ic9 - med chem of drugs for coagulation disorders and inflammation Flashcards
what are the classes of drugs that are used to tx coagulation disorders
VKA - warfarin, phenindione
direct thrombin inhibitor (under DOACs) - dabigatran
antifactor Xa inhibitor (under DOACs) - rivaroxaban, apixaban
antiplatelets - aspirin, clopidogrel, ticagrelor
what is warfarin a derivative of
coumarin
what is the structure of coumarin
fused bicyclic ring containing a lactone ring
(benzene with O hexacyclic with lactone)
substituents often at positions 3 and 4
what is the structure of warfarin
from coumarin structure then
OH substituted on position 3, CH(benzene)CH2C=O(CH3) on position 4
what is another derivative of coumarin apart from warfarin and what is its structure
from coumarin structure,
OH substituted on position 3
x2 the current structure
and connect the two with a methylene aka CH3
what is the pKa of warfarin and which is the ionisable group
warfarin is acidic as the OH substituted on position 3 (becomes an enol) and is ionisable (vs regular OH) and can form a Na salt
pKa is 5.1
O- conjugated with double bond thus can form resonance and is stable -> thus forming enolic anion
note that in order to form a Na salt, a base is required thus warfarin is acidic
what properties does warfarin have
warfarin has a chiral carbon thus it forms a racemic mixture (S-warfarin is active)
forms a hemiketal
highly protein bound
cross sensitivity with 1,3-indandiones
what is the r/s of the pKa values to acidity
lower pKa means more acidic (bc lower pKa means higher Ka)
strong acids usually pKa -ve
strong bases usaully pKa >14
what is the structure and properties of 1,3-indandione
indane structure (fused bicyclic hydrocarbon ring -> benzene fused with cyclopentane) with two ketone group on position 1 and 3
possessed renal and hepatic toxicities thus use is precluded
how to deduce which is S-enantiomer
rank the groups based on priority then direct the least priority group away from you
ranking for S-enantiomer should be ACW
how does warfarin form a hemiketal
OH on position 3 attack carbonyl C to form a six membered ring which is very stable (relate to stability of cyclohexane)
why is cyclohexane so stable
forms a chair conformation thus no angle strains
how are hemiketals formed
formation of hemiketals occur when an alcohol O atom adds to the carbonyl C of an aldehyde or a ketone through nucleophilic attack of the hydroxyl group at the electrophilic carbonyl group
what does it mean if a group or an atom is electrophilic
it is electron deficient (partial pos sign)
what is the structure and properties of phenindione
from indane structure (benzene fused with cyclopentane), add enol group at position 1 and a benzene at position 2 and a ketone group at position 3
acidic with pKa of 4
exhibits tautomerism
what is the structure and properties of phenindione (pKa)
from indane structure (benzene fused with cyclopentane), add enol group at position 1 and a benzene at position 2 and a ketone group at position 3
exhibits tautomerim
acidic with pKa of 4
what is tautomerism
converting between stable keto and stable enol
what is the moa of warfarin
vitK is a cofactor for glutamic acid residue on N terminal of II, VII, IX, X and protein C to form gamma glutamyl carboxylase (GGCX) enzyme which causes conformational changes to protein by chelation with Ca ions thus activating these vitK dependent clotting factor
these clotting factors and GGRX are important for post translational carboxylation of prothrombin
in this process, vitK hydroquinone is converted to vitK epoxide in presence of O2 and CO2 which then under goes redox cycling whereby the epoxide is reduced by vitK epoxide reductase (VKOR)C1 to vit K which is in turn converted back to vitK hydroquinone by vitK reductase (VKR)
warfarin is vitK antagonists that act on VKOR and VKR such that it leads to the eventual decr in recycling of vitK into vitK hydroquinone
draw the structures of vitK, vitK hydroquinone and vitK epoxide
vitK hydroquinone is reduced form while vitK epoxide is oxidised form
what is the moa of dabigatran
