- Synthesis of novel pyrido[1,2-c]pyrimidine derivatives with 6-fluoro-3-(4-piperidynyl)-1,2-benzisoxazole moiety as potential ssri and 5-ht1a receptor ligands
-
Two series of novel 4-aryl-2H-pyrido[1,2-c]pyrimidine (6a–i) and 4-aryl-5,6,7,8-tetrahydropyrido[1,2-c]pyrimidine (7a–i) derivatives were synthesized. The chemical structures of the new compounds were confirmed by1H and13C NMR spectroscopy and ESI-HRMS spectrome-try. The affinities of all compounds for the 5-HT1A receptor and serotonin transporter protein (SERT) were determined by in vitro radioligand binding assays. The test compounds demonstrated very high binding affinities for the 5-HT1A receptor of all derivatives in the series (6a–i and 7a–i) and generally low binding affinities for the SERT protein, with the exception of compounds 6a and 7g. Extended affinity tests for the receptors D2, 5-HT2A, 5-HT6 and 5-HT7 were conducted with regard to selected compounds (6a, 7g, 6d and 7i). All four compounds demonstrated very high affinities for the D2 and 5-HT2A receptors. Compounds 6a and 7g also had high affinities for 5-HT7, while 6d and 7i held moderate affinities for this receptor. Compounds 6a and 7g were also tested in vivo to identify their functional activity profiles with regard to the 5-HT1A receptor, with 6a demonstrating the activity profile of a presynaptic agonist. Metabolic stability tests were also conducted for 6a and 6d.
- Król, Marek,?lifirski, Grzegorz,Kleps, Jerzy,Ulenberg, Szymon,Belka, Mariusz,Baczek, Tomasz,Siwek, Agata,Stachowicz, Katarzyna,Szewczyk, Bernadeta,Nowak, Gabriel,Duszyńska, Beata,Herold, Franciszek
-
-
- Structure-activity relationship and cardiac safety of 2-aryl-2-(pyridin-2-yl)acetamides as a new class of broad-spectrum anticonvulsants derived from Disopyramide
-
A series of 2-aryl-2-(pyridin-2-yl)acetamides were synthesized and screened for their anticonvulsant activity in animal models of epilepsy. The compounds were broadly active in the ‘classical’ maximal electroshock seizure (MES) and subcutaneous Metrazol (scMET) tests as well as in the 6 Hz and kindling models of pharmacoresistant seizures. Furthermore, the compounds showed good therapeutic indices between anticonvulsant activity and motor impairment. Structure-activity relationship (SAR) trends clearly showed the highest activity resides in unsubstituted phenyl derivatives or compounds having ortho- and meta- substituents on the phenyl ring. The 2-aryl-2-(pyridin-2-yl)acetamides were derived by redesign of the cardiotoxic sodium channel blocker Disopyramide (DISO). Our results show that the compounds preserve the capability of the parent compound to inhibit voltage gated sodium currents in patch-clamp experiments; however, in contrast to DISO, a representative compound from the series 1 displays high levels of cardiac safety in a panel of in vitro and in vivo experiments.
- ?tengl, Milan,Chodkowski, Andrzej,Dawidowski, Maciej,El Harchi, Aziza,Hancox, Jules C.,Jarkovska, Dagmar,Konopelski, Piotr,Król, Marek,Mistrova, Eliska,Podsadni, Piotr,Popowicz, Grzegorz M.,Sviglerova, Jitka,Szuberski, Piotr,Szulczyk, Bart?omiej,Tur?o, Jadwiga,Ufnal, Marcin,Wróbel, Martyna Zofia,Zhang, Yihong
-
-
- Synthesis of novel pyrido[1,2-c]pyrimidine derivatives with rigidized tryptamine moiety as potential SSRI and 5-HT1A receptor ligands
-
The study enabled obtaining a number of new derivatives of 4-aryl-pyrido[1,2-c]pyrimidine 9.1–9.27 having conformationally restricted tryptamine moiety. In vitro studies (RBA) have shown that derivatives 9.1, 9.2, 9.4, 9.7, 9.9, 9.14 and 9.27 exhibit high affinity to molecular targets 5-HT1A receptor and SERT protein. In general, compounds with an unsubstituted or a para-substituted benzene ring of the pyrido[1,2-c]pyrimidine residue in the terminal part were characterized by higher binding ability, which can be justified by the greater flexibility of the structure. For the selected compounds 9.1, 9.7, 9.9 and 9.27, further in vitro, in vivo and metabolic stability tests were performed. The in vitro studies in the extended receptor profile (D2, 5-HT2A, 5-HT6 and 5-HT7) indicated their selectivity toward the 5-HT1A receptor and SERT protein. The in vivo studies (8-OH-DPAT-induced hypothermia in mice, FST) revealed that the compound 9.1 has the properties of presynaptic agonist of the 5-HT1A receptor, and compound 9.7 demonstrated the properties of a presynaptic antagonist of the 5-HT1A receptor. Metabolic stability studies, in turn, showed that compounds 9.1, 9.7 and 9.9, having an unsubstituted indole residue, were more resistant to biotransformation reactions of the first pass phase than was compound 9.27 containing a 5-methoxy-substituted indole residue. The obtained results allowed further optimization of the structure.
