Physico-chemical characterization of a novel group of dopamine D3/D2 receptor ligands, potential atypical antipsychotic agents

Deák, Katalin; Takács‐Novák, Krisztina; Kapás, Margit; Vastag, Mónika; Tihanyi, Károly; Noszál, Béla

doi:10.1016/j.jpba.2008.06.021

Cited by 9 publications

(4 citation statements)

References 22 publications

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“…Figure 1), was discovered in the course of medicinal chemistry optimization of an impurity leading to a new series of piperazine/piperidine derivatives having high affinity to both dopamine D3 and D2 receptors [6]. Of these compounds cariprazine demonstrated good absorption and brain penetration [6,18].…”

Section: Introduction To Cariprazinementioning

confidence: 99%

“…A PubMed search was conducted on 31 October 2012 using the search terms 'cariprazine,' 'RGH-188,' and 'RGH 188' without any date or language restrictions. The resulting 15 publications [5][6][7][8][9][10][11][12][13][14][15][16][17][18][19] and their reference lists were then specifically examined for primary sources of information with emphasis on the drug metabolism and pharmacokinetics of cariprazine in humans. Query of www.clinicaltrials.gov on 31 October 2012 yielded 18 separate records (see Table 1); however for the clinical trials that were completed, study results were not posted.…”

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confidence: 99%

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Cariprazine: chemistry, pharmacodynamics, pharmacokinetics, and metabolism, clinical efficacy, safety, and tolerability

Citrome

2013

Expert Opinion on Drug Metabolism & Toxicology

114

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Cariprazine is a dopamine D3-preferring D3/D2 receptor partial agonist. Doses ≥ 1.5 mg/d yielded 69 - 75% D2/D3 receptor occupancy as measured in positron emission tomography scans. Mean half-life for cariprazine was 2 - 5 d over a dose range of 1.5 - 12.5 mg. Cariprazine produces two clinically relevant metabolites: desmethyl-cariprazine and didesmethyl-cariprazine, the latter having a longer half-life than cariprazine. Exposure to didesmethyl-cariprazine exceeded that of the parent drug. Cariprazine is metabolized by CYP3A4 and to a lesser extent by CYP2D6. The efficacy and safety of cariprazine have been so far investigated only in a few short-term (unpublished) clinical trials; however, three studies in schizophrenia and three studies in bipolar mania/mixed episodes evidenced a statistically significant therapeutic effect compared to placebo for cariprazine at doses ranging from 1.5 to 12 mg/d. There does not appear to be clinically relevant adverse effects of cariprazine on metabolic variables. Commonly encountered adverse events associated with cariprazine include insomnia, extrapyramidal symptoms, akathisia, sedation, nausea, dizziness, and constipation.

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Section: Introduction To Cariprazinementioning

confidence: 99%

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confidence: 99%

Cariprazine: chemistry, pharmacodynamics, pharmacokinetics, and metabolism, clinical efficacy, safety, and tolerability

Citrome

2013

Expert Opinion on Drug Metabolism & Toxicology

114

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“…Based on their value we could predict possibility of passive transport of drugs through the lipoid membranes in the human body. Although logarithm of octanol/water partition coefficient (log P oct ) is the most extensively used parameter to quantify lipophilicity, nowadays extrapolated log k w values is a popular alternative of lipophilicity assessment which correlate well with log P oct values [ 26 , 27 , 28 ].…”

Section: Resultsmentioning

confidence: 99%

Synthesis, Analysis, Cholinesterase-Inhibiting Activity and Molecular Modelling Studies of 3-(Dialkylamino)-2-hydroxypropyl 4-[(Alkoxy-carbonyl)amino]benzoates and Their Quaternary Ammonium Salts

et al. 2017

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Tertiary amines 3-(dialkylamino)-2-hydroxypropyl 4-[(alkoxycarbonyl)amino]benzoates and their quaternary ammonium salts were synthesized. The final step of synthesis of quaternary ammonium salts was carried out by microwave-assisted synthesis. Software-calculated data provided the background needed to compare fifteen new resulting compounds by their physicochemical properties. The acid dissociation constant (pKa) and lipophilicity index (log P) of tertiary amines were determined; while quaternary ammonium salts were characterized by software-calculated lipophilicity index and surface tension. Biological evaluation aimed at testing acetylcholinesterase and butyrylcholinesterase-inhibiting activity of synthesized compounds. A possible mechanism of action of these compounds was determined by molecular modelling study using combined techniques of docking; molecular dynamics simulations and quantum mechanics calculations.

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“…The dual α 1 - and β-blockers (e.g., carvedilol, labetalol, vanylidilol) showed hemodynamic benefits, including reduction of peripheral vascular resistance, improvement of cardiac output and left ventricular function, which is why the vasodilatory activity is an enhancement to the antihypertensive effect of β-blockade and offsets its drawback [1,2,3]. The pharmacokinetic effect and toxicity of the newly prepared compound can be predicted also from the determination of their physicochemical properties [4,5].…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Determination of Physicochemical Properties of New 3-(4-Arylpiperazin-1-yl)-2-hydroxypropyl 4-Alkoxyethoxybenzoates

et al. 2016

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Abstract:Nine new dihydrochloride salts of 3-(4-arylpiperazin-1-yl)-2-hydroxypropyl 4-alkoxyethoxybenzoates were designed and synthesized. The physicochemical properties such as lipophilicity index (log k w ) and dissociation constant (pK a ) were experimentally determined and compared to the software calculated data. The lipophilicity index was determined by means of reversed-phase high performance liquid chromatography (RP-HPLC). The pK a values were determined by means of capillary zone electrophoresis. The "drug-likeness" properties according to the Lipinski Rule of Five and prediction of possible blood-brain barrier penetration were computed and discussed.

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Physico-chemical characterization of a novel group of dopamine D3/D2 receptor ligands, potential atypical antipsychotic agents

Cited by 9 publications

References 22 publications

Cariprazine: chemistry, pharmacodynamics, pharmacokinetics, and metabolism, clinical efficacy, safety, and tolerability

Cariprazine: chemistry, pharmacodynamics, pharmacokinetics, and metabolism, clinical efficacy, safety, and tolerability

Synthesis, Analysis, Cholinesterase-Inhibiting Activity and Molecular Modelling Studies of 3-(Dialkylamino)-2-hydroxypropyl 4-[(Alkoxy-carbonyl)amino]benzoates and Their Quaternary Ammonium Salts

Synthesis and Determination of Physicochemical Properties of New 3-(4-Arylpiperazin-1-yl)-2-hydroxypropyl 4-Alkoxyethoxybenzoates

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