4pm0
PDE7A catalytic domain in complex with 2-(Cyclopentylamino)thieno[3,2-d]pyrimidin-4(3H)-one derivativePDE7A catalytic domain in complex with 2-(Cyclopentylamino)thieno[3,2-d]pyrimidin-4(3H)-one derivative
Structural highlights
FunctionPDE7A_HUMAN Hydrolyzes the second messenger cAMP, which is a key regulator of many important physiological processes. May have a role in muscle signal transduction.[1] Publication Abstract from PubMedThe 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. Discovery 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 J Med Chem. 2014 Nov 19. PMID:25383422[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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