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

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

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

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2
Q

what is warfarin a derivative of

A

coumarin

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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

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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

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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

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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

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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

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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

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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

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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

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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)

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12
Q

why is cyclohexane so stable

A

forms a chair conformation thus no angle strains

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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

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14
Q

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

A

it is electron deficient (partial pos sign)

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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

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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

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16
Q

what is tautomerism

A

converting between stable keto and stable enol

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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

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18
Q

draw the structures of vitK, vitK hydroquinone and vitK epoxide

A

vitK hydroquinone is reduced form while vitK epoxide is oxidised form

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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

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20
Q

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

A

peptidic DTI: desirudin, bivalirudin

nonpeptidomimetic: dabigatran etexilate (DE)

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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

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22
Q

what does LogP value indicate

A

lipophilicity, higher LogP/cLogP means higher lipophilicity

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23
Q

why does DE have higher cLogP than dabigatran

A

DE has nonpolar groups like methyl groups which incr lipophilicity

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24
Q

what are the two key functional groups present in DE and what happens to the two groups when activated into dabigatran

A

ester and carbamate group -> hydrolyses into COOH group and C(NH2)=NH group aka amidine

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25
Q

why is amidine basic

A

stabilisation of the pair of electrons between NH2 and NH to give NH- and NH3+

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26
Q

what is the moa of rivaroxaban and apixaban

A

they target factor X and act as an antifactor Xa inhibitor

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27
Q

what is the difference in structure between apixaban and rivaroxaban

A

apixaban has a carboxamide structure while rivaroxaban has a oxazolidine structure

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28
Q

what are the key SAR of rivaroxaban and related analogues

A

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

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29
Q

what is the moa of aspirin

A

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)

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30
Q

draw the structure of Ser residue and the trans-esterification process (part of aspirin moa)

A

cyclooxygenase - NH - C=O - CH(CH2OH)NH - C=O - CR(NH)—-

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31
Q

what is the moa of clopidogrel

A

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

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32
Q

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

A
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33
Q

draw structures of thiolactone, lactam and lactone

A
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34
Q

which C atom is denoted as alpha carbon

A

C directly bonded to carbonyl O

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35
Q

what is the moa of paracetamol

A

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

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36
Q

what is the properties of paracetamol (toxicity and acidity and water solubility)

A

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
Q

draw structure of paracetamol and its hydroxyamide metabolite and its hepatotoxic N-acetyl imidoquinone metabolite

A
38
Q

list examples of NSAIDs and what group do majority of NSAIDs belong to

A

arylalkanoic acids: indomethacin, sulindac, diclofenac, nabumetone, ibuprofen

salicylic based: aspirin, oil of wintergreen

others: mefenamic acid

39
Q

what kind of inhibitor is aspirin

A

suicide enzyme inhibitor bc it permanently inactivates COX1 as it interact with the active site

40
Q

what functional group is essential for activity of aspirin and what can increase activity of aspirin

A

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
Q

what is the chemical name of aspirin and oil of wintergreen and draw structure

A

aspirin is acetylsalicylic acid

oil of wintergreen is methyl salicylate

42
Q

what is the general structure of arylalkanoic acids

A

Ar - C(R)H - COOH

where R is H, CH3 or alkyl
and Ar is aryl or heteroaryl

43
Q

if alpha carbon of a generic arylalkanoic acid is chiral, which enantiomer is active

A

S-enantiomer

44
Q

what is the moa of arylalkanoic acids and what kind of effects do they have

A

inhibit COX predominantly, exhibit anti-inflamm and to some extent antipyretic activity

45
Q

what is the chemical structure of indomethacin

A

heteroarylacetic acid with an indole ring

46
Q

what is the importance of COOH in indomethacin in terms of activity

A

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
Q

what happens if CH3 inserted to alpha C of indomethacine

A

makes alpha C chiral and thus only S-enantiomer becomes active

48
Q

what is the significance of aracylation of N of indole ring of indomethacin and what happens if the structure is altered

A

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
Q

what is the significance of the 2-methyl group of indomethacin

A

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
Q

what types of groups can be attached to position 5 on indole system in indomethacine

A

any e/d or e/w group

51
Q

what is the chemical structure of sulindac (specifically Z-sulindac)

A

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
Q

what is sulindac an analogue of

A

indomethacin -> N replaced by C

53
Q

is sulindac a prodrug and how to convert Z-sulindac into active and inactive metabolite (name func group change and draw their structure)

