3WD9
Crystal structure of phosphodiesterase 4B in complex with compound 10f
Summary for 3WD9
| Entry DOI | 10.2210/pdb3wd9/pdb |
| Descriptor | cAMP-specific 3',5'-cyclic phosphodiesterase 4B, 4-[(4-{2-[(2,2-dimethylpropyl)amino]-2-oxoethyl}phenyl)amino]-2-phenylpyrimidine-5-carboxamide, ZINC ION, ... (5 entities in total) |
| Functional Keywords | phosphodiesterase, copd, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 2 |
| Total formula weight | 87751.29 |
| Authors | Takahashi, M.,Hanzawa, H. (deposition date: 2013-06-11, release date: 2013-10-23, Last modification date: 2024-10-09) |
| Primary citation | Goto, T.,Shiina, A.,Yoshino, T.,Mizukami, K.,Hirahara, K.,Suzuki, O.,Sogawa, Y.,Takahashi, T.,Mikkaichi, T.,Nakao, N.,Takahashi, M.,Hasegawa, M.,Sasaki, S. Synthesis and biological evaluation of 5-carbamoyl-2-phenylpyrimidine derivatives as novel and potent PDE4 inhibitors Bioorg.Med.Chem., 21:7025-7037, 2013 Cited by PubMed Abstract: 5-Carbamoyl-2-phenylpyrimidine derivative 2 has been identified as a phosphodiesterase 4 (PDE4) inhibitor with moderate PDE4B inhibitory activity (IC50=200 nM). Modification of the carboxylic acid moiety of 2 gave N-neopentylacetamide derivative 10f, which had high in vitro PDE4B inhibitory activity (IC50=8.3 nM) and in vivo efficacy against lipopolysaccharide (LPS)-induced pulmonary neutrophilia in mice (ID50=16 mg/kg, ip). Furthermore, based on the X-ray crystallography of 10f bound to the human PDE4B catalytic domain, we designed 7,8-dihydro-6H-pyrido[4,3-d]pyrimidin-5-one derivative 39 which has a fused bicyclic lactam scaffold. Compound 39 exhibited excellent inhibitory activity against LPS-induced tumor necrosis factor alpha (TNF-α) production in mouse splenocytes (IC50=0.21 nM) and in vivo anti-inflammatory activity against LPS-induced pulmonary neutrophilia in mice (41% inhibition at a dose of 1.0 mg/kg, i.t.). PubMed: 24094436DOI: 10.1016/j.bmc.2013.09.013 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.5 Å) |
Structure validation
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