4PM0

PDE7A catalytic domain in complex with 2-(Cyclopentylamino)thieno[3,2-d]pyrimidin-4(3H)-one derivative

Summary for 4PM0

• Entry DOI: 10.2210/pdb4pm0/pdb
• Descriptor: High affinity cAMP-specific 3',5'-cyclic phosphodiesterase 7A, ZINC ION, MAGNESIUM ION, ... (5 entities in total)
• Functional Keywords: phosphodiesterase, pde7, hydrolase
• Biological source: Homo sapiens (Human)
• Cellular location: Isoform PDE7A1: Cytoplasm, cytosol. Isoform PDE7A2: Cytoplasm: Q13946
• Total number of polymer chains: 1
• Total formula weight: 44876.23

Authors

Kawai, K.,Endo, Y.,Asano, T.,Amano, S.,Sawada, K.,Ueo, N.,Takahashi, N.,Sonoda, Y.,Kamei, N.,Nagata, N. (deposition date: 2014-05-20, release date: 2014-12-03, Last modification date: 2023-11-08)

Primary citation

Kawai, K.,Endo, Y.,Asano, T.,Amano, S.,Sawada, K.,Ueo, N.,Takahashi, N.,Sonoda, Y.,Nagai, M.,Kamei, N.,Nagata, N.
Discovery of 2-(Cyclopentylamino)thieno[3,2-d]pyrimidin-4(3H)-one Derivatives as a New Series of Potent Phosphodiesterase 7 Inhibitors.
J.Med.Chem., 57:9844-9854, 2014

PubMed Abstract: The discovery of a new series of potent phosphodiesterase 7 (PDE7) inhibitors is described. Novel thieno[3,2-d]pyrimidin-4(3H)-one hit compounds were identified from our chemical library. Preliminary modifications of the hit compounds were performed, resulting in the discovery of a fragment-sized compound (10) with highly improved ligand efficiency. Compound design was guided by structure-activity relationships and computational modeling. The 6-substituted derivatives of the thienopyrimidinone showed diminished activity and enzyme selectivity. However, synthesis of the 7-substituted derivatives resulted in the discovery of 28e, a desirable lead compound that selectively inhibits PDE7 with single-digit nanomolar potency while displaying potent cellular efficacy.

PubMed: 25383422
DOI: 10.1021/jm5008215

Experimental method

X-RAY DIFFRACTION (2.1 Å)