- ?lifirski, Grzegorz,Król, Marek,Kleps, Jerzy,Ulenberg, Szymon,Belka, Mariusz,B?czek, Tomasz,Siwek, Agata,Stachowicz, Katarzyna,Szewczyk, Bernadeta,Nowak, Gabriel,Bojarski, Andrzej,Kozio?, Anna E.,Tur?o, Jadwiga,Herold, Franciszek
-
p. 144 - 158
(2019/01/30)
-
- Synthesis of new 5,6,7,8-tetrahydropyrido[1,2-c]pyrimidine derivatives with rigidized tryptamine moiety as potential SSRI and 5-HT1A receptor ligands
-
Extended studies in the 4-aryl-pyrido[1,2-c]pyrimidine group resulted in 27 new compounds (10.1-10.27), 5,6,7,8-tetrahydropyrido[1,2-c]pyrimidine derivatives. In vitro tests (RBA) were carried out for 10.1-10.27 compounds in order to determine their affinity to 5-HT1A receptor and SERT protein. 10.1-10.3, 10.6, 10.7, 10.16 and 10.27 compounds had high binding ability to both molecular targets (5-HT1A Ki = 8–87 nM; SERT Ki = 8–52 nM). For these compounds (10.1-10.3, 10.6, 10.7, 10.16, 10.27) further in vitro, in vivo and metabolic stability tests were performed. In vitro studies in the extended receptor profile (D2, 5-HT2A, 5-HT6 and 5-HT7) showed their selectivity towards 5-HT1A receptor and SERT protein. In vivo tests revealed that compounds 10.7 and 10.16 had the properties of presynaptic antagonists of the 5-HT1A receptor. The redesign of the 2H-pyrido[1,2-c]pyrimidine residue present in the terminal part towards 5,6,7,8-tetrahydropyrido[1,2-c]pyrimidine resulted in the improved metabolic stability and enhanced affinity to both molecular targets (5-HT1A-R and SERT) compared to the precursors.
- ?lifirski, Grzegorz,Król, Marek,Kleps, Jerzy,Podsadni, Piotr,Belka, Mariusz,B?czek, Tomasz,Siwek, Agata,Stachowicz, Katarzyna,Szewczyk, Bernadeta,Nowak, Gabriel,Bojarski, Andrzej,Kozio?, Anna E.,Tur?o, Jadwiga,Herold, Franciszek
-
p. 383 - 397
(2019/07/19)
-
- An Improved and Efficient Process for the Production of Highly Pure Dexmethylphenidate Hydrochloride
-
The present work describes an efficient and commercially viable process for the synthesis of dexmethylphenidate hydrochloride (1), a mild nervous system stimulant. The overall yield is 23% with ~99.9% purity (including seven chemical steps). Formation and control of possible impurities are also described in this report.
- Xing, Long-Xuan,Shen, Cheng-Wu,Sun, Yuan-Yuan,Huang, Lei,Zheng, Yong-Yong,Li, Jian-Qi
-
p. 1298 - 1303
(2017/03/27)
-
- Novel 4-aryl-pyrido[1,2-c ]pyrimidines with dual SSRI and 5-HT1A activity. Part 4
-
This project describes the synthesis, pharmacological and pharmacodynamic tests on two series of novel derivatives of 2H-pyrido[1,2-c]pyrimidine with potential binary binding to 5-HT1A receptors and SSRI + serotonin transporters. The influence of piperidinyl-indole (8.1-8.7) and tetrahydropyridinyl-indole (8.8-8.32) residues and indole 5-position substituents (R3 Combining double low line Br, Cl, F) present in the pharmacophore element of ligands on their binding to both molecular targets was tested.A considerable impact of piperidinyl-indole residue on binding to both targets was confirmed and compounds with a high binding affinity were identified: Ki 5-HT1A Combining double low line 12.4 nM; Ki SERT Combining double low line 15.6 nM 8.1; Ki 5-HT1A Combining double low line 5.6 nM; Ki SERT Combining double low line 20.7 nM 8.7, while the presence of a tetrahydropyridinyl-indole residue was found to reduce the affinity of ligands to 5-HT1AR. The presence of chlorine (R3) in this series resulted in a notable reduction in binding to both targets (5-HT1A and SERT). Selected compounds had their metabolic stability in a first-pass test (human liver microsomes, NADPH) determined in vitro, and R1 and R2 substituents present on the terminal residue of pyrido[1,2-c]pyrimidine were recognized as having an impact on stability.
