title: Synthesis and structure-activity relationships of indazole arylsulfonamides as allosteric CC-chemokine receptor 4 (CCR4) antagonists.
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.
authors: Department of Medicinal Chemistry, GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, United Kingdom. pan.a.procopiou@gsk.com
authors: Panayiotis A
authors: PA
authors: Procopiou
authors: John W
authors: JW
authors: Barrett
authors: Nicholas P
authors: NP
authors: Barton
authors: Malcolm
authors: M
authors: Begg
authors: David
authors: D
authors: Clapham
authors: Royston C B
authors: RC
authors: Copley
authors: Alison J
authors: AJ
authors: Ford
authors: Rebecca H
authors: RH
authors: Graves
authors: David A
authors: DA
authors: Hall
authors: Ashley P
authors: AP
authors: Hancock
authors: Alan P
authors: AP
authors: Hill
authors: Heather
authors: H
authors: Hobbs
authors: Simon T
authors: ST
authors: Hodgson
authors: Coline
authors: C
authors: Jumeaux
authors: Yannick M L
authors: YM
authors: Lacroix
authors: Afjal H
authors: AH
authors: Miah
authors: Karen M L
authors: KM
authors: Morriss
authors: Deborah
authors: D
authors: Needham
authors: Emma B
authors: EB
authors: Sheriff
authors: Robert J
authors: RJ
authors: Slack
authors: Claire E
authors: CE
authors: Smith
authors: Steven L
authors: SL
authors: Sollis
authors: Hugo
authors: H
authors: Staton
mesh_terms: D000818:Animals; D004285:Dogs; D006801:Humans; D007191:Indazoles / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D008297:Male; D051381:Rats; D054398:Receptors, CCR4 / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: D007191:Indazoles; C581002:N-((3-((3-(((5-chloro-2-thienyl)sulfonyl)amino)-4-(methyloxy)-1H-indazol-1-yl)methyl)phenyl)methyl)-2-hydroxy-2-methylpropanamide; D054398:Receptors, CCR4; D013449:Sulfonamides