3O57

Catalytic domain of human phosphodiesterase 4b2b in complex with a 5-heterocycle pyrazolopyridine inhibitor

Summary for 3O57

• Entry DOI: 10.2210/pdb3o57/pdb
• Related: 3D3P 3O56
• Descriptor: cAMP-specific 3',5'-cyclic phosphodiesterase 4B, ZINC ION, MAGNESIUM ION, ... (7 entities in total)
• Functional Keywords: pde, hydrolase, phosphodiesterase, camp binding, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 41505.14

Authors

Somers, D.O.,Neu, M. (deposition date: 2010-07-28, release date: 2011-08-03, Last modification date: 2023-09-06)

Primary citation

Mitchell, C.J.,Ballantine, S.P.,Coe, D.M.,Cook, C.M.,Delves, C.J.,Dowle, M.D.,Edlin, C.D.,Hamblin, J.N.,Holman, S.,Johnson, M.R.,Jones, P.S.,Keeling, S.E.,Kranz, M.,Lindvall, M.,Lucas, F.S.,Neu, M.,Solanke, Y.E.,Somers, D.O.,Trivedi, N.A.,Wiseman, J.O.
Pyrazolopyridines as potent PDE4B inhibitors: 5-heterocycle SAR.
Bioorg.Med.Chem.Lett., 20:5803-5806, 2010

PubMed Abstract: Following the discovery of 4-(substituted amino)-1-alkyl-pyrazolo[3,4-b]pyridine-5-carboxamides as potent and selective phosphodiesterase 4B inhibitors, [Hamblin, J. N.; Angell, T.; Ballentine, S., et al. Bioorg. Med. Chem. Lett.2008, 18, 4237] the SAR of the 5-position was investigated further. A range of substituted heterocycles showed good potencies against PDE4. Optimisation using X-ray crystallography and computational modelling led to the discovery of 16, with sub-nM inhibition of LPS-induced TNF-α production from isolated human peripheral blood mononuclear cells.

PubMed: 20732811
DOI: 10.1016/j.bmcl.2010.07.136

Experimental method

X-RAY DIFFRACTION (2 Å)