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Here we report a potent PDE9 inhibitor 3r that has an IC50 of 0.6 nM and &amp;gt;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.<\/jats:p>","DOI":"10.1021\/jm500836h","type":"journal-article","created":{"date-parts":[[2014,11,28]],"date-time":"2014-11-28T08:58:41Z","timestamp":1417165121000},"page":"10304-10313","source":"Crossref","is-referenced-by-count":61,"title":["Discovery of a Phosphodiesterase\n9A Inhibitor as a Potential Hypoglycemic Agent"],"prefix":"10.1021","volume":"57","author":[{"given":"Yong-xian","family":"Shao","sequence":"first","affiliation":[{"name":"Sun Yat-Sen University , , ,","place":["Guangzhou, P. R. China, 510006"]},{"name":"The University of North Carolina , , , ,","place":["Chapel Hill, North Carolina, United States, 27599-7260"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manna","family":"Huang","sequence":"additional","affiliation":[{"name":"Sun Yat-Sen University , , ,","place":["Guangzhou, P. R. China, 510275"]},{"name":"The University of North Carolina , , , ,","place":["Chapel Hill, North Carolina, United States, 27599-7260"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenjun","family":"Cui","sequence":"additional","affiliation":[{"name":"The University of North Carolina , , , ,","place":["Chapel Hill, North Carolina, United States, 27599-7260"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ling-Jun","family":"Feng","sequence":"additional","affiliation":[{"name":"Sun Yat-Sen University , , ,","place":["Guangzhou, P. R. China, 510006"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yinuo","family":"Wu","sequence":"additional","affiliation":[{"name":"Sun Yat-Sen University , , ,","place":["Guangzhou, P. R. China, 510006"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yinghong","family":"Cai","sequence":"additional","affiliation":[{"name":"Sun Yat-Sen University , , ,","place":["Guangzhou, P. R. 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China, 510275"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hengming","family":"Ke","sequence":"additional","affiliation":[{"name":"Sun Yat-Sen University , , ,","place":["Guangzhou, P. R. China, 510006"]},{"name":"The University of North Carolina , , , ,","place":["Chapel Hill, North Carolina, United States, 27599-7260"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hai-Bin","family":"Luo","sequence":"additional","affiliation":[{"name":"Sun Yat-Sen University , , ,","place":["Guangzhou, P. R. 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Biol."},{"key":"2026090218172543000_cit4","doi-asserted-by":"crossref","first-page":"2792","DOI":"10.2337\/db11-0255","article-title":"Endothelial NO\/cGMP\/VASP signaling attenuates Kupffer cell activation\nand hepatic insulin resistance induced by high-fat feeding","volume":"60","author":"Tateya","year":"2011","journal-title":"Diabetes"},{"key":"2026090218172543000_cit5","doi-asserted-by":"crossref","first-page":"11366","DOI":"10.1021\/bi060910e","article-title":"Activation of the\ncGMP signaling pathway is essential in delaying oocyte aging in diabetes\nmellitus","volume":"45","author":"Goud","year":"2006","journal-title":"Biochemistry"},{"key":"2026090218172543000_cit6","doi-asserted-by":"crossref","first-page":"290","DOI":"10.1038\/nrd4228","article-title":"Advances in targeting cyclic nucleotide\nphosphodiesterases","volume":"13","author":"Maurice","year":"2014","journal-title":"Nat. Rev. Drug Discovery"},{"key":"2026090218172543000_cit7","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1146\/annurev.biochem.76.060305.150444","article-title":"Biochemistry and physiology\nof cyclic nucleotide phosphodiesterases: essential components in cyclic\nnucleotide signaling","volume":"76","author":"Conti","year":"2007","journal-title":"Annu. Rev. Biochem."},{"key":"2026090218172543000_cit8","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1161\/01.RES.0000256354.95791.f1","article-title":"Overview of PDEs and\ntheir regulation","volume":"100","author":"Omori","year":"2007","journal-title":"Circ. Res."