in coagulation cascade, thrombin (factor IIa) catalyses the conversion of fibrinogen to soluble fibrin which turns insoluble by factor XIIa
DTI binds directly and reversibly to the active site of thrombin and inactivate free and fibrin bound thrombin
what are other examples of direct thrombin inhibitors (DTI) (peptidic and nonpeptidomimetic)
peptidic DTI: desirudin, bivalirudin
nonpeptidomimetic: dabigatran etexilate (DE)
what is the structure of DE and properties of dabigatran (indication, activation, cLogP of D and DE, s/e)
indication: used for prevention of stroke and blood clots in AF
activation: DE is a prodrug and is activated by esterase -> ester and carbamate hydrolyses to form dabigatran
cLogP: 0.79 for D vs 3.8 for DE
s/e: significant incr in risk for GI bleed
what does LogP value indicate
lipophilicity, higher LogP/cLogP means higher lipophilicity
why does DE have higher cLogP than dabigatran
DE has nonpolar groups like methyl groups which incr lipophilicity
what are the two key functional groups present in DE and what happens to the two groups when activated into dabigatran
ester and carbamate group -> hydrolyses into COOH group and C(NH2)=NH group aka amidine
why is amidine basic
stabilisation of the pair of electrons between NH2 and NH to give NH- and NH3+
what is the moa of rivaroxaban and apixaban
they target factor X and act as an antifactor Xa inhibitor
what is the difference in structure between apixaban and rivaroxaban
apixaban has a carboxamide structure while rivaroxaban has a oxazolidine structure
what are the key SAR of rivaroxaban and related analogues
hydrophobic interaction in morpholinone
substitution of H in phenyl ring reduces activity
H bond (3 H bond acceptors and 1 H bond donor)
5-chlorothiophen better activity than 6-chrlorobenzene in a hydrophobic pocket
S config required
key H bonding sites with target
what is the moa of aspirin
inhibiting the production of thromboxane A2 (TXA2) in platelets by irreversibly and permanently inactivating COX1 through acetylation of a key Ser (Ser530) residue (process is trans-esterification)
draw the structure of Ser residue and the trans-esterification process (part of aspirin moa)
cyclooxygenase - NH - C=O - CH(CH2OH)NH - C=O - CR(NH)—-
what is the moa of clopidogrel
thienopyridine prodrug that requires metabolic activation by cyp into active metabolite that irreversibly inhibits P2Y12 via covalent disulfide bond formation
3A4 oxidises thiophene ring into thiolactone which undergoes ring opening on hydrolysis to generate free thiol group that forms disulfide bond with assisting side chain in P2Y12 and the covalent bond formation inactivates binding of P2Y12 to ADP
ADP plays pivotal role in PLT activation and aggregation
draw the structure of S-clopidogrel (highlight thienopyridine class) then draw oxidation into thiolactone and hydrolysis into active metabolite and formation of disulfide bond with Cys of P2Y12
draw structures of thiolactone, lactam and lactone
which C atom is denoted as alpha carbon
C directly bonded to carbonyl O
what is the moa of paracetamol
act via a central antipyretic mechanism which is through inhibition of PG in CNS
does not possess anti inflamm but with produce analgesic (pain relief) in arthritic and musculoskeletal disorders
what is the properties of paracetamol (toxicity and acidity and water solubility)
not recommended for long term use bc potential hepatotoxicity bc of the minor hydroxyamide metabolite (action of 2E1/3A4) of paracetamol is converted to N-acetyl imidoquinone (NAPQI) that is assoc with hepatotoxicity
weakly acidic with pKa 9.5 due to phenol and has low water solubility
draw structure of paracetamol and its hydroxyamide metabolite and its hepatotoxic N-acetyl imidoquinone metabolite
list examples of NSAIDs and what group do majority of NSAIDs belong to
arylalkanoic acids: indomethacin, sulindac, diclofenac, nabumetone, ibuprofen
salicylic based: aspirin, oil of wintergreen
others: mefenamic acid
what kind of inhibitor is aspirin
suicide enzyme inhibitor bc it permanently inactivates COX1 as it interact with the active site
what functional group is essential for activity of aspirin and what can increase activity of aspirin
