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Discovery of 4-amino-3-arylsulfoquinolines, a novel non-acetylenic chemotype of metabotropic glutamate 5 (mGlu5) receptor negative allosteric modulators. / Galambos, János; Bielik, Attila; Wágner, Gábor; Domány, György; Kóti, János; Béni, Zoltán; Szigetvári, Áron; Sánta, Zsuzsanna; Orgován, Zoltán; Bobok, Amrita; Kiss, Béla; Mikó-Bakk, Mónika L.; Vastag, Mónika; Sághy, Katalin; Krasavin, Mikhail; Gál, Krisztina; Greiner, István; Szombathelyi, Zsolt; Keserű, György M.

в: European Journal of Medicinal Chemistry, Том 133, 01.01.2017, стр. 240-254.

Результаты исследований: Научные публикации в периодических изданиях › статья › Рецензирование

Harvard

Galambos, J, Bielik, A, Wágner, G, Domány, G, Kóti, J, Béni, Z, Szigetvári, Á, Sánta, Z, Orgován, Z, Bobok, A, Kiss, B, Mikó-Bakk, ML, Vastag, M, Sághy, K, Krasavin, M, Gál, K, Greiner, I, Szombathelyi, Z & Keserű, GM 2017, 'Discovery of 4-amino-3-arylsulfoquinolines, a novel non-acetylenic chemotype of metabotropic glutamate 5 (mGlu5) receptor negative allosteric modulators', European Journal of Medicinal Chemistry, Том. 133, стр. 240-254. https://doi.org/10.1016/j.ejmech.2017.03.071

APA

Galambos, J., Bielik, A., Wágner, G., Domány, G., Kóti, J., Béni, Z., Szigetvári, Á., Sánta, Z., Orgován, Z., Bobok, A., Kiss, B., Mikó-Bakk, M. L., Vastag, M., Sághy, K., Krasavin, M., Gál, K., Greiner, I., Szombathelyi, Z., & Keserű, G. M. (2017). Discovery of 4-amino-3-arylsulfoquinolines, a novel non-acetylenic chemotype of metabotropic glutamate 5 (mGlu5) receptor negative allosteric modulators. European Journal of Medicinal Chemistry, 133, 240-254. https://doi.org/10.1016/j.ejmech.2017.03.071

Vancouver

Galambos J, Bielik A, Wágner G, Domány G, Kóti J, Béni Z и пр. Discovery of 4-amino-3-arylsulfoquinolines, a novel non-acetylenic chemotype of metabotropic glutamate 5 (mGlu5) receptor negative allosteric modulators. European Journal of Medicinal Chemistry. 2017 Янв. 1;133:240-254. https://doi.org/10.1016/j.ejmech.2017.03.071

Author

Galambos, János ; Bielik, Attila ; Wágner, Gábor ; Domány, György ; Kóti, János ; Béni, Zoltán ; Szigetvári, Áron ; Sánta, Zsuzsanna ; Orgován, Zoltán ; Bobok, Amrita ; Kiss, Béla ; Mikó-Bakk, Mónika L. ; Vastag, Mónika ; Sághy, Katalin ; Krasavin, Mikhail ; Gál, Krisztina ; Greiner, István ; Szombathelyi, Zsolt ; Keserű, György M. / Discovery of 4-amino-3-arylsulfoquinolines, a novel non-acetylenic chemotype of metabotropic glutamate 5 (mGlu5) receptor negative allosteric modulators. в: European Journal of Medicinal Chemistry. 2017 ; Том 133. стр. 240-254.

BibTeX

@article{612fa61ce2b946cb8d8b78d21a3153d8,
title = "Discovery of 4-amino-3-arylsulfoquinolines, a novel non-acetylenic chemotype of metabotropic glutamate 5 (mGlu5) receptor negative allosteric modulators",
abstract = "Negative allosteric modulators of metabotropic glutamate receptor 5 (mGlu5) showed efficacy in a number of animal models of different CNS diseases including anxiety and depression. Virtually all of the compounds which reached the clinic belong to the same chemotype having an acetylenic linker that connects (hetero)cyclic moieties. Searching for new chemotypes we identified a morpholino-sulfoquinoline derivative (1) by screening our corporate compound deck. The HTS hit showed reasonable affinity and selectivity towards mGlu5 receptors, however, its inferior metabolic stability prevented its testing in vivo. In a chemical program we aimed to improve the affinity, physicochemical properties and metabolic stability exploring three regions of the hit. Systematic variation of different amines at position 4 (region I) led to the identification of 4-methyl-piperidinyl analogues. Substituents of the quinoline core (region II) and the phenylsulfonyl moiety (region III) were mapped by parallel synthesis. Evaluation of both morpholino- and 4-methyl-piperidinyl-sulfoquinoline libraries of about 270 derivatives revealed beneficial substituent combinations in regions II and III. Blood levels of optimized 4-methyl-piperidinyl-sulfoquinolines, however, were still insufficient for robust in vivo efficacy. Finally, introducing 4-hydoxymethyl-piperidinyl substituent to region I resulted in new sulfoquinolines with greatly improved solubility and reasonable affinity coupled with affordable metabolic stability. The most promising analogues (24 and 25) showed high blood levels and demonstrated significant efficacy in the experimental model of anxiety.",
keywords = "4-amino-3-arylsulfonyl-quinolines, mGlu receptor, Negative allosteric modulator, Optimization, Parallel synthesis",
author = "J{\'a}nos Galambos and Attila Bielik and G{\'a}bor W{\'a}gner and Gy{\"o}rgy Dom{\'a}ny and J{\'a}nos K{\'o}ti and Zolt{\'a}n B{\'e}ni and {\'A}ron Szigetv{\'a}ri and Zsuzsanna S{\'a}nta and Zolt{\'a}n Orgov{\'a}n and Amrita Bobok and B{\'e}la Kiss and Mik{\'o}-Bakk, {M{\'o}nika L.} and M{\'o}nika Vastag and Katalin S{\'a}ghy and Mikhail Krasavin and Krisztina G{\'a}l and Istv{\'a}n Greiner and Zsolt Szombathelyi and Keser{\H u}, {Gy{\"o}rgy M.}",
year = "2017",
month = jan,
day = "1",
doi = "10.1016/j.ejmech.2017.03.071",
language = "English",
volume = "133",
pages = "240--254",
journal = "European Journal of Medicinal Chemistry",
issn = "0223-5234",
publisher = "Elsevier",

