Transcript Benzodiazepines SAR

Benzodiazepine and benzodiazepine-like
drugs
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Outline
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Structure of Benzodiazepine (BZD)
Characteristics
GABAA receptor and agonists
BZD SAR
BZD Metabolism
Non-BZD – w site agonist
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diazepine
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1
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benzene
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5
2
4
3
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benzo-di-azepine
azepine
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Benzodiazepines
• GABA GABAA receptor
• Properties
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–
–
–
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Sedation/hypnosis
Decreased anxiety
Anterograde amnesia (negative)
Anticonvulsant
Muscle relaxation
g-aminobutyric acid
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Benzodiazepines
• Therapeutic and Efficacy half life
• Anticonvulsants  long half-lives
– CNS and Status epilepticus
alprazolam
• Sleep  short half-lives
(Xanax)
• Anti-anxiety  long half-life, except aprazolam
(Xanax) ~12 hours
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Examples
Anticonvulsant
clonazepam (Klonopin)
18-50 hours
Sleep
triazolam (Halcion)
1.5-5.5 hours
Anti-anxiety
diazepam (Valium)
36-200 hours
(active desmethyl metabolite)
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B
A
g-aminobutyric acid (GABA)
D
(w site)
Chloride Conductance
C
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KD’s of GABAA agonists
Compound
a1
Diazepam
a2
a3
a5
16 nM 16
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Clonazepam
Triazolam
Ro15-4513
1.3
1.8
2.6
1.7
1.2
2.6
2
3
1.3
1.2
0.24
Zolpidem
1.7
291
357
>15000
L-655-708
48
27
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0.45
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Rules
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a1-a3 and a5 non-selective
a1-a3 anticonvulsant
a1 sedation and hypnosis
a2 and a5 anxiolytic
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Benzodiazepines SAR
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CH3
O
N
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X
N
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• 1,4 benzodiazepine
• Electron withdrawing group (EWG)  7 position,
– X= Cl < Br < F < CN < CF3 < NO2
– Stronger EWG give more potent compounds
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Example
clonazepam (Klonopin)
equiv. dose = 0.5 mg
oxazepam (Serax)
equiv. dose = 20 mg
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Benzodiazepines SAR (6-9)
CH3
O
N
N
CF3
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CH3
F 8
CF3
N
CH3
F
O
9
N CF3
O
N
N
F
>
>
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Benzodiazepines SAR (5)
CH3
O
N
CF3
#1
5
CH3
N
N
O
#2
X
O
N
N
CF3
X
CH3
N
CF3
X
#3
>
ortho
para
X
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Benzodiazepines SAR (5)
CH3
N
O
N
CF3
5
H
• X aromatic ring  antagonist
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Flumazenil (Anexate)
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GABAA receptor antagonist
BZD overdoses
hypersomnia
X Patent
Liver  Carboxylic Acid Metabolite + Glucuronidation
ADR: headache and insomnia
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Benzodiazepines SAR (3-5)
CH3
N
CF3
O
NH
CF3
4,5 reduction
CH3
O
N
N
3,4 shift
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Benzodiazepines SAR (3)
CH3
CH3
O
N
N
potency
O
N
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CF3
CH3
O
CH3
CF3
O
N
3
N
half life
OH
3
CF3
O
CH2CH2CH3
N
prodrug
UGTs
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Benzodiazepines SAR (3)
(Prodrug)
CH3
H
CH
H 3
O
O
N
N
H
COOH
COOH
Cl3
CF
CF
Cl3
N
N
decarboxylase
clorazepate
desmethyldiazepam (active)
(a.k.a. nordazepam (Nordaz))
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Benzodiazepines SAR (2)
CH3
O
N
CF3
CH3
CH3
S
N
N
CF3
N
N
N CF3
N
2-Thione
>
NHCH3
NH
>
N
CF3
2-Imine
2-Methylamino
>
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Benzodiazepines SAR (1)
CH2CH3
CH2CF3
O
N
CF3
H
O
O
N
N
1
CF3
N
N
2
CF3
O
N
N
3
CF3
N
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Benzodiazepines SAR (1,2imidazo ring)
OH
CH3
CH3
N
CH2
N
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N
N
N
9
2
1
N
3
N
4
N
CF3
Triazole
CF3
N
CF3
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N
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6
5
Imidazole
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Examples
midazolam
triazolam