OH group ortho to COOH (which in aspirin becomes ester)
second phenyl ring conjugated with phenyl in salicylic acid can incr anti-inflamm activity
what is the chemical name of aspirin and oil of wintergreen and draw structure
aspirin is acetylsalicylic acid
oil of wintergreen is methyl salicylate
what is the general structure of arylalkanoic acids
Ar - C(R)H - COOH
where R is H, CH3 or alkyl
and Ar is aryl or heteroaryl
if alpha carbon of a generic arylalkanoic acid is chiral, which enantiomer is active
S-enantiomer
what is the moa of arylalkanoic acids and what kind of effects do they have
inhibit COX predominantly, exhibit anti-inflamm and to some extent antipyretic activity
what is the chemical structure of indomethacin
heteroarylacetic acid with an indole ring
what is the importance of COOH in indomethacin in terms of activity
COOH group in indomethacin is essential for activity as it ionises and interacts with Arg120 in COX
if replaced with other acidic group or amide, activity is reduced as only acetic group is active
what happens if CH3 inserted to alpha C of indomethacine
makes alpha C chiral and thus only S-enantiomer becomes active
what is the significance of aracylation of N of indole ring of indomethacin and what happens if the structure is altered
aracylation of N is essential for activity, if carbonyl group is reduced to methylene group activity is reduced
and if Cl is replaced with other lipophilic groups like F, CF3 or SCH3, activity is retained
what is the significance of the 2-methyl group of indomethacin
fits into small hydrophobic pocket and also produces steric hindrance such that the 4-chlorobenzoyl group becomes into a cis like position with the methoxyphenyl group to form the active conformation
what types of groups can be attached to position 5 on indole system in indomethacine
any e/d or e/w group
what is the chemical structure of sulindac (specifically Z-sulindac)
arylacetic acid with an indene with a double bond conjugated to the phenyl ring
for S-zulindac, sulfoxide (CH3SO-) is in cis position with F group
what is sulindac an analogue of
indomethacin -> N replaced by C
is sulindac a prodrug and how to convert Z-sulindac into active and inactive metabolite (name func group change and draw their structure)
yes sulindac is a prodrug
reduction by cyp/fmo to form active metabolite with sulfide group
oxidation by cyp/fmo to form inactive metabolite with sulfone group
how to arrange Z and E stereoisomers and what are they called
they are called diastereomers
assigning is more for when there is double bond -> based on double bond, assign one C as (a) and one C as (b) then compare adjacent C of each (a) and (b) to see the bonds to assign priority for each (a) and (b)
Z-stereoisomer has the two higher priority group in cis position (same side)
what is the chemical structure of diclofenac
arylacetic acid with 2,6-dichloroanilino substituent in ortho position
what kind of effects does diclofenac has
anti-inflamm, analgesic, antipyrotic
(better than aspirin and indomethacine)
what is the significance of the NH substituent in diclofenac
NH is a bioisosteric replacement of OH in salicylic acid
what is the significance of the two chloro groups in diclofenac
important for activity as they present steric hindrance to C3-H and COOH groups thus forcing a non planar conformation between the rings which optimises binding
what might long term and frequent use of diclofenac may cause and how
hepatotoxicity
major metabolite catalysed by 3A4 is 4’hydroxy derivative which can form a hepatotoxic quinonimine and is usually inactivated by glutathione but when GSH depleted, Cys residue in hepatocyte may attack the quinonimine forming an irreversible alkylation on the hepatocyte which causes hepatotoxicity
draw structures of diclophenac’s major metabolite and its hepatotoxic compound
what is the advantage of nabumetone
it is a nonacidic prodrug and thus it does not induce direct GI mucosal damage
how does the structure of nabumetone change for it to be eliminated
keto group reduced to alcohol then glucoronidation to form glucoronide then eliminated
