Download MendeleyDiscovery of 2-(Cyclopentylamino)thieno[3,2-d]pyrimidin-4(3H)-one Derivatives as a New Series of Potent Phosphodiesterase 7 Inhibitors.
Kawai, K., Endo, Y., Asano, T., Amano, S., Sawada, K., Ueo, N., Takahashi, N., Sonoda, Y., Nagai, M., Kamei, N., Nagata, N.(2014) J Med Chem 57: 9844-9854
- PubMed: 25383422
- DOI: https://doi.org/10.1021/jm5008215
- Primary Citation of Related Structures:
4PM0 - 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.
Organizational Affiliation:
Drug Research Center, Kaken Pharmaceutical Co. Ltd. , 14 Shinomiya Minamigawara-cho, Yamashina, Kyoto 607-8042, Japan.