alprazolam (Xanax)
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M etabolic Pathway of the Benzodiazepines and Their Half-lives
Chlordiazepoxide (10h)
desmethyl
-chlordiazepoxide (6-20 h)
demoxepam (72 h)
Temazepam (13 h)
3-OH Diazepam
Clorazepate
(decarboxylated in stomach)
Prazepam (1.3 h)
Desmethyldiazepam (73 h)
Nordiazepam
Oxazepam (6.8 h)
Desalkylflurazepam (74 h)
3-hydroxy desalkyl flurazepam
(6-14 h)
Halazepam (14 h)
Flurazepam (2.5 h)
Quazepam
(Short,No data)
2-Oxoquazepam
desulfuration
(39 h)
Lorazepam (14 h)
Triazolam (2.9 h)
a-Hydroxymethyl triazolam (<4 h)
Alprazolam (12 h)
a-Hydroxymethyl alprazolam
rapid conjugation and excretion
Midazolam
(1.9 h or 68 min)
a-Hydroxymethyl midazolam
rapid conjugation and excretion
GLUCURONIDATION
Diazepam (43 h)
METABOLISM
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M etabolic Pathway of the Benzodiazepines and Their Half-lives
desmethyl
-chlordiazepoxide (6-20 h)
Chlordiazepoxide (10h)
demoxepam (72 h)
Temazepam (13 h)
3-OH Diazepam
Clorazepate
(decarboxylated in stomach)
Prazepam (1.3 h)
Desmethyldiazepam (73 h)
Nordiazepam
Oxazepam (6.8 h)
Desalkylflurazepam (74 h)
3-hydroxy desalkyl flurazepam
(6-14 h)
Halazepam (14 h)
Flurazepam (2.5 h)
Quazepam
(Short,No data)
2-Oxoquazepam
desulfuration
(39 h)
diazepam (Valium)
Triazolam (2.9 h)
clorazepate
a-Hydroxymethyl
triazolam (<4 h)
Alprazolam (12 h)
a-Hydroxymethyl alprazolam
rapid conjugation and excretion
Midazolam
(1.9 h or 68 min)
a-Hydroxymethyl midazolam
rapid conjugation and excretion
prazepam
Lorazepam
(14 h)
halazepam
GLUCURONIDATION
Diazepam (43 h)
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M etabolic Pathway of the Benzodiazepines and Their Half-lives
Chlordiazepoxide (10h)
desmethyl
-chlordiazepoxide (6-20 h)
demoxepam (72 h)
Temazepam (13 h)
3-OH Diazepam
Clorazepate
(decarboxylated in stomach)
Prazepam (1.3 h)
Desmethyldiazepam (73 h)
Nordiazepam
Oxazepam (6.8 h)
Desalkylflurazepam (74 h)
3-hydroxy desalkyl flurazepam
(6-14 h)
OH
Halazepam (14 h)
Flurazepam (2.5 h)
Quazepam
(Short,No data)
2-Oxoquazepam
desulfuration
(39 h)
Lorazepam (14 h)
Triazolam (2.9 h)
a-Hydroxymethyl triazolam (<4 h)
Alprazolam (12 h)
a-Hydroxymethyl alprazolam
rapid conjugation and excretion
Midazolam
(1.9 h or 68 min)
a-Hydroxymethyl midazolam
rapid conjugation and excretion
midazolam
a-hydroxymethyl midazolam
GLUCURONIDATION
Diazepam (43 h)
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Non-benzodiazepines (NonBZD)
• imidazopyridines
• pyrazolopyrimidine
• cyclopyrrolones
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Non-BZD w site agonist
N
CH3
N
H 3C
CH2
O
N
CH3
H 3C
• Zolpidem (Ambien) - Insomnia
• Rapid absorption GI, but food delays 30 min
• CYP3A4 inactivates
– Duration 6-8 hours
– half-life 2.5 hours (Liver disease)
• 92% protein bound
• ADR: amnesia
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Non-BZD w site agonist
NC
N
N
N
CH3
5
N
O
O
CH3
• Zaleplon (Sonata) - Insomnia
• 30% bioavailable. Onset 1hr food delays
• Aldehyde oxidase  inactive metabolite (X CYP450)
– half-life 1 hour; duration 6-8 h
• 60% protein bound
• ADR Amnesia
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Non-BZD w site agonist
O
O
N
N
N
N
Cl
N
N
H
N
O
O
N
N
Cl
H
O
N
CH3
O
N
N
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CH3
Eszopiclone (Lunesta)- Insomnia
S isomer of racemic zopiclone (EU denied patent)
Rapid absorption peak in 1 hour, but food delays
50% protein binding
Metabolized by CYP3A4 and CYP2E1
– active–desmethyl
– inactive-N-oxide
Half-life 6h
ADR: headache, hallucinations anxiety, amnesia, Unpleasant taste (34%)
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Huedo-Medina, T. B., Kirsch, I., Middlemass, J., Klonizakis, M., and
Siriwardena, A. N. (2012) Effectiveness of non-benzodiazepine
hypnotics in treatment of adult insomnia: meta-analysis of data
submitted to the Food and Drug Administration, BMJ 345, e8343.
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Alternative: Ramelteon
(Rozerem)
1/10 M-II
CH3
HN
HN
O
O
O
H3CO
N
H
Melatonin
• Insomnia
• Melatonin receptor (MT1 and MT2) agonist (No GABAA)
– sleep-wake cycle and circadian rhythm
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Onset 30 mins
Bioavailable is 1.8%
Metabolized by CYP1A2, first pass converts to active metabolite M-II
Food delays absorption
82% protein bound
ADR: headache, depression, insomnia worsened
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Outline
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Structure of Benzodiazepine (BZD)
Characteristics
GABAA receptor and agonists
BZD SAR
BZD Metabolism
Non-BZD – w site agonist
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