3D3P

Crystal structure of PDE4B catalytic domain in complex with a pyrazolopyridine inhibitor

Summary for 3D3P

• Entry DOI: 10.2210/pdb3d3p/pdb
• Descriptor: cAMP-specific 3',5'-cyclic phosphodiesterase 4B, ZINC ION, MAGNESIUM ION, ... (6 entities in total)
• Functional Keywords: pde, phosphodiesterase, camp, alternative splicing, hydrolase, phosphoprotein, polymorphism
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 41277.89

Authors

Somers, D.O.,Neu, M. (deposition date: 2008-05-12, release date: 2009-05-19, Last modification date: 2023-08-30)

Primary citation

Hamblin, J.N.,Angell, T.D.,Ballantine, S.P.,Cook, C.M.,Cooper, A.W.,Dawson, J.,Delves, C.J.,Jones, P.S.,Lindvall, M.,Lucas, F.S.,Mitchell, C.J.,Neu, M.Y.,Ranshaw, L.E.,Solanke, Y.E.,Somers, D.O.,Wiseman, J.O.
Pyrazolopyridines as a novel structural class of potent and selective PDE4 inhibitors.
Bioorg.Med.Chem.Lett., 18:4237-4241, 2008

PubMed Abstract: 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.

PubMed: 18539455
DOI: 10.1016/j.bmcl.2008.05.052

Experimental method

X-RAY DIFFRACTION (1.75 Å)