Identification of PDE4B Over 4D subtype-selective inhibitors revealing an unprecedented binding mode

…, S Ballantine, C Delves, B Dombroski, J Gross…

Index: Kranz, Michael; Wall, Michael; Evans, Brian; Miah, Afjal; Ballantine, Stuart; Delves, Chris; Dombroski, Brian; Gross, Jeffrey; Schneck, Jessica; Villa, James P.; Neu, Margarete; Somers, Don O. Bioorganic and Medicinal Chemistry, 2009 , vol. 17, # 14 p. 5336 - 5341

Full Text: HTML

Citation Number: 46

Abstract

A PDE4B over 4D-selective inhibitor programme was initiated to capitalise on the recently discovered predominance of the PDE4B subtype in inflammatory cell regulation. The SAR of a tetrahydrobenzothiophene (THBT) series did not agree with either of two proposed docking modes in the 4B binding site. A subsequent X-ray co-crystal structure determination revealed that the THBT ligand displaces the Gln-443 residue, invariably ligand-anchoring ...