Brainscape's Knowledge GenomeTM


Top Flashcards (Certified)
All Flashcards

pr3154 > ic9 - med chem of drugs for coagulation disorders and inflammation > Flashcards

ic9 - med chem of drugs for coagulation disorders and inflammation Flashcards

(91 cards)

Start Studying
1
Q

what are the classes of drugs that are used to tx coagulation disorders

A

VKA - warfarin, phenindione
direct thrombin inhibitor (under DOACs) - dabigatran
antifactor Xa inhibitor (under DOACs) - rivaroxaban, apixaban
antiplatelets - aspirin, clopidogrel, ticagrelor

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

what is warfarin a derivative of

A

coumarin

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

what is the structure of coumarin

A

fused bicyclic ring containing a lactone ring
(benzene with O hexacyclic with lactone)

substituents often at positions 3 and 4

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

what is the structure of warfarin

A

from coumarin structure then
OH substituted on position 3, CH(benzene)CH2C=O(CH3) on position 4

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

what is another derivative of coumarin apart from warfarin and what is its structure

A

from coumarin structure,
OH substituted on position 3
x2 the current structure
and connect the two with a methylene aka CH3

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

what is the pKa of warfarin and which is the ionisable group

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

what properties does warfarin have

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

what is the r/s of the pKa values to acidity

A

lower pKa means more acidic (bc lower pKa means higher Ka)

strong acids usually pKa -ve
strong bases usaully pKa >14

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

what is the structure and properties of 1,3-indandione

A

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 well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

how to deduce which is S-enantiomer

A

rank the groups based on priority then direct the least priority group away from you

ranking for S-enantiomer should be ACW

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

how does warfarin form a hemiketal

A

OH on position 3 attack carbonyl C to form a six membered ring which is very stable (relate to stability of cyclohexane)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

why is cyclohexane so stable

A

forms a chair conformation thus no angle strains

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

how are hemiketals formed

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

what does it mean if a group or an atom is electrophilic

A

it is electron deficient (partial pos sign)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

what is the structure and properties of phenindione

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

what is the structure and properties of phenindione (pKa)

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

what is tautomerism

A

converting between stable keto and stable enol

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
17
Q

what is the moa of warfarin

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
18
Q

draw the structures of vitK, vitK hydroquinone and vitK epoxide

A

vitK hydroquinone is reduced form while vitK epoxide is oxidised form

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
19
Q

what is the moa of dabigatran

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
20
Q

what are other examples of direct thrombin inhibitors (DTI) (peptidic and nonpeptidomimetic)

A

peptidic DTI: desirudin, bivalirudin

nonpeptidomimetic: dabigatran etexilate (DE)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
21
Q

what is the structure of DE and properties of dabigatran (indication, activation, cLogP of D and DE, s/e)

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
22
Q

what does LogP value indicate

A

lipophilicity, higher LogP/cLogP means higher lipophilicity

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
23
Q

why does DE have higher cLogP than dabigatran

A

DE has nonpolar groups like methyl groups which incr lipophilicity

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
24
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
25
why is amidine basic
stabilisation of the pair of electrons between NH2 and NH to give NH- and NH3+
26
what is the moa of rivaroxaban and apixaban
they target factor X and act as an antifactor Xa inhibitor
27
what is the difference in structure between apixaban and rivaroxaban
apixaban has a carboxamide structure while rivaroxaban has a oxazolidine structure
28
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
29
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)
30
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)----
31
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
32
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
33
draw structures of thiolactone, lactam and lactone
34
which C atom is denoted as alpha carbon
C directly bonded to carbonyl O
35
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
36
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
37
draw structure of paracetamol and its hydroxyamide metabolite and its hepatotoxic N-acetyl imidoquinone metabolite
38
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
39
what kind of inhibitor is aspirin
suicide enzyme inhibitor bc it permanently inactivates COX1 as it interact with the active site
40
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
41
what is the chemical name of aspirin and oil of wintergreen and draw structure
aspirin is acetylsalicylic acid oil of wintergreen is methyl salicylate
42
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
43
if alpha carbon of a generic arylalkanoic acid is chiral, which enantiomer is active
S-enantiomer
44
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
45
what is the chemical structure of indomethacin
heteroarylacetic acid with an indole ring
46
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
47
what happens if CH3 inserted to alpha C of indomethacine
makes alpha C chiral and thus only S-enantiomer becomes active
48
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
49
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
50
what types of groups can be attached to position 5 on indole system in indomethacine
any e/d or e/w group
51
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
52
what is sulindac an analogue of
indomethacin -> N replaced by C
53
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
54
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)
55
what is the chemical structure of diclofenac
arylacetic acid with 2,6-dichloroanilino substituent in ortho position
56
what kind of effects does diclofenac has
anti-inflamm, analgesic, antipyrotic (better than aspirin and indomethacine)
57
what is the significance of the NH substituent in diclofenac
NH is a bioisosteric replacement of OH in salicylic acid
58
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
59
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
60
draw structures of diclophenac's major metabolite and its hepatotoxic compound
61
what is the advantage of nabumetone
it is a nonacidic prodrug and thus it does not induce direct GI mucosal damage
62
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)
63
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)
64
draw structure of nabumetone, its reduced and oxidised form
recall structure of naphthalene as base structure
65
what is the structure of ibuprofen
2-arylpropionoic acid with a chiral centre
66
why does ibuprofen has a short duration of action
ibuprofen is metabolised into many inactive metabolites
67
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
68
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
69
what is the structure of mefenamic acid
2-arylanthranilic acid
70
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
71
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
72
list examples of selective COX2 inhibitors
celecoxib and etoricoxib
73
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
74
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
75
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
76
is ibuprofen and etoricoxib acidic
ibuprofen is acidic but etoricoxib is non acidic
77
why do gout attacks occur
occurs when uric acid accumulates and increases in conc such that there is precipitation of uric acid crystals
78
what is the etiology of a gout attack
xanthine oxidase converts hypoxanthine to xanthine and further oxidises xanthine into uric acid
79
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)
80
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
81
draw structure of hypoxanthine, xanthine, uric acid and urate monoanion
82
what are the tx options for gout attacks
colchicine, allopurinol, febuxostat
82
what are the tx options for gout attacks
colchicine, allopurinol, febuxostat
83
what is the chemical structure of a purine
a pyrimidine ring fused with an imidazole
84
what is the moa of colchicine
for prophylaxis and tx of gout attack by aiming to decr formation of uric acid
85
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)
86
what is the moa of allopurinol
competitive inhibitor for xanthine oxidase which has 15-20x more affinity to XO than xanthine
87
what is the indication for febuxostat
for chronic management of hyperuricemia in pt with gout and if cannot tolerate allopurinol
88
what is the moa of febuxostat
nonpurine selective inhibitor of xanthine oxidase non competitive inhibitor of both reduced and oxidised form of xanthine oxidase
89
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

pr3154 (20 decks)

Brainscape helps you reach your goals faster, through stronger study habits.
© 2025 Bold Learning Solutions. Terms and Conditions