Structural highlights
Publication Abstract from PubMed
Phosphodiesterase 9 (PDE9) inhibitors have been studied as potential therapeutics for treatment of diabetes and Alzheimer's disease. Here we report a potent PDE9 inhibitor 3r that has an IC50 of 0.6 nM and >150-fold selectivity over other PDEs. The HepG2 cell-based assay shows that 3r inhibits the mRNA expression of phosphoenolpyruvate carboxykinase and glucose 6-phosphatase. These activities of 3r, together with the reasonable pharmacokinetic properties and no acute toxicity at 1200 mg/kg dosage, suggest its potential as a hypoglycemic agent. The crystal structure of PDE9-3r reveals significantly different conformation and hydrogen bonding pattern of 3r from those of previously published 28s. Both 3r and 28s form a hydrogen bond with Tyr424, a unique PDE9 residue (except for PDE8), but 3r shows an additional hydrogen bond with Ala452. This structure information might be useful for design of PDE9 inhibitors.
Discovery of a Phosphodiesterase 9A Inhibitor as a Potential Hypoglycemic Agent.,Shao YX, Huang M, Cui W, Feng LJ, Wu Y, Cai Y, Li Z, Zhu X, Liu P, Wan Y, Ke H, Luo HB J Med Chem. 2014 Dec 8. PMID:25432025[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Shao YX, Huang M, Cui W, Feng LJ, Wu Y, Cai Y, Li Z, Zhu X, Liu P, Wan Y, Ke H, Luo HB. Discovery of a Phosphodiesterase 9A Inhibitor as a Potential Hypoglycemic Agent. J Med Chem. 2014 Dec 8. PMID:25432025 doi:http://dx.doi.org/10.1021/jm500836h
