title: Lead identification of benzimidazolone and azabenzimidazolone arylsulfonamides as CC-chemokine receptor 4 (CCR4) antagonists.
abstract: A knowledge-based library of 2,3-dichlorophenylsulfonyl derivatives of commercially available aryl amines was synthesised and screened as human CCR4 antagonists, in order to identify a suitable hit for the start of a lead-optimisation programme. Hits were required to be more potent than an existing indazole series, have better physicochemical properties (clogP <3.5, chrom logD₇.₄ <5.3 and CLND solubility >116 μg/mL), and be stable to acid and light. The benzimidazol-2-one core was identified as a hit suitable for further investigation. Substitution at N1 with small alkyl groups was tolerated; however, these analogues were inactive in the whole blood assay (pA₂ <5). Azabenzimidazolone analogues were all found to be active, with compound 38 exhibiting whole blood activity of 6.1, low molecular weight (389) and chrom logD₇.₄ (2.4), high LE (0.43), and solubility (152 μg/mL). In addition, 38 had human serum albumin binding of around 93% and met all the criteria for progression to lead optimisation.
authors.affiliation: Department of Medicinal Chemistry, Respiratory TAU, GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, United Kingdom.
authors.forename: Afjal H
authors.initials: AH
authors.lastname: Miah
authors.affiliation: Department of Medicinal Chemistry, Respiratory TAU, GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, United Kingdom.
authors.forename: Hossay
authors.initials: H
authors.lastname: Abas
authors.affiliation: Department of Respiratory Biology, Respiratory TAU, GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, United Kingdom.
authors.forename: Malcolm
authors.initials: M
authors.lastname: Begg
authors.affiliation: Department of Medicinal Chemistry, Respiratory TAU, GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, United Kingdom.
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Marsh
authors.affiliation: Department of Medicinal Chemistry, Respiratory TAU, GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, United Kingdom.
authors.forename: Daniel E
authors.initials: DE
authors.lastname: O'Flynn
authors.affiliation: Department of Respiratory Biology, Respiratory TAU, GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, United Kingdom.
authors.forename: Alison J
authors.initials: AJ
authors.lastname: Ford
authors.affiliation: WestCHEM, Department of Pure and Applied Chemistry, University of Strathclyde, 295 Cathedral Street, Glasgow G1 1XL, United Kingdom.
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Percy
authors.affiliation: Department of Medicinal Chemistry, Respiratory TAU, GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, United Kingdom. Electronic address: pan.a.procopiou@gsk.com.
authors.forename: Panayiotis A
authors.initials: PA
authors.lastname: Procopiou
authors.affiliation: UK Analytical Chemistry, Platform Technology & Science, GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, United Kingdom.
authors.forename: Steve A
authors.initials: SA
authors.lastname: Richards
authors.affiliation: Department of Respiratory Biology, Respiratory TAU, GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, United Kingdom.
authors.forename: Sally-Anne
authors.initials: SA
authors.lastname: Rumley
mesh_terms: D001372:Aza Compounds / Q000737:chemistry; D001562:Benzimidazoles / Q000737:chemistry*; D006801:Humans; D007191:Indazoles / Q000737:chemistry; D011485:Protein Binding; D054398:Receptors, CCR4 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012709:Serum Albumin / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism
chemical_list: D001372:Aza Compounds; D001562:Benzimidazoles; D007191:Indazoles; D054398:Receptors, CCR4; D012709:Serum Albumin; D013449:Sulfonamides; C014353:benzimidazolone
keywords: Azabenzimidazolone; Benzimidazolone; CCR4 antagonist