826b med chem exam 2

benzodiazepines interaction with alpha 1 subunit chloride ion channel cause

• sedation

  • temazepam, triazolam

benzodiazepines interaction with alpha 2 subunit of chloride ion channel produces

• anxiolytic

alprazolam

• anti-anxiety

• panic disorder

clonazepam

• NO2 is EWG on position 7= hypnotic activity

• Cl is EWG at R2’ in aryl ring= increase activity

lorazepam

• 3-hydroxy benzodiazepines

diazepam

tempazepam

• 3-hydroxy benzodiazepines

SAR of benzos

• R1 on 7 member diazepine ring: substituent here does not affect activity

• R2(keto group): O, S, N→ interacts with H-bonding donor groups on receptor

• R3: alkyl substitution(methyl,ethyl,etc) decreases activity

• R4: usually not substituted(except chlordiazepoxide)

• if 4,5 double bond is saturated or moves to 3,4 position→ decreases activity

• R5:

  • 5-aryl or 5-cyclohexenyl group = CNS depressant

  • phenyl group promotes activity

  • EWG(halogen) at R2’ of aryl ring increase the activity(lorazepam, flurazepam)

• R7: EWG(halogen or nitro group) is required for hypnotic activity

flumazenil

• antidote for benzo

• imidazobenzodiazepine derivative

• no aryl substituent at R5

• no 4,5 double bond

• methyl group at R4

benzodiazepines used for sedation/hypnotics

• flurazepam

• tempazepam

• estazolam

• triazolam

• quazepam

benzodiazepines for panic disorder

• alprazolam

• clonazepam

benzodiazepines for anti-anxiety

• alprazolam

• lorazepam

• oxazepam

• diazepam

• chlordiazepoxide

• clorazepate

benzodiazepines for anticonvulsants

• diazepam

• lorazepam

• clonazepam

• clorazepate

benzodiazepines for alcohol withdrawal

• chlordiazepoxide

• clorazepate

• diazepam

• oxazepam

flurazepam

• long acting benzodiazepine

• partial agonist

• short-term treatment of patients with anxiety induced insomnia

• residual hangover effects(sleepiness, impaired psychomotor and cognitive function)= increase risk of falls and hip fractures in elderly

• CYP3A4 metabolism→ N-1-hydroxylation →N-dealkyation → 3-hydroxylation(inactive metabolite)

quazepam

• triflurorethyl benzodiazepine

• selectively targets GABA-A receptor( alpha 1)= little to no muscle relaxant properties

• S atom increases lipid solubility

• two active metabolites

• MOA similar to zolpidem and zaleplon

diazepam

• 3-hydroxylation to Temazepam → N1-demethylation to oxazepam

• N1-demethylation to Nordiazepam → 3-hydroxylation to oxazepam

• temazepam and oxazepam are largely eliminated by glucuronidaton

triazolo-benzodiazepines

• 1,2,4 triazole ring fused to the benzodiazepine core at the 1,2 position= increased stability of the drug

• triazolam: short acting

• alprazolam: intermediate acting

• estazolam: intermediate acting

oxidized metabolites are inactive due to glucoronide conjugation

fused imidazo-benzodiazepine

• imidazole ring fused to benzodiazepine core at 1,2 position= increased stability of the drug

• midazolam: short acting

  • metabolized by CYP3A4 to alpha 1 hydroxytriazolam followed by glucuronide conjugation

3-hydroxy- 1,4 benzodiazepines

“LOT”- metabolized via direct conjugation with glucuronide, more rapid than oxidation and no active metabolites→ glucuronide conjugation at 3-hydroxyl group

• lorazepam

• oxazepam

• temazepam

what benzodiazepine has a N-oxide in the R4 position

• chlordiazepoxide

  • has increased activity due to the Cl (EWG) at R7

Z compounds

• zaleplon

• zolpidem

• eszopiclone

show rapid onset of action due to being very lipophilic, rapid absorption and then rapid onset of action

zaleplon pharmacophore and subtype selectivity

• pharmacophore: pyrazolopyrimidine?

