflammation, and therefore it cannot work there
tylenol has been showed to be stronger at inhibiting COX3 in the brain rather than COX2 and COX1
this leads to antipyretic and analagesic activity
what does IC50 mean?
concentration of drug at which it inhibits the enzyme by 50%
if the IC50 of a drug is low for a particular enzyme, what does this mean?
it is able to block the enzyme at low concentrations – more potent/more drawn to inhibit that enzyme
true or false
the IC50 of tylenol for COX3 is higher than COX1
FALSE - LOWER
lower concentration is needed to inhibit COX3
true or false
tylenol is a weak COX inhibitor
true
in the structure of tylenol, what group is preferred at NH
acetyl group
the structure of tylenol has an OH attached to a benzene ring.
explain how this could be changed, and what the result was found to be
when OH is etherified to OCH3 or O-isoPropyl, more side effects are produced than -OEthyl derivates and NO gain in pharmacologic activity
tylenol in which the OH has been etherified is phenacetin
explain the relationship between phenacetin and tylenol, both structurally and functionally
phenacetin is structurally the same as tylenol, it just has been ehterified from OH to Oethyl (CH2CH3) also called ethoxy
functionally, phenacetin is converted into tylenol upon phase 1 metabolism - same pharmacologic activity
what is the major pathway of acetaminophen metabolism?
in adults - glucuronidation (O-glucuronide)
in infants - sulfation (O-sulfate)
when is the minor metabolism pathway of acetaminophen important?
in case of an overdose
what is the name of the toxic metabolite produced from the minor pathway of acetaminophen metabolism?
NAPQI (N-acetylimidoquinone)
true or false
NAPQI is a nucleophile
FALSE - electrophile
very reactive
has partial positive charges on carbons next to =O
What are the enzymes that produce NAPQI
CYP2E1 and CYP3A4
explain why it is not recommended to drink alcohol and take tylenol at the same time
alcohol induces CYP2E1, the same enzyme that produces the toxic and reactive tylenol metabolite - NAPQI
more of NAPQI may be produced, causing liver damage
name the 3 fates of NAPQI
- the endogenous way to clear it is by GSH (glutathione) conjugation. it is then renally excreted as mercapturic acid
- An antidote, N-acetyl cysteine, can be administered. it will also be excreted as a mercapturic acid derivative
- if these 2 pathways cannot handle the amount of NAPQI, it will covalently bind to hepatic proteins and create a toxic hepatic complex, causing hepatic necrosis and renal failure
in GENERAL, what structures are used as antidotes for tylenol overdose?
name a specific antidote
-SH containing compounds
N-acetyl cysteine is one
what is GSH
a tripeptide made of glutamic acid, cysteine, and glycine
a well known reducing molecule. used endogenously in cases of tylenol overdose
how is GSH and N-acetyl cysteine able to detoxify NAPQI
cysteine binds and is able to take care of the highly reactive and electrodeficient carbon
true or false
tylenol overdose is not common
FALSE - it is
so many OTC products contain tylenol without explicitly stating it
recap - name 2 salicylic acid derivatives that are NSAIDS
aspirin
diflunisal
ortho vs para vs meta
ortho - 2 subst next to each other
para - opposite sides
meta - 1,3 position
what is an important SAR (structure activity relationship) of salicylic acid derviatives
(if this is done, the drug is inactive)
the OH and COOH must be ORTHO - NOT para or meta
otherwise, the drug is not active
name 2 ways in which the potency of salicylic acid derivatives can be enhanced
- Add a lipophilic group at C5 position (diflunisal)
- Esterification of phenolic OH with acetic acid (aspirin)
salicylic acid derivatives (salicylates) inhibit COX in a __________- manner
what is the exception
competitive and reversible manner
exception is ASPIRIN - inhibition is pseudo irreversible
true or false
all NSAIDS are competitive and reversible inhibitors of COX, with the exception of tylenol
FALSE - tylenol is not an NSAID
answer is aspirin - pseudoirreversible inhibitor
what is the role of the carboxylate group in aspirin?
hydrophilic component - pulls proton from serine on COX
this leaves an O on serine with a negative charge which quickly binds to an acetyl group on aspirin
chemical name for aspirin
acetylsalicylic acid
explain the mechanism of action of aspirin and include why its action is “pseudoirreversible”
an acetyl group binds covalently to serine on COX.
after an acetyl group leaves aspirin, it becomes salicylic acid. this salicylic acid stays within the enzyme pocket and blocks the access of arachidonic acid
however, this acetylated serine on cox is easily hydrolyzed and converted back to the unrestricted enzyme.
