Issue 11, 2014

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

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.

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

Supplementary files

Article information

Article type
Paper
Submitted
06 Dec 2013
Accepted
03 Feb 2014
First published
03 Feb 2014

Org. Biomol. Chem., 2014,12, 1779-1792

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 and P. A. Procopiou, Org. Biomol. Chem., 2014, 12, 1779 DOI: 10.1039/C3OB42443J

To request permission to reproduce material from this article, please go to the Copyright Clearance Center request page.

If you are an author contributing to an RSC publication, you do not need to request permission provided correct acknowledgement is given.

If you are the author of this article, you do not need to request permission to reproduce figures and diagrams provided correct acknowledgement is given. If you want to reproduce the whole article in a third-party publication (excluding your thesis/dissertation for which permission is not required) please go to the Copyright Clearance Center request page.

Read more about how to correctly acknowledge RSC content.

Social activity

Spotlight

Advertisements