  • pyrazolo-pyrimidine heterocycle ring

  • cyano group(CN) on pyrazole ring

  • N-ethylacetamide group on upper benzene ring

• subtype selectivity

  • alpha 1» alpha 2=alpha 3

zaleplon

• full agonist for type 1 benzo alpha 1 receptor

• good at sleep initiation→ not sleep maintenance

• no significant rebound insomnia

• all metabolites are inactive(demethylation, oxidation(major pathway))

zolpidem pharmacophore and subtype selectivity

• pharmacophore

  • imidazopyridine ring

  • amide/acetamide group attached to imidazole ring

• subtype selectivity

  • alpha 1»alpha 2=alpha 6

zolpidem

• higher affinity to type 1 GABA a receptors containing alpha 1 in the brain→ strong hypnotic activity

• rapid onset dur to rapid absorption through GI due to weak base and high lipophilicity

• good at sleep maintenance

• inactive metabolites

eszopiclone pharmacophore and subtype selectivity

• pharmacophore

  • pyrrolopyrazine derivative

  • cyclopyrrolone ring

  • Cl on the pyridine ring

• subtype selectivity

  • not selective for alpha 1

eszopiclone

• S- enantiomer of zopiclone

• not specific for alpha 1

• effective in chronic insomnia

• longer elimination half life than other Z drugs

Which of the following statements concerning SAR of benzodiazepines is correct?

A. bulky alky substitutions at R1 increase activity

B. an EWG at R2’ of aryl ring increases activity

C. O, S, or N substituents at R2 increase lipophilicity of benzos

D. substitution at R6 is required for sedative activity

E. the saturation of 4,5 double bond increases sedative activity

B. an EWG at R2’ of aryl ring increases activity

blood coagulation

• extrinsic(damage to endothelial tissue), intrinsic(injured endothelium of damaged BV) and common pathways→ interact to form stable clot

• lots of tissue factors that meet at activating factor X(common pathway)

• platelet activation: changes in morphologic and biochemical state of platelet→ the bind and stick together

fibronolysis

• break down of clots→ tPA is protein that helps this

• tPA binds to plasminogen→ plasmin

• plasmin leads to break down of the clot

anticoagulants

• blood thinners→ slow down clotting

  • reduce fibrin formation and prevent clots from forming and growing

anticoagulant drugs

• VKORC1 inhibitor: warfarin

• indirect thrombin and Xa inhibitor: heparin, LMWH/enoxaparin, fondaparinux

• direct thrombin inhibitors: agatroban, daigatran, bivalirudin

• factor Xa inhibitors: rivaroxaban, apixaban, edoxaban, betrixaban

antiplatelets

• prevent platelets from clumping→ in turn prevents forming and growing of clots

antiplatelet drugs

• COX inhibitor: aspirin

• PAR-1 antagonist: vorapaxar

• PDE inhibitors: dipyridamole, cilostazol

• P2Y12 receptor antagonists: ticlopidine, clopidogrel, prasugrel, cangrelor, ticagrelor

• GpIIb/IIIa receptor antagonist: abciximab, eptifibatide, tirofiban

thrombolytics(fibrinolytics)

• breakdown/ lyse blood clots already formed within blood vessels

  • increase plasmin

thrombolytic drugs

• tissue plasminogen activator: tPA/Alteplase

• Reteplase

• tenecteplase

• streptokinase, urokinase

dicoumarol

• naturally occuring anticoagulant that is derivative of coumadin

• replaced by simpler derivative warfarin

• is cause of naturally occurring bleeding disease in cattle

warfarin

• coumarin derivative

• racemic mixture: S is more potent than R

• MOA: competitively inhibits VKORC1 limiting production of carboxylated vitamin K dependent blood clotting factors

• pharmacophore: 1,2 benzopyrone

• indications for use: treating blood clots, preventing stroke

heparin

• sulfated polysaccharide= glycosaminoglycan

• potentiates actions of antithrombin (AT)

• inhibits fXa and thrombin to similar extent

low molecular weight heparins

• enoxaparin, dalteparin, tinzaparin

• inhibit factor Xa via AT with much less inhibition of thrombin that heparin

• greater inhibitory action of fXa

fondaparinux

• synthetic anticoagulant→ based on pentasaccharide sequence making up the minimal AT binding region of heparin

• antithrombin-dependent pentasaccharide

• higher anti-Xa activity

direct thrombin inhibitor drugs

• agatroban

• dabigatran

• bivalirudin

• hirudin

agatroban

• synthetic direct inhibitor derived from amino acid Arginine of fibrinogen

• binds into thrombin active site

dabigatran etexilate

• orally active doube prodrug due to ethyl ester and hexyloxycarbonyl carbamide side chains

dabigatran

• contains alpha-NAPAP

• serine proteases inhibitor

bivalirudin

• 20 AA peptide containing active site thrombin inhibitor (D-Phe-Pro-Arg)

