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Pyrazolopyridines as a novel structural class of potent and selective PDE4 inhibitors

2008; Elsevier BV; Volume: 18; Issue: 14 Linguagem: Inglês

10.1016/j.bmcl.2008.05.052

1464-3405

J. Hamblin, Tony D. Angell, Stuart P. Ballantine, Caroline M. Cook, Anthony W. J. Cooper, John A. Dawson, C. J. Delves, Paul S. Jones, Mika Lindvall, Fiona S. Lucas, Charlotte Mitchell, Margarete Neu, Lisa E. Ranshaw, Yemisi Solanke, Don O. Somers, Joanne Wiseman,

Cholinesterase and Neurodegenerative Diseases

Optimisation of a high-throughput screening hit resulted in the discovery of 4-(substituted amino)-1-alkyl-pyrazolo[3,4-b]pyridine-5-carboxamides as potent and selective inhibitors of Phosphodiesterase 4 (PDE4). Herein, we describe early SAR studies around this novel template highlighting preferred substituents and rationalization of SAR through X-ray crystal structures of analogues bound to the PDE4 active site. Pyrazolopyridine 20a was found to be a potent and selective PDE4 inhibitor which also inhibits LPS induced TNF-alpha production from isolated human peripheral blood mononuclear cells and has an encouraging rat PK profile suitable for oral dosing.