}

RIS

TY - JOUR

T1 - Discovery of 4-amino-3-arylsulfoquinolines, a novel non-acetylenic chemotype of metabotropic glutamate 5 (mGlu5) receptor negative allosteric modulators

AU - Galambos, János

AU - Bielik, Attila

AU - Wágner, Gábor

AU - Domány, György

AU - Kóti, János

AU - Béni, Zoltán

AU - Szigetvári, Áron

AU - Sánta, Zsuzsanna

AU - Orgován, Zoltán

AU - Bobok, Amrita

AU - Kiss, Béla

AU - Mikó-Bakk, Mónika L.

AU - Vastag, Mónika

AU - Sághy, Katalin

AU - Krasavin, Mikhail

AU - Gál, Krisztina

AU - Greiner, István

AU - Szombathelyi, Zsolt

AU - Keserű, György M.

PY - 2017/1/1

Y1 - 2017/1/1

N2 - Negative allosteric modulators of metabotropic glutamate receptor 5 (mGlu5) showed efficacy in a number of animal models of different CNS diseases including anxiety and depression. Virtually all of the compounds which reached the clinic belong to the same chemotype having an acetylenic linker that connects (hetero)cyclic moieties. Searching for new chemotypes we identified a morpholino-sulfoquinoline derivative (1) by screening our corporate compound deck. The HTS hit showed reasonable affinity and selectivity towards mGlu5 receptors, however, its inferior metabolic stability prevented its testing in vivo. In a chemical program we aimed to improve the affinity, physicochemical properties and metabolic stability exploring three regions of the hit. Systematic variation of different amines at position 4 (region I) led to the identification of 4-methyl-piperidinyl analogues. Substituents of the quinoline core (region II) and the phenylsulfonyl moiety (region III) were mapped by parallel synthesis. Evaluation of both morpholino- and 4-methyl-piperidinyl-sulfoquinoline libraries of about 270 derivatives revealed beneficial substituent combinations in regions II and III. Blood levels of optimized 4-methyl-piperidinyl-sulfoquinolines, however, were still insufficient for robust in vivo efficacy. Finally, introducing 4-hydoxymethyl-piperidinyl substituent to region I resulted in new sulfoquinolines with greatly improved solubility and reasonable affinity coupled with affordable metabolic stability. The most promising analogues (24 and 25) showed high blood levels and demonstrated significant efficacy in the experimental model of anxiety.

AB - Negative allosteric modulators of metabotropic glutamate receptor 5 (mGlu5) showed efficacy in a number of animal models of different CNS diseases including anxiety and depression. Virtually all of the compounds which reached the clinic belong to the same chemotype having an acetylenic linker that connects (hetero)cyclic moieties. Searching for new chemotypes we identified a morpholino-sulfoquinoline derivative (1) by screening our corporate compound deck. The HTS hit showed reasonable affinity and selectivity towards mGlu5 receptors, however, its inferior metabolic stability prevented its testing in vivo. In a chemical program we aimed to improve the affinity, physicochemical properties and metabolic stability exploring three regions of the hit. Systematic variation of different amines at position 4 (region I) led to the identification of 4-methyl-piperidinyl analogues. Substituents of the quinoline core (region II) and the phenylsulfonyl moiety (region III) were mapped by parallel synthesis. Evaluation of both morpholino- and 4-methyl-piperidinyl-sulfoquinoline libraries of about 270 derivatives revealed beneficial substituent combinations in regions II and III. Blood levels of optimized 4-methyl-piperidinyl-sulfoquinolines, however, were still insufficient for robust in vivo efficacy. Finally, introducing 4-hydoxymethyl-piperidinyl substituent to region I resulted in new sulfoquinolines with greatly improved solubility and reasonable affinity coupled with affordable metabolic stability. The most promising analogues (24 and 25) showed high blood levels and demonstrated significant efficacy in the experimental model of anxiety.

KW - 4-amino-3-arylsulfonyl-quinolines

KW - mGlu receptor

KW - Negative allosteric modulator

KW - Optimization

KW - Parallel synthesis

UR - http://www.scopus.com/inward/record.url?scp=85017010704&partnerID=8YFLogxK

U2 - 10.1016/j.ejmech.2017.03.071

DO - 10.1016/j.ejmech.2017.03.071

M3 - Article

C2 - 28390229

AN - SCOPUS:85017010704

VL - 133

SP - 240

EP - 254

JO - European Journal of Medicinal Chemistry

JF - European Journal of Medicinal Chemistry

SN - 0223-5234

ER -

ID: 34633844