| Reference | 1. Bioorg Med Chem Lett. 2012 May 15;22(10):3437-40. doi:
10.1016/j.bmcl.2012.03.104. Epub 2012 Apr 4.
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Discovery of cariprazine (RGH-188): a novel antipsychotic acting on dopamine
D3/D2 receptors.
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Agai-Csongor E(1), Domány G, Nógrádi K, Galambos J, Vágó I, Keserű GM, Greiner I,
Laszlovszky I, Gere A, Schmidt E, Kiss B, Vastag M, Tihanyi K, Sághy K, Laszy J,
Gyertyán I, Zájer-Balázs M, Gémesi L, Kapás M, Szombathelyi Z.
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Author information: <br>
(1)Gedeon Richter Plc, Budapest, Hungary. [email protected]
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Medicinal chemistry optimization of an impurity isolated during the scale-up
synthesis of a pyridylsulfonamide type dopamine D(3)/D(2) compound (1) led to a
series of new piperazine derivatives having affinity to both dopamine D(3) and
D(2) receptors. Several members of this group showed excellent pharmacokinetic
and pharmacodynamic properties as demonstrated by outstanding activities in
different antipsychotic tests. The most promising representative, 2m
(cariprazine) had good absorption, excellent brain penetration and advantageous
safety profile. Based on its successful clinical development we are looking
forward to the NDA filing of cariprazine in 2012.
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2. Curr Opin Investig Drugs. 2010 Jul;11(7):823-32.
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Cariprazine, an orally active D2/D3 receptor antagonist, for the potential
treatment of schizophrenia, bipolar mania and depression.
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Gründer G(1).
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Author information: <br>
(1)RWTH Aachen University, Department of Psychiatry and Psychotherapy, and JARA –
Translational Brain Medicine, Pauwelsstrasse 30, Aachen, Germany.
[email protected]
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Cariprazine (RGH-188), which is being codeveloped by Gedeon Richter Ltd, Forest
Laboratories Inc and Mitsubishi Tanabe Pharma Corp, is a novel putative
antipsychotic drug that exerts partial agonism at dopamine D2/D3 receptors, with
preferential binding to D3 receptors, and partial agonism at serotonin 5-HT1A
receptors. Its activity at D2/D3 receptors may be lower than that of the
prototype partial agonist aripiprazole. The antipsychotic activity of cariprazine
was demonstrated in animal models, and data also suggest that the propensity for
extrapyramidal side effects is low and that the drug may have procognitive
properties. Cariprazine is rapidly absorbed, with high oral bioavailability and a
long plasma elimination t1/2. Cariprazine is in phase III clinical trials in
patients with schizophrenia and in patients with bipolar disorder. Data from
phase II trials in patients with schizophrenia and bipolar mania indicate that
the drug has antipsychotic and antimanic properties that are superior to placebo.
With its unique receptor affinity profile, cariprazine may represent a potential
enrichment of the therapeutic armamentarium for schizophrenia and affective
disorders. Its activity against the cognitive deficits associated with
schizophrenia has to be carefully investigated.
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3. J Pharmacol Exp Ther. 2010 Apr;333(1):328-40. doi: 10.1124/jpet.109.160432. Epub
2010 Jan 21.
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Cariprazine (RGH-188), a dopamine D(3) receptor-preferring, D(3)/D(2) dopamine
receptor antagonist-partial agonist antipsychotic candidate: in vitro and
neurochemical profile.
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Kiss B(1), Horváth A, Némethy Z, Schmidt E, Laszlovszky I, Bugovics G, Fazekas K,
Hornok K, Orosz S, Gyertyán I, Agai-Csongor E, Domány G, Tihanyi K, Adham N,
Szombathelyi Z.
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Author information: <br>
(1)Department of Molecular Pharmacology, Gedeon Richter Plc., P.O. Box 27.,
Budapest, H-1475 Hungary. [email protected]
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Cariprazine {RGH-188;
trans-N-[4-[2-[4-(2,3-dichlorophenyl)piperazin-1-yl]ethyl]cyclohexyl]-N’,N’-dimet
hylurea hydrochloride}, a novel candidate antipsychotic, demonstrated
approximately 10-fold higher affinity for human D(3) versus human D(2L) and human
D(2S) receptors (pKi 10.07, 9.16, and 9.31, respectively). It displayed high
affinity at human serotonin (5-HT) type 2B receptors (pK(i) 9.24) with pure
antagonism. Cariprazine had lower affinity at human and rat hippocampal 5-HT(1A)
receptors (pK(i) 8.59 and 8.34, respectively) and demonstrated low intrinsic
efficacy. Cariprazine displayed low affinity at human 5-HT(2A) receptors (pK(i)
7.73). Moderate or low affinity for histamine H(1) and 5-HT(2C) receptors (pK(i)
7.63 and 6.87, respectively) suggest cariprazine’s reduced propensity for adverse
events related to these receptors. Cariprazine demonstrated different functional
profiles at dopamine receptors depending on the assay system. It displayed D(2)
and D(3) antagonism in [(35)S]GTPgammaS binding assays, but stimulated inositol
phosphate (IP) production (pEC(50) 8.50, E(max) 30%) and antagonized
(+/-)-quinpirole-induced IP accumulation (pK(b) 9.22) in murine cells expressing
human D(2L) receptors. It had partial agonist activity (pEC(50) 8.58, E(max) 71%)
by inhibiting cAMP accumulation in Chinese hamster ovary cells expressing human
D(3) receptors and potently antagonized
R(+)-2-dipropylamino-7-hydroxy-1,2,3,4-tetrahydronaphtalene HBr
(7-OH-DPAT)-induced suppression of cAMP formation (pK(b) 9.57). In these
functional assays, cariprazine showed similar (D(2)) or higher (D(3))
antagonist-partial agonist affinity and greater (3- to 10-fold) D(3) versus D(2)
selectivity compared with aripiprazole. In in vivo turnover and biosynthesis
experiments, cariprazine demonstrated D(2)-related partial agonist and antagonist
properties, depending on actual dopaminergic tone. The antagonist-partial agonist
properties of cariprazine at D(3) and D(2) receptors, with very high and
preferential affinity to D(3) receptors, make it a candidate antipsychotic with a
unique pharmacological profile among known antipsychotics.
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