Cariprazine

"目錄號: HY-14763

GPCR/G ProteinNeuronal Signaling-

Cariprazine 是一種新型的抗精神病試劑,高親和力作用于D3(Ki=0.085 nM) 和D2(Ki=0.49 nM) 受體合敦,稍低親和力作用于5-HT1A受體 (Ki=2.6 nM)。

Dopamine Receptor5-HT Receptor

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Clozapine N-oxide-Chlorpromazine hydrochloride-Pimavanserin-Brexpiprazole-Lorcaserin Hydrochloride-Haloperidol-Cabergoline-Scopolamine hydrobromide-Cariprazine hydrochloride-Harmine-Lu AE58054 Hydrochloride-TG6-10-1-L-DOPA-Perphenazine-Aripiprazole-

生物活性

Description

Cariprazine is a novel antipsychotic drug candidate that exhibits high affinity for theD3(Ki=0.085 nM) andD2(Ki=0.49 nM) receptors, and moderate affinity for the5-HT1Areceptor (Ki=2.6 nM).

IC50& Target

Ki: 0.49 nM (D2 receptor), 0.085 nM (D3 receptor), 2.6 nM (5-HT1A receptor)[1]

In Vitro

Cariprazine stimulates inositol phosphate (IP) formation with a high potency (pEC508.5) with relatively low efficacy (Emax30%)[2]. Cariprazine, a novel candidate antipsychotic, demonstrated approximately 10-fold higher affinity for human D3versus human D2Land human D2Sreceptors (pKi10.07, 9.16, and 9.31, respectively). Cariprazine displays high affinity at human serotonin (5-HT) type 2B receptors (pKi9.24) with pure antagonism. Cariprazine has lower affinity at human and rat hippocampal 5-HT1Areceptors (pKi8.59 and 8.34, respectively) and demonstrates low intrinsic efficacy. Cariprazine displays low affinity at human 5-HT2Areceptors (pKi7.73). Moderate or low affinity for histamine H1and 5-HT2Creceptors (pKi7.63 and 6.87, respectively) suggest Cariprazine's reduced propensity for adverse events related to these receptors[2]. Cariprazine is over sixfold more potent (EC50=1.4 nM) than Aripiprazole (EC50=9.2 nM) in inhibiting isoproterenol-induced cAMP production in HEK-293 cells[4].

In Vivo

Administration of Cariprazine (30 μg/kg) reduces the striatal uptake of both radioligands to the level of nonspecific binding compared with baseline PET measurements. Cariprazine has negligible effect on the time-activity curves in the cerebellum. At doses of 5.0 and 30 μg/kg, Cariprazine causes a dose-dependent dopamine D2/D3receptor occupancy of ~45% and ~80% for both antagonist [11C] raclopride and agonist radioligand [11C]MNPA. Receptor occupancy of dopamine D2/D3receptors calculated using the transient equilibrium and the MRTM2 methods ranged from 5% at the lowest dose (1.0 μg/kg) to 94% at the highest dose (300 μg/kg)[1]. The effects of 5 doses of Cariprazine (ranging from 0.005 to 0.15 mg/kg) are examined on EPM behavior of wild-type mice. Whereas lower doses of Cariprazine (0.005 to 0.02 mg/kg) do not alter the time spent in open arms, the two higher doses (0.08 and 0.15 mg/kg) lead to a significant decline of this measure (ANOVA, (F(5,52)=4.20; p=0.0032)). Moreover, the two higher doses of Cariprazine also lead to a significant decrease in the total number of arm entries (F(5,52)=7.21; p=0.0001)) but this decrease in the total number of arm entries is largely accounted for by a significant decrease in the number of closed arm entries (F(5,52)=11.75; p=0.0001)). The two highest doses of Cariprazine (0.08 and 0.15 mg/kg) have significant effects on locomotor activity, but doses ranging from 0.005 to 0.02 mg/kg do not affect anxiety-like behavior or locomotor activity in the EPM test[3]. A significant (P<0.01) reduction in ouabain-induced hyperactivity is observed after acute i.p. administration of all doses of Cariprazine (mean±SEM: 0.06 mg/kg, 64.2±3.88; 0.25 mg/kg, 72.7±11.67; 0.5 mg/kg, 40.6±5.32; 1 mg/kg, 19.5±8.78) and lithium (40.4±12.78), compared with ouabain injection alone (114.6±14.33). The highest Cariprazine dose produced significant sedation (72% inhibition for Cariprazine 1.0 mg/kg aCSF vs. saline aCSF; P<0.05)[4].

Clinical Trial

NCT01838876

Forest Laboratories-Gedeon Richter Ltd.

Major Depressive Disorder

May 2013

Phase 3

NCT01104792

Forest Laboratories-Gedeon Richter Ltd.

Schizophrenia

April 2010

Phase 3

NCT02670551

Forest Laboratories, LLC, an Allergan Affiliate-Forest Laboratories

Bipolar Disorder-Depression

March 2016

Phase 3

NCT02670538

Forest Laboratories

Bipolar Disorder-Depression

March 2016

Phase 3

NCT01058096

Forest Laboratories-Gedeon Richter Ltd.

