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

!

"



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



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



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



NH

N

N

N

CH3

NH

N

N

N

CH3

Cl

S CH3

Clozapine (Clozaril®)Atypical antipsychotic

Dibenzazepines (Dibenzodiazepines)

Olanzapine (Zyprexa®)Atypical antipsychotic



O

N

N

N

CH3

Cl

S

N

N

N

O

OH

Dibenzazepines (Dibenzothiazepines)

Loxapine (Loxitane®)

Dibenzazepines (Dibenzooxazepines)

Quetiapine (Seroquel®)Atypical antipsychotic



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



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)



N

N CH3

N

O

NO

FH

Cl

N

N

NS

HN

O

Risperidone (Risperdal®)

Ziprasidone (Geodon®)

Miscellaneous Heterocyclic Compounds

Atypical antipsychotic


N

N CH3

N

O

NO

FH

OH

Paliperidone (= 9-hydroxyrisperidone)




ON

N

Aripiprazole (Abilify®)

Miscellaneous Heterocyclic Compounds


Cl

Cl

HNO

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