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

7 Citations (Scopus)

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.
LanguageEnglish
Pages1779-1792
Number of pages14
JournalOrganic and Biomolecular Chemistry
Volume12
Issue number11
Early online date3 Feb 2014
DOIs
Publication statusPublished - 2014

Fingerprint

CCR4 Receptors
clips
Structure-Activity Relationship
Surgical Instruments
Conformations
optimization
rings
Sulfonamides
Hydrogen Bonding
X-Ray Diffraction
Biological Assay
Libraries
pyridines
electronic structure
crystal structure
Electronic structure
Assays
Hydrogen bonds
hydrogen
Crystal structure

Keywords

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

Cite this

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Lead identification and structure-activity relationships of heteroarylpyrazole arylsulfonamides as allosteric CC-chemokine receptor 4 (CCR4) antagonists. / Miah, A.H.; Copley, R.C.B.; O'Flynn, D.; Percy, J.M.; Procopiou, P.A.

In: Organic and Biomolecular Chemistry, Vol. 12, No. 11, 2014, p. 1779-1792.

Research output: Contribution to journalArticle

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