| Structural highlights
6cyc is a 2 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Ligands: | , , , |
| Activity: | 3',5'-cyclic-nucleotide phosphodiesterase, with EC number 3.1.4.17 |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Function
[PDE2A_HUMAN] Cyclic nucleotide phosphodiesterase with a dual-specificity for the second messengers cAMP and cGMP, which are key regulators of many important physiological processes.[1] [2]
Publication Abstract from PubMed
Herein we describe the development of a series of pyrazolopyrimidinone phosphodiesterase 2A (PDE2) inhibitors using structure-guided lead identification and design. The series was derived from informed chemotype replacement based on previously identified internal leads. The initially designed compound 3, while potent on PDE2, displayed unsatisfactory selectivity against the other PDE2 isoforms. Compound 3 was subsequently optimized for improved PDE2 activity and isoform selectivity. Insights into the origins of PDE2 selectivity are described and verified using cocrystallography. An optimized lead, 4, demonstrated improved performance in both a rodent and a nonhuman primate cognition model.
Structure-Guided Design and Procognitive Assessment of a Potent and Selective Phosphodiesterase 2A Inhibitor.,Stachel SJ, Berger R, Nomland AB, Ginnetti AT, Paone DV, Wang D, Puri V, Lange H, Drott J, Lu J, Marcus J, Dwyer MP, Suon S, Uslaner JM, Smith SM ACS Med Chem Lett. 2018 Jul 26;9(8):815-820. doi: 10.1021/acsmedchemlett.8b00214., eCollection 2018 Aug 9. PMID:30128073[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Iffland A, Kohls D, Low S, Luan J, Zhang Y, Kothe M, Cao Q, Kamath AV, Ding YH, Ellenberger T. Structural determinants for inhibitor specificity and selectivity in PDE2A using the wheat germ in vitro translation system. Biochemistry. 2005 Jun 14;44(23):8312-25. PMID:15938621 doi:10.1021/bi047313h
- ↑ Pandit J, Forman MD, Fennell KF, Dillman KS, Menniti FS. Mechanism for the allosteric regulation of phosphodiesterase 2A deduced from the X-ray structure of a near full-length construct. Proc Natl Acad Sci U S A. 2009 Oct 14. PMID:19828435
- ↑ Stachel SJ, Berger R, Nomland AB, Ginnetti AT, Paone DV, Wang D, Puri V, Lange H, Drott J, Lu J, Marcus J, Dwyer MP, Suon S, Uslaner JM, Smith SM. Structure-Guided Design and Procognitive Assessment of a Potent and Selective Phosphodiesterase 2A Inhibitor. ACS Med Chem Lett. 2018 Jul 26;9(8):815-820. doi: 10.1021/acsmedchemlett.8b00214., eCollection 2018 Aug 9. PMID:30128073 doi:http://dx.doi.org/10.1021/acsmedchemlett.8b00214
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