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

János Galambos, Attila Bielik, Gábor Wágner, György Domány, János Kóti, Zoltán Béni, Áron Szigetvári, Zsuzsanna Sánta, Zoltán Orgován, Amrita Bobok, Béla Kiss, Mónika L. Mikó-Bakk, Mónika Vastag, Katalin Sághy, Mikhail Krasavin, Krisztina Gál, István Greiner, Zsolt Szombathelyi, György M. Keserű

    Research output

    4 Citations (Scopus)

    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.

    Original languageEnglish
    Pages (from-to)240-254
    Number of pages15
    JournalEuropean Journal of Medicinal Chemistry
    Volume133
    DOIs
    Publication statusPublished - 1 Jan 2017

    Scopus subject areas

    • Pharmacology
    • Drug Discovery
    • Organic Chemistry

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  • Cite this

    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