- Chodkowski, Andrzej,Wróbel, Martyna Z.,Turlo, Jadwiga,Kleps, Jerzy,Siwek, Agata,Nowak, Gabriel,Belka, Mariusz,Baczek, Tomasz,Mazurek, Aleksander P.,Herold, Franciszek
-
-
- Novel 4-aryl-pyrido[1,2-c]pyrimidines with dual SSRI and 5-HT1A activity. part 5
-
A series of novel 4-aryl-pyrido[1,2-c]pyrimidine derivatives containing a 1-(2-quinoline)piperazine moiety was synthesized. The chemical structure of new compounds was confirmed by FT-IR, 1H NMR, 13C NMR and HRMS spectra as well as elemental analysis. Affinity of the novel pyrido[1,2-c]pyrimidine derivatives for 5-HT1A, 5-HT2A receptors and serotonin transporter (SERT) was evaluated in an in vitro radioligand binding assay. Tested compounds showed moderate to high affinity for 5-HT1AR and SERT and low affinity for 5-HT2AR. Selected ligands were subjected to in vivo tests, such as induced hypothermia and the forced swimming test in mice, which determined presynaptic agonistic activity of the ligands 8d, 8e, 9d and 9e and presynaptic antagonistic activity of the ligands 8a, 8b, 9a, 9b. Additionally, metabolic stability evaluation was performed for selected ligands, proving that a para-substitution in the 4-aryl-pyrido[1,2-c]pyrimidine moiety leads to an increase in stability, whereas a substitution in the ortho-position lowers the stability.
- Gomolka, Anna,Ciesielska, Agnieszka,Wróbel, Martyna Z.,Chodkowski, Andrzej,Kleps, Jerzy,Dawidowski, MacIej,Siwek, Agata,Wolak, Malgorzata,Stachowicz, Katarzyna,Slawinska, Anna,Nowak, Gabriel,Satala, Grzegorz,Bojarski, Andrzej J.,Belka, Mariusz,Ulenberg, Szymon,Baczek, Tomasz,Skowronek, Pawel,Turlo, Jadwiga,Herold, Franciszek
-
p. 221 - 236
(2015/06/08)
-
- Novel 4-aryl-pyrido[1,2-c]pyrimidines with dual SSRI and 5-HT1A activity. Part 3
-
A number of 4-aryl-5,6,7,8-tetrahydropyrido[1,2-c]pyrimidine with 3-(1,2,3,6-tetrahydro-pyridin-4-yl)-1H-indole or 2-methyl-3-(1,2,3,6-tetrahydro- pyridin-4-yl)-1H-indole residues were synthesized for further investigation of SAR in a group of pyrido[1,2-c]pyrimidine derivatives with dual 5-HT 1A/SERT activity. Compounds 8a-8p were found to be potent ligands for both 5-HT1A and SERT with Ki ranging from 28,3 to 642 nM and 42,4 nM-1,8 μM, respectively. Moreover compounds 8a, 8b, 8c, 8d, 8e and 8g were found to be selective agonists, while 8i as an antagonist of 5-HT 1A presynaptic receptors in the inducible hypothermia test in mice.
