title: Lead identification and structure-activity relationships of heteroarylpyrazole arylsulfonamides as allosteric CC-chemokine receptor 4 (CCR4) antagonists.
abstract: A knowledge-based library of aryl 2,3-dichlorophenylsulfonamides was synthesised and screened as human CCR4 antagonists, in order to identify a suitable hit for the start of a lead-optimisation programme. X-ray diffraction studies were used to identify the pyrazole ring as a moiety that could bring about intramolecular hydrogen bonding with the sulfonamide NH and provide a clip or orthogonal conformation that was believed to be the preferred active conformation. Replacement of the core phenyl ring with a pyridine, and replacement of the 2,3-dichlorobenzenesulfonamide with 5-chlorothiophenesulfonamide provided compound 33 which has excellent physicochemical properties and represents a good starting point for a lead optimisation programme. Electronic structure calculations indicated that the preference for the clip or orthogonal conformation found in the small molecule crystal structures of 7 and 14 was in agreement with the order of potency in the biological assay.
authors: Allergy & Inflammation DPU, Respiratory TAU, GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK. pan.a.procopiou@gsk.com.
authors: Afjal H
authors: AH
authors: Miah
authors: Royston C B
authors: RC
authors: Copley
authors: Daniel
authors: D
authors: O'Flynn
authors: Jonathan M
authors: JM
authors: Percy
authors: Panayiotis A
authors: PA
authors: Procopiou
mesh_terms: D000494:Allosteric Regulation; D008958:Models, Molecular; D008968:Molecular Conformation; D011720:Pyrazoles / Q000737:chemistry*; D054398:Receptors, CCR4 / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D011720:Pyrazoles; D054398:Receptors, CCR4; D013449:Sulfonamides