• competitive and reversible inhibitor of thrombin→ prevents major bleeding events

function of factor Xa

• activated fX assembles with Va to form prothrombinase→ cleave prothrombin to produce active thrombin

• inhibition of Xa activity is believed to be more efficient approach to anticoag than direct

  • wider therapeutic window and decrease risk of rebound thrombosis

direct Xa inhibitors

L shaped molecules

• rivaroxaban

• apixaban

• edoxaban

• betrixaban

rivaroxaban

• high affinity to factor Xa and good oral bioavailability

• no substitutions on benzene ring=highest potency

• morpholinone group= important role in binding affinity and bioavailability

• chiral center (S)- in oxazolidine ring

  • S enantiomer is only with pharmacological activity

SAR of apixaban

• pyrazolopyridine w/ these groups:

• S1 pocket: (P1)p-methoxyphenyl stablizes complex through interaction with non-active site, (P3)carbonyl oxygen of pyrazolopyridine interacts with Gly-216 as well as H2O molecule, (P2) carboxamide group contributes to greatest binding and similar clotting activity with favorable PK among others

• S4 pocket: (P3)-pyrazole N-2 nitrogen atom interacts with AA Glutamine-192, (P4) lactam analogues have very high binding affinity in this pocket and selectivity vs other proteases

molecular targets for antiplatelet agents

• cyclooxygenases

• P2Y12- clopidogrel, prasugrel, ticlopidine, ticagrelor, cangrelor

• Gp alpha-IIb beta3- abciximab, tirofiban, eptifibatide

• phosphodiesterases- dipyridamole, cilostazol

• PAR1- vorapaxar

thromboxane A2(TXA2)

• produced by activated platelets

• has prothrombotic properties→ stimulates activation of new platelets and increasing platelet aggregation

• action is mediated through binding to TP receptors

aspirin

• irreversible inhibitor of COX activity→ acetylation of serine residue in active site(ser 529 in cox1, ser 516 in cox2)

• “suicide inhibitor”

• works by the same mechanism to block cox2 in other tissues

vorapaxar

• PAR-1 antagonist

• PAR-1 GPCR which is activated by cleavage of part of their extracellular domain by thrombin in the platelet → activation of platelet

• drug works by binding to PAR1’s ectodomain→ antagonizes and doesn’t allow for cleavage

• synthetic derivative of himbacine(piperdine alkaloid)

anticoagulants that target PDE can -

• increase the concentration of cAMP or cGMP in platelets

  • PDE normally catalyzed and decreased the level→ regulating platelet function, this inhibits PDE allowing for more cAMP and cGMP to be available to inhibit platelet functions

dipyridamole

• inhibits PDE5 and PDE3

• member of piperdines, pyrimidopyrimidine, tertiary amino compound and tetrol

cilostazol

• selective PDE3 inhibitor

• increase in cAMP increase active form of protein kinase A(PKA)→ directly related to inhibition of platelet aggregation

• contains heterocycle, phenyl and imidazole ring

role of ADP receptor (P2Y12) in platelet activation

• when platelets activated by collagen or thrombin→ release ADP from dense granules

• ADP binds to P2Y12 receptor and activated receptors on the platelet membrane→ leads to change in platelet shape and results in amplified and sustained aggregation of platelets

thienopyridine derivatives

• selective, irreversible ADP receptor/P2Y12 inhibitors

  • ticlopidine

  • clopidogrel

  • prasugrel

• all prodrugs that are activated by cytochrome p450

ticlopidine

clopidogrel

prasugrel

• developed by replace the ester group of clopidogrel with a metabolically stable ketone and adding a ester group at the thiophene 5-position

cangrelor

• nucleotide analogue→ chemical structure that resembles ATP→ natural antagonist at P2Y12 receptor

• IV non prodrug

• reversible antagonist, superior to the irreversible P2Y12 antagonist

• replacement of anhydride oxygen between Ph-beta and Ph-gamma w/ dichloro methylene to keep potency of ATP with similar pKa to avoid metabolism to proaggretory ADP

• addition of S-propyl at the purine moiety- enhanced affinity

• methylsulfanylethylamino group at C6 position can lead to a tenfold increase in activity