- Herold, Franciszek,Chodkowski, Andrzej,Izbicki, ?ukasz,Tur?o, Jadwiga,Dawidowski, MacIej,Kleps, Jerzy,Nowak, Gabriel,Stachowicz, Katarzyna,Dyba?a, Ma?gorzata,Siwek, Agata,Mazurek, Aleksander P.,Mazurek, Andrzej,Pluciński, Franciszek
-
scheme or table
p. 142 - 149
(2011/02/27)
-
- Novel 4-aryl-pyrido[1,2-c]pyrimidines with dual SSRI and 5-HT1A activity, Part 1
-
A series of new derivatives of 4-aryl-pyrido[1,2-c]pyrimidine containing the 3-(4-piperidyl)-1H-indole residue or its 5-methoxy derivative were synthesized. They were characterized (i) in vitro by binding to 5-HT1A receptors and 5-HT transporter proteins in rat brain cortex membranes and (ii) in vivo in the mouse by induced hypothermia and forced swimming models for antagonist/agonist activity against the 5-HT1A autoreceptors and postsynaptic 5-HT1A receptors, respectively. Structure activity relationship evaluation indicated that the presence of the 3-(4-piperidyl)-1H-indole residue and ortho- or para-substituents with -F or -CH3 groups in the aryl ring as well as an unsubstituted aryl in the 4-aryl-pyrido[1,2-c]pyrimidine moiety promoted low Ki values for both receptors. In contrast, the presence of a 5-methoxy-3-(4-piperidyl)-1H-indole residue as well as -Cl or -OCH3 substituents at the para position markedly reduced the receptor affinity.
- Herold, Franciszek,Chodkowski, Andrzej,Izbicki, Lukasz,Krol, Marek,Kleps, Jerzy,Turlo, Jadwiga,Nowak, Gabriel,Stachowicz, Katarzyna,Dybala, Malgorzata,Siwek, Agata
-
body text
p. 1710 - 1717
(2009/05/26)
-
- Novel 4-aryl-pyrido[1,2-c]pyrimidines with dual SSRI and 5-HT1A activity: Part 2
-
Derivatives of 4-aryl-5,6,7,8-tetrahydro-pyrido[1,2-c]pyrimidine were synthesized. These compounds contain the 3-(4-piperidyl)-1H-indole residue or its 5-methoxy or 2-methyl derivative. In vitro binding tests were performed to determine the affinity of the compounds for the 5-HT1A receptor and serotonin transporter (SERT) proteins in the rat brain cortex. In vivo studies, particularly the inducible hypothermia test and forced swimming test, were conducted to determine agonistic/antagonistic activity with pre- and postsynaptic 5-HT1A receptors. Molecular modeling techniques were used to determine the binding modes of the selected compounds at the 5-HT1A receptor and SERT. The SAR analysis showed that the presence of the 3-(4-piperidyl)-1H-indole group or its 5-methoxy derivative, as well as a para substitution with -OCH3 or -F in the aryl ring of 4-aryl-5,6,7,8-tetrahydro-pyrido[1,2-c]pyrimidine, results in an increased affinity for both the 5-HT1A receptors and SERT. In contrast, the presence of the 2-methyl-3-(4-piperidyl)-1H-indole group resulted in a considerable decrease in binding affinity.
- Herold, Franciszek,Izbicki, Lukasz,Chodkowski, Andrzej,Dawidowski, Maciej,Krol, Marek,Kleps, Jerzy,Turlo, Jadwiga,Wolska, Irena,Nowak, Gabriel,Stachowicz, Katarzyna,Dybala, Malgorzata,Siwek, Agata,Nowak, Mateusz,Pieniazek, Elzbieta,Jaronczyk, Malgorzata,Sylte, Ingebrigt,Mazurek, Aleksander P.
-
scheme or table
p. 4702 - 4715
(2009/12/28)
-
- Synthesis of new hexahydro- and octahydropyrido[1,2-c]pyrimidine derivatives with an arylpiperazine moiety as ligands for 5-HT1A and 5-HT2A receptors. Part 4
-
New 4-aryl-2H-pyrido[1,2-c]pyrimidine-1,3-dione derivatives of arylpiperazine (6-18) were prepared and evaluated in vitro for their affinity for 5-HT1A, 5-HT2A, and α1 receptors. The influence of ortho substitution in the phenyl ring, substitution at position 4 of the pyrido[1,2-c]pyrimidine system, and its unsaturation degree were explored. The tested compounds showed high affinity for the 5-HT1A receptor (Ki = 1.3-79.2:nM) and moderate to low affinity for the 5-HT2A (Ki = 51.7-1405:nM) and α1 receptors (Ki = 19.7-382.3:nM). Compounds 8 and 10 showed the highest 5-HT1A receptor affinity (Ki = 1.3 and 2.2:nM, respectively) and were 37- and 35.9-fold, respectively, more selective in relation to α1 adrenoreceptors.
