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

2009; Elsevier BV; Volume: 17; Issue: 14 Linguagem: Inglês

10.1016/j.bmc.2009.03.061

1464-3391

Michael Kranz, Michael Wall, Brian Evans, Afjal H. Miah, Stuart P. Ballantine, Chris J. Delves, Brian Dombroski, Jeffrey W. Gross, Jessica L. Schneck, James P. Villa, Margarete Neu, Don O. Somers,

Synthesis and Catalytic Reactions

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 in previous PDE4 co-crystal structures, and even shifts helix-15 by 1–2 Å. For the first time, several residues of the C-terminus previously proposed to be involved in subtype selectivity are resolved and three of them extend into the ligand binding site potentially allowing for selective drug design.