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J Med Chem. 2014 Dec 11;57(23):9844-54. doi: 10.1021/jm5008215. Epub 2014 Nov 19.

Discovery of 2-(cyclopentylamino)thieno[3,2-d]pyrimidin-4(3H)-one derivatives as a new series of potent phosphodiesterase 7 inhibitors.

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Drug Research Center, Kaken Pharmaceutical Co. Ltd. , 14 Shinomiya Minamigawara-cho, Yamashina, Kyoto 607-8042, Japan.


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.

[Indexed for MEDLINE]

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