- Herold, Franciszek,Krol, Marek,Kleps, Jerzy,Nowak, Gabriel
-
p. 125 - 134
(2007/10/03)
-
- Method for treating conditions related to the glutamate receptor using carboxylic acid amide derivatives
-
The present invention is concerned with the use of carbonylamino derivatives of the formula wherein R signifies lower alkyl, lower alkenyl, lower alkinyl, cycloalkyl, lower alkoxy or CF3; R1signifies hydrogen or lower alkyl; R2and R3signify, independently from each other, hydrogen, halogen or nitro; Y signifies CH or N; n is 0-6; m is 0-2; as well as with their pharmaceutically acceptable salts for the treatment of diseases, which relate to metabotropic glutamate receptor antagonists and/or agonists.
- -
-
-
- Methods for production of piperidyl acetamide stereoisomers
-
Synthetic methods are provided comprising the steps of racemizing l-threo-piperidyl acetamides to form a mixture of d-threo, l-threo, d-erythro, and l-erythro-piperidyl acetamides by reacting said l-threo-piperidyl acetamides with alkanoic acid.
- -
-
-
- Synthesis and molecular structure of novel 4-aryloctahydropyrido-[1,2-c]pyrimidine derivatives
-
A series of new 4-aryloctahydropyrido[1,2-c]pyrimidine-1,3-diones 6a,b,d-h and j were synthesized by intramolecular cyclization of α-aryl-α(1-ethoxycarbonyl-2-piperidyl)-acetamide derivatives 5a,b,d-h and j. The structures of compounds were determined by 1H and 13C nmr spectroscopy. Nmr and X-ray diffraction data indicate that the configuration at the C4, C4a stereocenters constitute RR and SS pair.
- Herold, Franciszek,Kleps, Jerzy,Anulewicz-Ostrowska, Romana,Szczesna, Beata
-
p. 773 - 782
(2007/10/03)
-
- Processes and intermediates for resolving piperidyl acetamide stereoisomers
-
Processes and intermediates for preparing 2-substituted piperidines such as 2-substituted d-threo piperidines are provided, including processes and intermediates for resolution of piperidyl acetamide stereoisomers.
- -
-
-
- Synthesis and structure of novel 4-arylhexahydro-1h,3h-pyrido[1,2- c]pyrimidine derivatives
-
A series of new 4-aryl-hexahydro-IH,3H-pyrido[1,2-c]pyrimidine-1,3- dione derivatives 4a-k were prepared by catalytic hydrogenation of 4-aryl- 1H,2H-pyrido[1,2-c]pyrimidine-1,3-diones 3a-k. The structures of compounds were determined by 1H and 13C nmr spectroscopy in solution. Steric hindrance caused twisting of the phenyl ring with respect to the pyridopyrimidine system, the effect was confirmed by X-ray diffraction.
- Herold, Franciszek,Wolska, Irena,Helbin, Ewa,Krol, Marek,Kleps, Jerzy
-
p. 389 - 396
(2007/10/03)
-
- Synthesis and pharmacology of potential cocaine antagonists. 2. Structure-activity relationship studies of aromatic ring-substituted methylphenidate analogs
-
As part of a program, to develop medications which can block the binding of cocaine to the dopamine transporter, yet spare dopamine uptake, a series of aromatic ring-substituted methylphenidate derivatives was synthesized and tested for inhibitory potency in [3H]WIN 35,428 binding and [3H]dopamine uptake assays using rat striatal tissue. Synthesis was accomplished by alkylation of 2-bromopyridine with anions derived from various substituted phenylacetonitriles. In most cases, erythro compounds were markedly less potent than the corresponding (±)-threo-methylphenidate (TMP; Ritalin) derivatives. The ortho-substituted compounds were much less potent than the corresponding meta- and/or para-substituted derivatives. The most potent compound against [3H]WIN 35,428 binding, m-bromo-TMP, was 20-fold more potent than the parent compound, whereas the most potent compound against [3H]dopamine uptake, m,p-dichloro-TMP, was 32-fold more potent. Threo derivatives with m-or p-halo substituents were more potent than TMP, while electron-donating substituants caused little change or a small loss of potency. All of the derivatives had Hill coefficients approaching unity, except m,p-dichloro-TMP, which had an nH of 2.0. Although the potency of the (±)-methylphenidate derivatives in the two assays was highly correlated (R2 = 0.986), the compounds m-chloro-, m-methyl-, and p-iodo-TMP were 4-5-fold more potent at inhibiting [3H]-WIN 35,428 binding than [3H]dopamine uptake (cocaine has a ratio of 2.3). These and other compounds may be promising candidates for further testing as potential partial agonists or antagonists of cocaine.
- Deutsch, Howard M.,Shi, Qing,Gruszecka-Kowalik, Ewa,Schwer, Margaret M.
-
p. 1201 - 1209
(2007/10/03)
-