• trifluoropropylsulfanyl group at C2 enhance activity

ticagrelor

• triazolopyrimidine- adenosine isostere

• cyclopentane ring is similar to ribose and the 1,2,3 triazolo- 4,5-d pyrimidine moiety resembles nucleobase adenine

• PO non prodrug

SAR of ticagrelor

1. replacement of Ph chain with a 2-hydroxyethoxy group to make the drug reversible and orally available→ 300 fold reduction in potency

2. changing the purine with triazolopyrimide to bring potency to the same level

3. replacement of ribose with cyclopentyl group to avoid chemical instability of the glycosidic bond

4. addition of phenyl cyclopropylamine substituents in the 6 position to offer high affienities to P2Y12 receptor, introduction of fluorines at the phenyl ring leads to further improved metabolic stability

5. variation of C2 minor impact on activity, improves PK properties→ ex. thioether alkylchain

eptifibatide

• glycoprotein IIb/IIIa inhibitor

• cyclic heptapeptide derived from disintegrin protein found in snake venom (Barbourin)

• disintergrins work by inhibiting the clumping of platelets

tirofiban

• small molecule inhibitor of the protein-protein interactin between fibrinogen and GpIIb/IIIa→ developed from pharmacophore based virtual screen lead

• it is an arginylglycylaspartic acid (RGD) mimetic

fibrin-specific thrombolytics

• alteplase- recombinant form of tPA(serine protease found on endothelial cells)

• reteplase- recombinant plasminogen activator

• tenecteplase(TNKase)- recombinant tPA w/ high fibrin selectivity

tPA- alteplase

• substrate is plasminogen

• tPA specifically acts on plasminogen to convert it into the active enzyme plasmin→ crucial for breaking down blood clots

reteplase

• recombinant non-glycosylated form of human tissue plasminogen activator

• also binds to fibrin with lower affinity than alteplase→ improving ability to penetrate into clots without retention within fibrin= enhanced fibrinolytic activity will be achieved

tenecteplase

• tetra-alanine substitution makes it resistant to inhibition by PAI-1

• administered IV as a single bolus

• greater fibrin specificity than alteplase

urokinase

• non-fibrin-specific agent to catalyze systemic fibrinolysis

• present in blood and in extracellular matrix of many tissues

• not tPA derivative

Which of following statements is not correct regarding heparin and its derivatives?
A. Enoxaparin has a preferential and longer lasting effect on factor Xa compared to heparin.
B. Heparin shows more inter-patient variability than others.
C. Enoxaparin is a synthetic anticoagulant based on the pentasaccharide sequence.
D. Fondaparinux has no direct effect on thrombin.

C. Enoxaparin is a synthetic anticoagulant based on the pentasaccharide sequence.

Which of following drugs is not a direct factor Xa inhibitor?
A. Rivaroxaban
B. Apixaban
C. Edoxaban
D. Agatroban

D. Agatroban

Which of following ADP receptor antagonists is not a prodrug?
A. Clopidogrel
B. Cangrelor
C. Prasugrel
D. Ticlopidine

B. Cangrelor

Which of following thrombolytic drugs is not a derivative of Tissue plasminogen activator (tPA)?
A. Reteplase
B. Urokinase
C. Tenecteplase
D. All of them

B. Urokinase

drugs approved for spasticity

• diazepam: benzo

• baclofen: GABA derivative

• tizanidine: sympatholytic

• dantrolene: direct skeletal muscle relaxant

• gabapentin: antiepileptic

• botulinum toxin

drugs approved for spasm

• cyclobenzaprine: 5HT2 receptor antagonist

• metaxalone: 2-oxazolidone

• carisoprodol: carbamate derivatives

• chlorzoxazone: 2-benzoxazolinone

• ophenadrine: muscarinic antagonist

• methocarbamol: glycerol monoether

• diazepam: benzo

antispastic drugs targeting GABA receptors

• baclofen

• benzodiazepines

antispastic drugs targeting alpha 2 adnergic receptors

• tizanidine

antispastic drug act directly on skeletal muscle cells

• dantrolene

benzodiazepines

• inhibit excessive muscle tone and hyperactive stretch reflexes by potentiating GABA activity

• relieve skeletal muscle spasticity and accompanying pain in variety of neurological disorders

• pharmacologic effect mediated via positive modulation of four different subtypes of GABA a receptors (chloride channels)

  • diazepam

  • clonazepam

  • lorazepam

baclofen

• specific agonist at GABA B receptors (potassium channels)

