Document Report Card

ID: ALA2321840

Journal: J Med Chem

Title: Synthesis and structure-activity relationships of indazole arylsulfonamides as allosteric CC-chemokine receptor 4 (CCR4) antagonists.

Authors: Procopiou PA, Barrett JW, Barton NP, Begg M, Clapham D, Copley RC, Ford AJ, Graves RH, Hall DA, Hancock AP, Hill AP, Hobbs H, Hodgson ST, Jumeaux C, Lacroix YM, Miah AH, Morriss KM, Needham D, Sheriff EB, Slack RJ, Smith CE, Sollis SL, Staton H.

Abstract: A series of indazole arylsulfonamides were synthesized and examined as human CCR4 antagonists. Methoxy- or hydroxyl-containing groups were the more potent indazole C4 substituents. Only small groups were tolerated at C5, C6, or C7, with the C6 analogues being preferred. The most potent N3-substituent was 5-chlorothiophene-2-sulfonamide. N1 meta-substituted benzyl groups possessing an α-amino-3-[(methylamino)acyl]-group were the most potent N1-substituents. Strongly basic amino groups had low oral absorption in vivo. Less basic analogues, such as morpholines, had good oral absorption; however, they also had high clearance. The most potent compound with high absorption in two species was analogue 6 (GSK2239633A), which was selected for further development. Aryl sulfonamide antagonists bind to CCR4 at an intracellular allosteric site denoted site II. X-ray diffraction studies on two indazole sulfonamide fragments suggested the presence of an important intramolecular interaction in the active conformation.

CiteXplore: 23409871

DOI: 10.1021/jm301572h