3W5E

Crystal structure of phosphodiesterase 4B in complex with compound 31e

Summary for 3W5E

• Entry DOI: 10.2210/pdb3w5e/pdb
• Descriptor: cAMP-specific 3',5'-cyclic phosphodiesterase 4B, N-tert-butyl-2-{4-[(5,5-dioxido-2-phenyl-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino]phenyl}acetamide, ZINC ION, ... (5 entities in total)
• Functional Keywords: phosphodiesterase, copd, inhibitor, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 87845.45

Authors

Takahashi, M.,Hanzawa, H. (deposition date: 2013-01-28, release date: 2013-05-29, Last modification date: 2024-11-13)

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.
Identification of the fused bicyclic 4-amino-2-phenylpyrimidine derivatives as novel and potent PDE4 inhibitors
Bioorg.Med.Chem.Lett., 23:3325-3328, 2013

PubMed Abstract: 2-Phenyl-4-piperidinyl-6,7-dihydrothieno[3,4-d]pyrimidine derivative (2) was found to be a new PDE4 inhibitor with moderate PDE4B activity (IC50=150 nM). A number of derivatives with a variety of 4-amino substituents and fused bicyclic pyrimidines were synthesized. Among these, 5,5-dioxo-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine derivative (18) showed potent PDE4B inhibitory activity (IC50=25 nM). Finally, N-propylacetamide derivative (31b) was determined as a potent inhibitor for both PDE4B (IC50=7.5 nM) and TNF-α production in mouse splenocytes (IC50=9.8 nM) and showed good in vivo anti-inflammatory activity in the LPS-induced lung inflammation model in mice (ID50=18 mg/kg). The binding mode of the new inhibitor (31e) in the catalytic site of PDE4B is presented based on an X-ray crystal structure of the ligand-enzyme complex.

PubMed: 23602400
DOI: 10.1016/j.bmcl.2013.03.104

Experimental method

X-RAY DIFFRACTION (2.3 Å)