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

作者：Galambos Janos; Bielik Attila; Wagner Gabor; Domany Gyoergy^*; Koti Janos; Beni Zoltan; Szigetvari Aron; Santa Zsuzsanna; Orgovan Zoltan; Bobok Amrita; Kiss Bela; Miko Bakk Monika L; Vastag Monika; Saghy Katalin; Krasavin Mikhail; Gal Krisztina; Greiner Istvan; Szombathelyi Zsolt; Keseru Gyoergy M^*

来源：European Journal of Medicinal Chemistry, 2017, 133: 240-254.

DOI：10.1016/j.ejmech.2017.03.071

• mGlu(5) receptor
• Negative allosteric modulator
• 4-amino-3-arylsulfonyl-quinolines
• Parallel synthesis
• Optimization

Negative allosteric modulators of metabotropic glutamate receptor 5 (mGlu(5)) 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 mGlu(5) 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.

• 出版日期2017-6-16