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

Afjal H. Miah, Hossay Abas, Malcolm Begg, Benjamin J. Marsh, Daniel E. O'Flynn, Jonathan M. Percy, Alison J. Ford, Panayiotis A. Procopiou, Steve A. Richards

Research output: Contribution to journalArticle

7 Citations (Scopus)
191 Downloads (Pure)

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.

Original languageEnglish
Pages (from-to)4298-4311
Number of pages14
JournalBioorganic and Medicinal Chemistry
Volume22
Issue number15
Early online date21 May 2014
DOIs
Publication statusPublished - 1 Aug 2014

Keywords

  • azabenzimidazolone
  • benzimidazolone
  • CCR4 antagonist

Fingerprint Dive into the research topics of 'Lead identification of benzimidazolone and azabenzimidazolone arylsulfonamides as CC-chemokine receptor 4 (CCR4) antagonists'. Together they form a unique fingerprint.

  • Cite this

    Miah, A. H., Abas, H., Begg, M., Marsh, B. J., O'Flynn, D. E., Percy, J. M., Ford, A. J., Procopiou, P. A., & Richards, S. A. (2014). Lead identification of benzimidazolone and azabenzimidazolone arylsulfonamides as CC-chemokine receptor 4 (CCR4) antagonists. Bioorganic and Medicinal Chemistry , 22(15), 4298-4311. https://doi.org/10.1016/j.bmc.2014.05.021