• binding opens the potassium channel and hyperpolarizes the neuron= reduction of the release of excitatory NT in both brain and spinal cord

• relieves muscle tightness, muscle spasms and stabbing nerve pain related to spine injuries and MS

dantrolene

• directly acting skeletal muscle relaxant

• hydrantoin derivative→ without antiepileptic activity

• lessens excitation-contraction coupling in muscle cells by binding to ryanodine receptor as an antagonist and inhibiting Ca efflux into cytoplasm from sacoplasmic reticulum

tizanidine

• centrally acting alpha2 adrenergic agonist

• sympathetic antagonist by inhibiting nonadrenergic neurotransmission→ originates from Locus Ceruleus

• 1,2,5- thiadiazole→ 2-amioninidazoline

• slows excitatory action in the brain and nervous system→ allows muscles to relax with much less hypotensive effects than clonidine

• MOA: bind to alpha 2 adrenergic→ dissociation of an alpha subunit from inhibitory Gi protein→ inactivation of adenylate cyclase through the association of an alpha subunit→ decrease of intracellular cAMP→ inactivation of protein kinase A(PKA)→ decrease of noradrenaline release

cyclobenzaprine

• 5-HT2 receptor antagonist→ inhibits neuronal excitation originating from raphe nuclei that travel to alpha motor neurons

• influences both gamma and alpha motor neurons→ leads to reduction in muscle spasms

• contains dibenzo(a,d)cycloheptene, methylidene group substituted by 2-(dimethylamino)-ethyl group

orphenadrine

• centrally acting- nonopiate analgesic and muscle relaxant

• an amino-alcohol ether structurally related to diphenhydramine

• NMDA-type glutamate antagonist (phencyclidine binding site) to reduce excitatory neurotransmission in brain stem

• histamine H1 receptor antagonist with anticholinergic activity as well

• skeletal muscle relaxant for shhort term treatment of muscle discomfort cause by health problems or injuries such as sprains or strains

carbamate ester muscle relaxants

• methocarbamol

• carisoprodol

• meprobamate→ 2 carbamates on each side (metabolite of carisoprodol from N-dealkylation)

metaxalone

• general CNS depressant with no significant anticholinergic effects

• lack of abuse, few ADE and relatively low degree of sedation

• contains 2-oxazolidinone

• aromatic ether

carisoprodol

• effects mutliple sites in the CNS including the thalamus and limbic system

meprobamate

• in the absence of GABA→ directly activates GABA a receptors

chlorzoxazone

• inhibits muscle spasm by exerting an effect primarily at the level of the spinal cord and subcortical areas of the brain

• less effective than others

Which of the following statements about Cyclobenzaprine is NOT correct?
A. It is a directly acting muscle relaxant.
B. It is a 5-HT2 receptor antagonist.
C. It is structurally similar to amitriptyline.
D. It has anticholinergic effects.
E. It decreases the activity of descending serotonergic neurons in the spinal cord.

A. It is a directly acting muscle relaxant.

pharmacophoric pattern of AEDs

• red rectangle: hydrophobic domain

• green rectangle: hydrogen bond acceptor/donor

• blue rectangle: electron donor moiety

phenytoin/ fosphenytoin

• hydantoin derivatives (imidazolidine)

• substituting a phenyl group position 5 of the hydantoin molecule

• 2 phenyl groups at position 5 produces most anticonvulsant activity

• fosphenytoin(IV/IM)→ phenytoin(IV) + a phosphate ester

  • conversion occurs by phosphates in the liver and RBC

dibenzazepine 5-carboxamide derivatives

• carbamazepine, oxcarbazepine, eslicarbazepine

• bind to a stabilize the inactive state of voltage-gated sodium channels

carbamazepine

• CI in patients with hx of hypersensitivity to TCAs

• chemically reactive metabolites cause CBZ induced hypersensitivity

oxcarbazepine

• less potent with less serious SE due to absence of epoxide or iminoquinone metabolites

• keto group in 10 position

eslicarbazepine acetate

• prodrug, acetate ester with S configuration

• less potent with less serious SE due to absence of epoxide of iminoquinone metabolites

• hydrolyzed into active metabolite→ licarbazepine

• hydroxy group in the 10 position of ring minimizes the enzymatic induction of the cytochrome P450 and autoinduction

rufinamide

• triazole derivative(5 membered nitrogen heterocycle) that binds to inactivated form of voltage gated sodium channels

• lennox gastaut syndrome