note nabumetone can be reduced or oxidised (two paths)
is nabumetone a prodrug, if yes what is it converted to
yes it is a prodrug
converted into 6-methoxynaphthaleneacetic acid through beta-oxidation and 6-MNA is the active metabolite that exerts anti inflamm effect
note nabumetone can be reduced or oxidised (two paths)
draw structure of nabumetone, its reduced and oxidised form
recall structure of naphthalene as base structure
what is the structure of ibuprofen
2-arylpropionoic acid with a chiral centre
why does ibuprofen has a short duration of action
ibuprofen is metabolised into many inactive metabolites
what is meant by bioequivalence and which stereoisomers do we see it
R-isomer is metabolised into S-isomer
interconversion observed in -profens and naproxen
what is the structure of anthranilic acid and what is it an analogue of
analogue of salicylic acid
NH2 is a bioisosteric replacement of OH
what is the structure of mefenamic acid
2-arylanthranilic acid
what are the features of the functional groups in mefenamic acid
ortho-anilino group increases COX binding and the two CH3 groups promote non coplanarity
how is mefenamic acid converted to eventually becoming eliminated
3’ CH3 group oxidised into CH2OH then COOH during phase 1 metabolism then COOH undergo glucoronidation in phase 2 metabolism then eliminated
list examples of selective COX2 inhibitors
celecoxib and etoricoxib
how is selectivity for a target site (specifically COX2) achieved
by having a large enough structure to be rejected by COX1 active site but is able to bind to an allosteric binding pocket that serves as a secondary site for enzyme inhibition
what are the properties of COX2 inhibitors (regarding s/e)
reduced damaging effects to gastric and intestinal mucosa bc of its larger size
but more selective COX2 inhibition may give risk to higher risk for PLT aggregation-facilitated cardiovascular damage
where do COX2 inhibitors bind to and its moa
bind to allosteric site of enzyme such that enzyme undergoes conformational changes thus cannot bind to its target
is ibuprofen and etoricoxib acidic
ibuprofen is acidic but etoricoxib is non acidic
why do gout attacks occur
occurs when uric acid accumulates and increases in conc such that there is precipitation of uric acid crystals
what is the etiology of a gout attack
xanthine oxidase converts hypoxanthine to xanthine and further oxidises xanthine into uric acid
what is the pKa of uric acid and which func group is responsible for this
uric acid is a weak acid with pKa 5.7
OH group in pyrimidine ring (uric acid is a purine derivative)
what does uric acid exist as in physiological pH and how does it affect its water solubility when the conc of uric acid becomes very high
monoanion which is 50x more water soluble
when level of uric acid is high, it can precipitate out as crystals in the joints and connective tissue and initiates as a gout attack
draw structure of hypoxanthine, xanthine, uric acid and urate monoanion
what are the tx options for gout attacks
colchicine, allopurinol, febuxostat
what are the tx options for gout attacks
colchicine, allopurinol, febuxostat
what is the chemical structure of a purine
a pyrimidine ring fused with an imidazole
what is the moa of colchicine
for prophylaxis and tx of gout attack by aiming to decr formation of uric acid
what is the structure of allopurinol
allopurinol is a xanthine mimic such that there is a subtle change in position of N
pyrimidine ring is fused with pyrazole (instead of imidazole as per in xanthine)
what is the moa of allopurinol
competitive inhibitor for xanthine oxidase which has 15-20x more affinity to XO than xanthine
what is the indication for febuxostat
for chronic management of hyperuricemia in pt with gout and if cannot tolerate allopurinol
what is the moa of febuxostat
nonpurine selective inhibitor of xanthine oxidase
non competitive inhibitor of both reduced and oxidised form of xanthine oxidase
what might presence of purine cause
purine can raise uric acid levels ( by producing them as waste upon digestion of purine) which when in excess it can produce uric acid crystals