Bipolar Disorder-Mania

February 2010

Phase 3

NCT01059539

Forest Laboratories-Gedeon Richter Ltd.

Bipolar I Disorder

January 2010

Phase 3

NCT01715805

Forest Laboratories-Gedeon Richter Ltd.

Major Depressive Disorder

November 2012

Phase 3

NCT01058668

Forest Laboratories-Gedeon Richter Ltd.

Mania-Bipolar I Disorder

February 2010

Phase 3

NCT01396447

Forest Laboratories-Gedeon Richter Ltd.

Depression, Bipolar

July 2011

Phase 2

NCT00839852

Forest Laboratories-Gedeon Richter Ltd.

Schizophrenia

May 2009

Phase 2

NCT01412060

Forest Laboratories-Gedeon Richter Ltd.

Schizophrenia

August 2011

Phase 3

NCT01469377

Forest Laboratories-Gedeon Richter Ltd.

Major Depressive Disorder

December 2011

Phase 2

NCT00852202

Forest Laboratories-Gedeon Richter Ltd.

Bipolar Depression

June 2009

Phase 2

NCT01104779

Forest Laboratories-Gedeon Richter Ltd.

Schizophrenia

April 2010

Phase 3

NCT02165098

Gedeon Richter Plc.

Pharmacokinetic Profile

June 2014

Phase 1

NCT01376076

Forest Laboratories

Schizophrenia

June 2011

Phase 1

NCT01104766

Forest Laboratories-Gedeon Richter Ltd.

Schizophrenia

April 2010

Phase 3

NCT00854100

Forest Laboratories-Gedeon Richter Ltd.

Major Depressive Disorder

June 2009

Phase 2

NCT00488618

Forest Laboratories-Gedeon Richter Ltd.

Bipolar Disorder

June 2007

Phase 2

NCT00862992

Mitsubishi Tanabe Pharma Corporation

Schizophrenia

April 2008

Phase 2

NCT01838876

Forest Laboratories-Gedeon Richter Ltd.

Major Depressive Disorder

May 2013

Phase 3

NCT01104792

Forest Laboratories-Gedeon Richter Ltd.

Schizophrenia

April 2010

Phase 3

NCT02670551

Forest Laboratories, LLC, an Allergan Affiliate-Forest Laboratories

Bipolar Disorder-Depression

March 2016

Phase 3

NCT02670538

Forest Laboratories

Bipolar Disorder-Depression

March 2016

Phase 3

NCT01058096

Forest Laboratories-Gedeon Richter Ltd.

Bipolar Disorder-Mania

February 2010

Phase 3

NCT01059539

Forest Laboratories-Gedeon Richter Ltd.

Bipolar I Disorder

January 2010

Phase 3

NCT01715805

Forest Laboratories-Gedeon Richter Ltd.

Major Depressive Disorder

November 2012

Phase 3

NCT01058668

Forest Laboratories-Gedeon Richter Ltd.

Mania-Bipolar I Disorder

February 2010

Phase 3

NCT01396447

Forest Laboratories-Gedeon Richter Ltd.

Depression, Bipolar

July 2011

Phase 2

NCT00839852

Forest Laboratories-Gedeon Richter Ltd.

Schizophrenia

May 2009

Phase 2

NCT01412060

Forest Laboratories-Gedeon Richter Ltd.

Schizophrenia

August 2011

Phase 3

NCT01469377

Forest Laboratories-Gedeon Richter Ltd.

Major Depressive Disorder

December 2011

Phase 2

NCT00852202

Forest Laboratories-Gedeon Richter Ltd.

Bipolar Depression

June 2009

Phase 2

NCT01104779

Forest Laboratories-Gedeon Richter Ltd.

Schizophrenia

April 2010

Phase 3

NCT02165098

Gedeon Richter Plc.

Pharmacokinetic Profile

June 2014

Phase 1

NCT01376076

Forest Laboratories

Schizophrenia

June 2011

Phase 1

NCT01104766

Forest Laboratories-Gedeon Richter Ltd.

Schizophrenia

April 2010

Phase 3

NCT00854100

Forest Laboratories-Gedeon Richter Ltd.

Major Depressive Disorder

June 2009

Phase 2

NCT00488618

Forest Laboratories-Gedeon Richter Ltd.

Bipolar Disorder

June 2007

Phase 2

NCT00862992

Mitsubishi Tanabe Pharma Corporation

Schizophrenia

April 2008

Phase 2

NCT00404573

Forest Laboratories

Schizophrenia

November 2006

Phase 2

NCT00694707

Forest Laboratories-Gedeon Richter Ltd.

Schizophrenia

June 2008

Phase 2

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References

[1].Seneca N, et al. Occupancy of dopamine D2 and D3 and serotonin 5-HT1A receptors by the novel antipsyc

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