Lead identification of benzimidazolone and azabenzimidazolone arylsulfonamides as CC-chemokine receptor 4 (CCR4) antagonists

Miah, Afjal H. and Abas, Hossay and Begg, Malcolm and Marsh, Benjamin J. and O'Flynn, Daniel E. and Percy, Jonathan M. and Ford, Alison J. and Procopiou, Panayiotis A. and Richards, Steve A. (2014) Lead identification of benzimidazolone and azabenzimidazolone arylsulfonamides as CC-chemokine receptor 4 (CCR4) antagonists. Bioorganic and Medicinal Chemistry, 22 (15). pp. 4298-4311. ISSN 0968-0896 (https://doi.org/10.1016/j.bmc.2014.05.021)

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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 (c log P <3.5, chrom log D7.4 <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 log D7.4 (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.

ORCID iDs

Miah, Afjal H., Abas, Hossay, Begg, Malcolm, Marsh, Benjamin J., O'Flynn, Daniel E., Percy, Jonathan M. ORCID logoORCID: https://orcid.org/0000-0001-8636-2704, Ford, Alison J., Procopiou, Panayiotis A. and Richards, Steve A.;
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