Eva Schmidt
Egis Group
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Publication
Featured researches published by Eva Schmidt.
Journal of Pharmacology and Experimental Therapeutics | 2010
Bela Kiss; Attila Horváth; Zsolt Némethy; Eva Schmidt; István Laszlovszky; Gyula Bugovics; Károly Fazekas; Katalin Hornok; Szabolcs Orosz; István Gyertyán; Éva Ágai-Csongor; György Domány; Károly Tihanyi; Nika Adham; Zsolt Szombathelyi
Cariprazine {RGH-188; trans-N-[4-[2-[4-(2,3-dichlorophenyl)piperazin-1-yl]ethyl]cyclohexyl]-N′,N′-dimethylurea hydrochloride}, a novel candidate antipsychotic, demonstrated approximately 10-fold higher affinity for human D3 versus human D2L and human D2S receptors (pKi 10.07, 9.16, and 9.31, respectively). It displayed high affinity at human serotonin (5-HT) type 2B receptors (pKi 9.24) with pure antagonism. Cariprazine had lower affinity at human and rat hippocampal 5-HT1A receptors (pKi 8.59 and 8.34, respectively) and demonstrated low intrinsic efficacy. Cariprazine displayed low affinity at human 5-HT2A receptors (pKi 7.73). Moderate or low affinity for histamine H1 and 5-HT2C receptors (pKi 7.63 and 6.87, respectively) suggest cariprazines reduced propensity for adverse events related to these receptors. Cariprazine demonstrated different functional profiles at dopamine receptors depending on the assay system. It displayed D2 and D3 antagonism in [35S]GTPγS binding assays, but stimulated inositol phosphate (IP) production (pEC50 8.50, Emax 30%) and antagonized (±)-quinpirole-induced IP accumulation (pKb 9.22) in murine cells expressing human D2L receptors. It had partial agonist activity (pEC50 8.58, Emax 71%) by inhibiting cAMP accumulation in Chinese hamster ovary cells expressing human D3 receptors and potently antagonized R(+)-2-dipropylamino-7-hydroxy-1,2,3,4-tetrahydronaphtalene HBr (7-OH-DPAT)-induced suppression of cAMP formation (pKb 9.57). In these functional assays, cariprazine showed similar (D2) or higher (D3) antagonist–partial agonist affinity and greater (3- to 10-fold) D3 versus D2 selectivity compared with aripiprazole. In in vivo turnover and biosynthesis experiments, cariprazine demonstrated D2-related partial agonist and antagonist properties, depending on actual dopaminergic tone. The antagonist–partial agonist properties of cariprazine at D3 and D2 receptors, with very high and preferential affinity to D3 receptors, make it a candidate antipsychotic with a unique pharmacological profile among known antipsychotics.
Bioorganic & Medicinal Chemistry Letters | 2012
Éva Ágai-Csongor; György Domány; Katalin Nógrádi; János Galambos; István Vágó; György M. Keserű; István Greiner; István Laszlovszky; Aniko Gere; Eva Schmidt; Bela Kiss; Monika Vastag; Károly Tihanyi; Katalin Saghy; Judit Laszy; István Gyertyán; Mária Zájer-Balázs; Larisza Gémesi; Margit Kapás; Zsolt Szombathelyi
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.
Drug Development Research | 1997
Istvan Gacsalyi; Eva Schmidt; Istvan Gyertyan; Eero Vasar; Aavo Lang; Antti Haapalinna; Marton Fekete; Jarmo Hietala; Erkka Syvälahti; Päivi Tuomainen; Pekka T. Männistö
The present series of experiments was done to characterize the properties of deramciclane, a new antiserotonergic drug, in both receptor binding studies in vitro and in a number of anxiolytic, antidepressant, and antidopaminergic tests in rodents. A striking property of deramciclane was its high affinity to both 5‐HT2A and 5‐HT2C receptors (Ki = 8.7–27 nM/l). Deramciclane had also a moderate affinity to dopamine D2 and sigma receptors but did not interact with any of the adrenergic receptors.
Bioorganic & Medicinal Chemistry Letters | 2012
János Éles; Gyula Beke; István Vágó; Eva Bozo; József Huszár; Ákos Tarcsay; Sándor Kolok; Eva Schmidt; Monika Vastag; Katalin Hornok; Sandor Farkas; György Domány; György M. Keserű
A new series of quinolinyl- and phenantridinyl-acetamides were synthesizer and evaluated against bradykinin B1 receptor. In vitro metabolic stability data were reported for the key compounds.The analgesic effect of compound 20 from the phenantridine series was proved in-vivo.
Molecular Informatics | 2014
Robert Kiss; Balázs Jójárt; Eva Schmidt; Bela Kiss; György M. Keserű
We report the identification of novel histamine H4 receptor ligands by ensemble docking on homology model conformers derived from molecular dynamics simulations. Selected receptor models from the trajectories demonstrated superior virtual screening performance compared to the initial models. The ensemble of the best models was able to retrieve a diverse set of known H4 ligands. Prospective virtual screening against these models and subsequent in vitro experimental validation identified novel H4 ligands. Compound 3 showing highest affinity and ligand efficiency represents an interesting scaffold for further medicinal chemistry exploration.