this is why it is “pseudoirreversible” – it COVALENTLY BINDS – but does hydrolyze back easily
true or false
the mechanism of aspirin occurs through an ionic bond
FALSE
covalent bonding of acetyl group to an O on serine (but easily hydrolyzed back)
once an acetyl group from aspirin binds to serine in COX, what is left?
salicylic acid + inactivated acetylated COX1
explain how the name “aspirin” can help to determine its structure
spirin = salicylic acid
A = acetyl
its acetylated salicylic acid
as mentioned, aspirin works through acetylating serine on COX.
which serine?
for COX1 - Ser530
for COX2 - Ser516
what is the largest class of NSAIDs
arylalkanoic acids
what 2 categories of drugs are part of Arylalkanoic acids?
phenacs and profens
explain how phenacs and profens differ and how they are similar (as far as structure)
they are both in the aryl alkanoic acid class
however, the R group for phenacs is H and the R group for profens is CH3
this, phencs belong to aryl acetic acid class and profens to aryl propionic acid class.
can the aryl ring of aryl alkanoic acids be conjugated with another ring?
explain
yes, but they must be noncoplanar to achieve maximum hydrophobic contact with COX – necessary for binding
what is the structural relationship between indomethacin and sulindac
indomethacin has an indole group while sulindac has an indene group instead
true or false
the indole ring in indomethacin is ESSENTIAL for activity
false
bc indene ring of sulindac also is active
indomethacin has an N-benzoyl group.
if it was replaced with _____, activity would be decreased
alkanoyl or arylalkanoyl groups
indomethacin has a chlorine group attached to N-benzoyl.
what could chlorine be replaced with to still retain the activity of indomethacin? why?
F or CF3
electron withdrawing groups are desired at this para position
true or false
the COOH group in Indomethacin is not important
FALSE - it is very important
this is what is making the molecule a lipophilic ACID, and similar enough in structure to arachidonic acid to compete with it
how is it that aryl alkanoic acids all have an issue of GI irritation?
the presence of acid (COOH) alone irritates GI.
additionally, the inhibition of COX in the GI mucosa has bad effects. this prevents the synthesis of prostaglandins that have cytoprotective functions.
damage to the GI is possible
prostaglandins have cytoprotective functions in the GI
which prostaglandin is mainly responsible for this protective role?
PGE1
which enantiomer of indomethacin is preferred and what is keeping it in this conformation?
why is it important?
when the N-para-chlorobenzyl group is CIS to the methoxy ring
this is due to steric hindrance of:
-CH3 on carbon 2
-Hydrogen on carbon 7
on either side
this is important because this steric hindrance makes either ring NON COPLANAR with each other - easier to bind to hydrophobic channel in COX
what drug is an isostere of indomethacin?
sulindac
name the 2 ways in which Indomethacin is metabolized
when does it become inactive
CYP2C9 mediated O-demethylation (inactive)
amide hydrolysis (inactive)
why was sulindac discovered?
bc indomethacin was associated with GI irritation
Sulindac was discovered as a PRODRUG – eliminates the secondary mechanism of GI irritation that occurs when the drug inhibits COX in the GI mucosa, and thus inhibiting production of PGE1, which has protective roles in the stomach
true or false
sulindac is not associated with GI irritation
FALSE - it still is
eliminated secondary mechanism, but still has a COOH group in its structure.
primary mechanism of irritation still exists
true or false
Sulindac is not an active drug
true
it is an inactive prodrug
as far as structure, explain the difference between sulindac and its metabolite
sulindac itself is an INACTIVE polar sulfoxide. it is a prodrug
its metabolite is an ACTIVE nonpolar sulfide
which isomer of sulindac is more potent and why?
Z (cis) isomer is more potent
this was already established from indomethacin
the 2 rings must be cis to each other to be NONCOPLANAR and more easily bind to COX
what enzyme converts Sulindac into its active metabolite?
where?
is this reaction reversible?
CYP/FMO system in the liver
yes, it’s reversible
true or false
sulindac is analgous to indomethacin and they are isosteres
true
which has a longer half life – sulindac or indomethacin?
why?
SULINDAC (8hrs - Indomethacin is 4)
as mentioned, Indomethacin has 2 methods of metabolism and inactivation:
-O-dethylation at H3CO
-Hydrolysis of amide
however, in the structure of Sulindac, H3CO has been replaced with F which is VERY STABLE TO METABOLISM! therefore, it only has 1 method if metabolism/inactivation has opposed to 2
