title: Discovery of a phosphodiesterase 9A inhibitor as a potential hypoglycemic agent.
abstract: 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.
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-Sen University , Guangzhou 510006, P. R. China.
authors.forename: Yong-xian
authors.initials: YX
authors.lastname: Shao
authors.forename: Manna
authors.initials: M
authors.lastname: Huang
authors.forename: Wenjun
authors.initials: W
authors.lastname: Cui
authors.forename: Ling-Jun
authors.initials: LJ
authors.lastname: Feng
authors.forename: Yinuo
authors.initials: Y
authors.lastname: Wu
authors.forename: Yinghong
authors.initials: Y
authors.lastname: Cai
authors.forename: Zhe
authors.initials: Z
authors.lastname: Li
authors.forename: Xinhai
authors.initials: X
authors.lastname: Zhu
authors.forename: Peiqing
authors.initials: P
authors.lastname: Liu
authors.forename: Yiqian
authors.initials: Y
authors.lastname: Wan
authors.forename: Hengming
authors.initials: H
authors.lastname: Ke
authors.forename: Hai-Bin
authors.initials: HB
authors.lastname: Luo
mesh_terms: D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D000818:Animals; D015153:Blotting, Western; D001826:Body Fluids / Q000737:chemistry; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D055808:Drug Discovery; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D005952:Glucose-6-Phosphatase / Q000037:antagonists & inhibitors*; D056945:Hep G2 Cells; D006801:Humans; D006860:Hydrogen Bonding; D007004:Hypoglycemic Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D051379:Mice; D008862:Microsomes, Liver / Q000187:drug effects* / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure; D010726:Phosphodiesterase Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011720:Pyrazoles / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D011744:Pyrimidinones / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013329:Structure-Activity Relationship; D014018:Tissue Distribution
chemical_list: C000595865:2-((1-cyclopentyl-4-hydroxy-1H-pyrazolo(3,4-d)pyrimidin-6-yl)amino)-N-(4-methoxyphenyl)propanamide; D007004:Hypoglycemic Agents; D010726:Phosphodiesterase Inhibitors; D011720:Pyrazoles; D011744:Pyrimidinones; D012333:RNA, Messenger; C069767:phosphoenolpyruvate carboxylase kinase; D017346:Protein Serine-Threonine Kinases; D005952:Glucose-6-Phosphatase; D015105:3',5'-Cyclic-AMP Phosphodiesterases; C116137:PDE9A protein, human