752antipsychoticagents.pdf
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PHAR 752 Antipsychotic Agents(Medicinal Chemistry)
Wilson + Gisvold, Ch. 14, pp. 496-503.
Six classes of antipsychoticsPhenothiazines
Propyl dialkylamino side chainChlorpromazine (Thorazine®)
Propyl piperazine side chainFluphenazine (Prolixin® or Prolixin® Enanthoate or Prolixin® Decanoate) Alkyl piperidyl side chain
Thioridazine HCl (Mellaril®)Thioxanthenes
Thiothixene HCl (Navane®)Dibenzazepines
DibenzodiazepineClozapine (Clozaril®)Olanzepine (Zyprexa®)
DibenzooxazepineLoxapine (Loxitane®)
Dibenzothiazepine
Quetiapine (Seroquel®)Fluorobutyrophenones
Haloperidol (Haldol® or Haldol® decanoate)Droperidol (component of Innovar®)
DiphenylbutylpiperidinesPimozide (Orap®)
Miscellaneous heterocyclic compoundsRisperidone (Risperdal®)Ziprasidone (Geodon®)
Aripiprazole (Abilify®)
Phenothiazines - SAR
1) Position 2 is the best position for substitution. Activity generallyincreases with the electron-withdrawing ability of the substituent.2) Substitution at positions 1 and 4 both decrease antipsychoticactivity (position 1 > position 4). Unsubstituted phenothiazines haveweak antipsychotic activity.3) Three carbon chain connecting nitrogens is required. Two or fourcarbon chain greatly decreases activity.4) Branching on the sidechain with large groups decreases activity.Branching at the ! carbon (as is seen in alkyl piperidyl side chains) istolerated.5) Basic nitrogen substituents –Tertiary amines provide optimalactivity; secondary amines have decreased activity. Significant
increases in size from the dimethylamino group (see chlorpromazine) decrease activity.Piperidine (see thioridazine) and piperazine rings (fluphenazine) are allowed. Addition of chainlength on the N2 of the piperazine ring is proposed to increase receptor binding forces.
The tertiary amine is required for passage thru BBB, but the protonated ammonium species is theimportant form at the receptor.
N
S
R1
N
R
R
1
2
3
4
7
10
!
"
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O CH3
N
CH3
O
N
CH3
CH3
N CH3
N
N
CH3
N CH3
N
CH3
N CH3
N
CH3
S
N CH3
N
CH3
S CH3
Evolution of the Phenothiazine Antipsychotics
Diphenhydramine(antihistamine)
Ethanolamines(antihistamine activity)
Ethylenediamines(antihistamine activity) Tripelennamine
(antihistamine)
Diethazine(anti-Parkinson)
Promethazine(antihistamine)
Chlorpromazine(antipsychotic)
N N
S
Cl
CH3
CH3
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N
S
Cl
N
S
CF3
N
NOH
NCH3
CH3
Chlorpromazine(Thorazine®)
Fluphenazine HCl(Permitil®)
Fluphenazine decanoate(Prolixin®)
Primary hydroxyl is site of esterification to formlipophilic decanoate ester which is used for depot injections.
Antipsychotics - PhenothiazinesPropyl dialkylamino sidechain
Propyl piperazine sidechain
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N
S
Cl
NCH3
CH3
N
S
Cl
NCH3
CH3
N
S
CO2H
ClN
S
Cl
N
CH3
CH3
N
S
CPZ sulfoxide(inactive)
Nor 1-CPZ
(weakly active)
Metabolism of Chlorpromazine
Cl
NH
CH3
Over 100 metabolites of chlorpromazine havebeen identified.Examples below demonstrate major routes.
HO
O
Chlorpromazine
(CPZ)
7-Hydroxy CPZ(weakly active)
CPZ propionic acid(inactive)
Cyp2D6 (major)Cyp1A2 (minor)
Cyp2D6
Glucuronidation and excretion
Cyp3A4
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NH
N
N
N
CH3
NH
N
N
N
CH3
Cl
S CH3
Clozapine (Clozaril®)Atypical antipsychotic
Dibenzazepines (Dibenzodiazepines)
Olanzapine (Zyprexa®)Atypical antipsychotic
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O
N
N
N
CH3
Cl
S
N
N
N
O
OH
Dibenzazepines (Dibenzothiazepines)
Loxapine (Loxitane®)
Dibenzazepines (Dibenzooxazepines)
Quetiapine (Seroquel®)Atypical antipsychotic
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X NF
Fluorobutyrophenones
Haloperidol (Haldol®), Y = OH
Haldol® decanoate (decanoateester of tertiary alcohol)
Y =
AR
Y
Fluorobutyrophenones SAR
1) X = C=O (ketone) for optimal activity. X = C(H)OH or C(H)aryl also yield good activity.
2) Altering length or branching of the three-carbon chain linking keto and amino group decreasesantipsychotic activity.
3) Basic nitrogen is incorporated into a six-membered ring for optimal activity.4) AR is an aromatic ring attached directly to or separated by one atom from position 4 of the six-
membered ring.5) The Y group is variable and can enhance activity (Y= OH in haloperidol)
4
O
N
Y
Cl
F
C(CH2)8CH3
O
O
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N
N
O
NH
F
FPimozide(Orap®)
O
N
N
O
NH
F
Diphenylbutylpiperidines
Analogs of butyrophenones in whichcarbonyl is replaced by a CH-phenylgroup (compare to haloperidol).
Pimozide is approved for the treatment
of Tourette's syndrome.
Fluorobutyrophenones
Droperidol(in Innovar® with fentanyl)
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N
N CH3
N
O
NO
FH
Cl
N
N
NS
HN
O
Risperidone (Risperdal®)
Ziprasidone (Geodon®)
Miscellaneous Heterocyclic Compounds
Atypical antipsychotic
Atypical antipsychotic
N
N CH3
N
O
NO
FH
OH
Paliperidone (= 9-hydroxyrisperidone)
Atypical antipsychotic
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ON
N
Aripiprazole (Abilify®)
Miscellaneous Heterocyclic Compounds
Atypical antipsychotic
Cl
Cl
HNO