A

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
Q

how to arrange Z and E stereoisomers and what are they called

A

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
Q

what is the chemical structure of diclofenac

A

arylacetic acid with 2,6-dichloroanilino substituent in ortho position

56
Q

what kind of effects does diclofenac has

A

anti-inflamm, analgesic, antipyrotic

(better than aspirin and indomethacine)

57
Q

what is the significance of the NH substituent in diclofenac

A

NH is a bioisosteric replacement of OH in salicylic acid

58
Q

what is the significance of the two chloro groups in diclofenac

A

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
Q

what might long term and frequent use of diclofenac may cause and how

A

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
Q

draw structures of diclophenac’s major metabolite and its hepatotoxic compound

A
61
Q

what is the advantage of nabumetone

A

it is a nonacidic prodrug and thus it does not induce direct GI mucosal damage

62
Q

how does the structure of nabumetone change for it to be eliminated

A

keto group reduced to alcohol then glucoronidation to form glucoronide then eliminated

note nabumetone can be reduced or oxidised (two paths)

63
Q

is nabumetone a prodrug, if yes what is it converted to

A

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
Q

draw structure of nabumetone, its reduced and oxidised form

A

recall structure of naphthalene as base structure

65
Q

what is the structure of ibuprofen

A

2-arylpropionoic acid with a chiral centre

66
Q

why does ibuprofen has a short duration of action

A

ibuprofen is metabolised into many inactive metabolites

67
Q

what is meant by bioequivalence and which stereoisomers do we see it

A

R-isomer is metabolised into S-isomer

interconversion observed in -profens and naproxen

68
Q

what is the structure of anthranilic acid and what is it an analogue of

A

analogue of salicylic acid

NH2 is a bioisosteric replacement of OH

69
Q

what is the structure of mefenamic acid

A

2-arylanthranilic acid

70
Q

what are the features of the functional groups in mefenamic acid

A

ortho-anilino group increases COX binding and the two CH3 groups promote non coplanarity

71
Q

how is mefenamic acid converted to eventually becoming eliminated

A

3’ CH3 group oxidised into CH2OH then COOH during phase 1 metabolism then COOH undergo glucoronidation in phase 2 metabolism then eliminated

72
Q

list examples of selective COX2 inhibitors

A

celecoxib and etoricoxib

73
Q

how is selectivity for a target site (specifically COX2) achieved

A

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
Q

what are the properties of COX2 inhibitors (regarding s/e)

A

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
Q

where do COX2 inhibitors bind to and its moa

A

bind to allosteric site of enzyme such that enzyme undergoes conformational changes thus cannot bind to its target

76
Q

is ibuprofen and etoricoxib acidic

A

ibuprofen is acidic but etoricoxib is non acidic

77
Q

why do gout attacks occur

A

occurs when uric acid accumulates and increases in conc such that there is precipitation of uric acid crystals

78
Q

what is the etiology of a gout attack

A

xanthine oxidase converts hypoxanthine to xanthine and further oxidises xanthine into uric acid

79
Q

what is the pKa of uric acid and which func group is responsible for this

A

uric acid is a weak acid with pKa 5.7

OH group in pyrimidine ring (uric acid is a purine derivative)

80
Q

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

A

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
Q

draw structure of hypoxanthine, xanthine, uric acid and urate monoanion

A
82
Q

what are the tx options for gout attacks

A

colchicine, allopurinol, febuxostat

82
Q

what are the tx options for gout attacks

A

colchicine, allopurinol, febuxostat

83
Q

what is the chemical structure of a purine

A

a pyrimidine ring fused with an imidazole

84
Q

what is the moa of colchicine

A

for prophylaxis and tx of gout attack by aiming to decr formation of uric acid

85
Q

what is the structure of allopurinol

A

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
Q

what is the moa of allopurinol

A

competitive inhibitor for xanthine oxidase which has 15-20x more affinity to XO than xanthine

87
Q

what is the indication for febuxostat

A

for chronic management of hyperuricemia in pt with gout and if cannot tolerate allopurinol

88
Q

what is the moa of febuxostat

A

nonpurine selective inhibitor of xanthine oxidase

non competitive inhibitor of both reduced and oxidised form of xanthine oxidase

89
Q

what might presence of purine cause

A

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

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