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

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Miah, A.H. and Copley, R.C.B. and O'Flynn, D. and Percy, J.M. and Procopiou, P.A. (2014) Lead identification and structure-activity relationships of heteroarylpyrazole arylsulfonamides as allosteric CC-chemokine receptor 4 (CCR4) antagonists. Organic and Biomolecular Chemistry, 12 (11). pp. 1779-1792. ISSN 1477-0520 (https://doi.org/10.1039/c3ob42443j)

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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.

ORCID iDs

Miah, A.H., Copley, R.C.B., O'Flynn, D., Percy, J.M. ORCID logoORCID: https://orcid.org/0000-0001-8636-2704 and Procopiou, P.A.;
CORE (COnnecting REpositories)