3-Substituted Quinolines as RORγt Inverse Agonists. Issue 12 (15th June 2019)

• Record Type: Journal Article
• Authors: Tanis, Virginia M.; Venkatesan, Hariharan; Cummings, Maxwell D.; Albers, Michael; Kent Barbay, J.; Herman, Krystal; Kummer, David A.; Milligan, Cynthia; Nelen, Marina I.; Nishimura, Rachel; Schlueter, Thomas; Scott, Brian; Spurlino, John; Wolin, Ronald; Woods, Craig; Xue, Xiaohua; Edwards, James P.; Fourie, Anne M.; Leonard, Kristi
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 29:Issue 12(2019)
• Page Start: 1463
• Page End: 1470
• Publication Date: 2019-06-15
• Subjects: RORγt -- Retinoic acid-related orphan nuclear receptor gamma t -- Inverse agonist -- Th17 -- IL-17; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2019.04.021
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: We have previously reported the syntheses of a series of 3, 6-disubstituted quinolines as modulators of the retinoic acid receptor-related orphan receptor gamma t (RORγt). These molecules, such as 1, are potent binders but are high molecular weight and they exhibited poor solubility at pH 2 and pH 7. This manuscript details our efforts at improving physical chemical properties for this series of compounds by increasing the diversity at the 3-position ( i.e. introducing heteroatoms and lowering the molecular weight). These efforts have led to molecules such as 27 and 30 which are potent binders with improved solubility. Abstract: We have previously reported the syntheses of a series of 3, 6-disubstituted quinolines as modulators of the retinoic acid receptor-related orphan receptor gamma t (RORγt). These molecules are potent binders but are high molecular weight and they exhibited poor solubility at pH 2 and pH 7. This manuscript details our efforts at improving physical chemical properties for this series of compounds by increasing the diversity at the 3-position ( i.e. introducing heteroatoms and lowering the molecular weight). These efforts have led to molecules which are potent binders with improved solubility.