Journal of Chemical Information and Modeling | 2012
Robert Kiss; Mark Sandor; Aniko Gere; Eva Schmidt; György T. Balogh; Bela Kiss; László Molnár; Christian Lemmen; György M. Keserű
Ligand-based approaches are particularly important in the hit identification process of drug discovery when no structural information on the target is available. Pharmacophore descriptors that use a topological representation of the ligands are usually fast enough to screen large compound libraries effectively when seeking novel lead candidates. One example of this kind is the Feature Tree descriptor, a reduced graph representation implemented in the FTrees software. In this study, we tested the screening efficiency of FTrees by both retrospective and prospective screens using known histamine H4 antagonists and serotonin transporter (SERT) inhibitors as query molecules. Our results demonstrate that FTrees can effectively find actives. Particularly when combined with a subsequent 2D fingerprint-based diversity selection, FTrees was found to be extremely effective at discovering a diverse set of scaffolds. Prospective screening of our in-house compound deck provided several novel H4 and SERT ligands that could serve as suitable starting points for further optimization.
Cardiovascular Drugs and Therapy | 2003
Anikó Kovács; Istvan Gacsalyi; Janos Wellmann; Eva Schmidt; Zsuzsanna Szücs; Valérie Dubreuil; Jean Paul Nicolas; Jean A. Boutin; Daniel Bozsing; Andras Egyed; Kasoly Tihanyi; Michael Spedding; Gábor Szénási
Our aim was to specify the 5-HT2 subtype selectivity of EGIS-7625 (1-benzyl-4-[(2-nitro-4-methyl-5-amino)-phenyl]-piperazine), a new 5-HT2B ligand, in receptor binding studies and characterize its pharmacology at 5-HT2A, 5-HT2B and 5-HT2C receptors in in vivo experiments and in isolated organs, in vitro. EGIS-7625 had high affinity for recombinant human 5-HT2B receptors (pKi = 9.0) but much weaker affinity for 5-HT2A and 5-HT2C receptors (pKi = 6.2 and 7.7, respectively). In the classic 5-HT2B test, EGIS-7625 produced a concentration-related parallel rightward shift in the concentration-response relationship for the 5-HT-induced smooth muscle constriction in rat stomach fundus strips with a pA2 of 9.4. On the other hand, EGIS-7625 was a weak competitive antagonist at 5-HT2A receptors as it shifted 5-HT-induced concentration-response curves to the right at high concentrations (pA2 = 6.7) in rabbit pulmonary artery strips. The m-chlorophenylpiperazine-induced hypomotility and hypophagia was only partially attenuated by EGIS-7625 even at a dose of 30 mg/kg i.p. while mianserin, a non-selective 5-HT antagonist was almost fully effective in these tests at 3 mg/kg i.p., suggesting weak antagonistic effect of EGIS-7625 at neuronal 5-HT2C receptors, in vivo. In conclusion, EGIS-7625 is a potent, selective and competitive 5-HT2B antagonist that seems to be a good research tool for the separation of the functional roles of vascular 5-HT2A and 5-HT2B receptors.
Bioorganic & Medicinal Chemistry Letters | 2017
Istvan Ledneczki; Pál Tapolcsányi; Eszter Gábor; János Éles; István Greiner; Eva Schmidt; Zsolt Némethy; Rita Kedves; Ottilia Balázs; Viktor Román; György Lévay; Sándor Mahó
Emerging from an HTS campaign, novel steroid-based histamine H3 receptor antagonists were identified and characterized. Structural moieties of the hit compounds were combined to improve binding affinities which resulted in compound 4 as lead molecule. During the lead optimization due to the versatile modifications of diamino steroid derivatives, several in vitro potent compounds with subnanomolar binding affinities to histamine H3 receptors were found. The unfavorable binding to rat muscarinic receptors was successfully reduced by tuning the basicity. Compound 20 showed significant in vivo activity in the rat dipsogenia model and could serve as a pharmacological tool in the future.
Bioorganic & Medicinal Chemistry Letters | 2002
Daniel Bozsing; Ildikó Rátzné Simonek; Gyula Simig; Ivan Jakoczi; Istvan Gacsalyi; Gyoergy Levay; Károly Tihanyi; Eva Schmidt
In an effort to find potential anxiolytic and/or antipsychotic agents with selective 5-HT(2C) affinity a series of new pyrimidine derivatives was prepared and the binding affinities for 5-HT(2A) and 5-HT(2C) receptors were determined.
Pharmacology, Biochemistry and Behavior | 2003
Laszlo Gabor Harsing; Istvan Gacsalyi; Geza Szabo; Eva Schmidt; Nora Sziray; Claude Sebban; Brigitte Tesolin-Decros; Péter Mátyus; Andras Egyed; Michael Spedding; György Lévay