Lead identification and structure-activity relationships of heteroarylpyrazole arylsulfonamides as allosteric CC-chemokine receptor 4 (CCR4) antagonists

A.H. Miah, R.C.B. Copley, D. O'Flynn, J.M. Percy, P.A. Procopiou

Research output: Contribution to journalArticle

10 Citations (Scopus)
84 Downloads (Pure)

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.
Original languageEnglish
Pages (from-to)1779-1792
Number of pages14
JournalOrganic and Biomolecular Chemistry
Volume12
Issue number11
Early online date3 Feb 2014
DOIs
Publication statusPublished - 2014

Keywords

  • lead identification
  • structure-activity relationships
  • allosteric CC-chemokine receptor 4 (CCR4) antagonists
  • (CCR4) antagonists
  • heteroarylpyrazole arylsulfonamides

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

Cite this