},{"key":"2026090218172543000_cit9","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1007\/978-3-642-17969-3_4","article-title":"Structural insight into the substrate\nspecificity of phosphodiesterases","volume":"204","author":"Ke","year":"2011","journal-title":"Handb. Exp.\nPharmacol."},{"key":"2026090218172543000_cit10","doi-asserted-by":"crossref","first-page":"6823","DOI":"10.1074\/jbc.272.11.6823","article-title":"Structure,\nlocalization, and regulation of cGMP-inhibited phosphodiesterase (PDE3)","volume":"272","author":"Degerman","year":"1997","journal-title":"J. Biol. Chem."},{"key":"2026090218172543000_cit11","doi-asserted-by":"crossref","first-page":"3152","DOI":"10.1210\/en.2012-2185","article-title":"A role for\nphosphodiesterase 3B in acquisition of brown fat characteristics by\nwhite adipose tissue in male mice","volume":"154","author":"Guirguis","year":"2013","journal-title":"Endocrinology."},{"key":"2026090218172543000_cit12","first-page":"221","article-title":"Proinsulin C-peptide inhibits lipolysis in diabetic\nrat adipose tissue through phosphodiestrase-3B enzyme","volume":"45","author":"Ghorbani","year":"2013","journal-title":"Horm. Metab Res."},{"key":"2026090218172543000_cit13","doi-asserted-by":"crossref","first-page":"E342","DOI":"10.1152\/ajpendo.00691.2010","article-title":"cGMP phosphodiesterase\ninhibition improves the vascular and metabolic actions of insulin\nin skeletal muscle","volume":"301","author":"Genders","year":"2011","journal-title":"Am. J. Physiol. Endocrinol.\nMetab."},{"key":"2026090218172543000_cit14","doi-asserted-by":"crossref","first-page":"124","DOI":"10.4239\/wjd.v4.i4.124","article-title":"Diabetic nephropathy:\nTreatment with phosphodiesterase type 5 inhibitors","volume":"4","author":"Thompson","year":"2013","journal-title":"World J. Diabetes"},{"key":"2026090218172543000_cit15","doi-asserted-by":"crossref","first-page":"300","DOI":"10.2337\/db13-0247","article-title":"Genetic deletion and pharmacological\ninhibition of phosphodiesterase 10A protects mice from diet-induced\nobesity and insulin resistance","volume":"63","author":"Nawrocki","year":"2014","journal-title":"Diabetes"},{"key":"2026090218172543000_cit16","doi-asserted-by":"crossref","unstructured":"Fryburg, D. A.; et al.; Treatment of insulin resistance syndrome\nand type 2 diabetes with PDE9 inhibitors. WO 03\/037432 A1, 2003.","DOI":"10.4158\/EP.9.S2.73"},{"key":"2026090218172543000_cit17","unstructured":"Deninno, M. P.; et al.; PDE9 inhibitors for treating cardiovascular disorders. WO 03\/037899, 2003; Pfizer Inc."},{"key":"2026090218172543000_cit18","unstructured":"Bell, A. S.; et al.; PDE9 inhibitors for treating type 2 diabetes, metabolic syndrome,\nand cardiovasculate disease. WO 2004\/096811, 2004."},{"key":"2026090218172543000_cit19","unstructured":"Black, S. C.; Gibbs, E. M.; McNeish, J. D.\n          Phosphodiesterase\n9 inhibition as treatment for obesity-related conditions. WO 2005\/041972, 2005."},{"key":"2026090218172543000_cit20","doi-asserted-by":"crossref","first-page":"2537","DOI":"10.1016\/j.bmcl.2009.03.024","article-title":"The discovery of potent, selective, and orally bioavailable\nPDE9 inhibitors as potential hypoglycemic agents","volume":"19","author":"Deninno","year":"2009","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"2026090218172543000_cit21","doi-asserted-by":"crossref","first-page":"1775","DOI":"10.1124\/mol.105.017608","article-title":"Characterization of the first potent and selective\nPDE9 inhibitor using a cGMP reporter cell line","volume":"68","author":"Wunder","year":"2005","journal-title":"Mol. Pharmacol."},{"key":"2026090218172543000_cit22","doi-asserted-by":"crossref","first-page":"9045","DOI":"10.1021\/jm3007799","article-title":"Design and discovery of 6-[(3S,4S)-4-methyl-1-(pyrimidin-2-ylmethyl)pyrrolidin-3-yl]-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (PF-04447943), a selective brain penetrant\nPDE9A inhibitor for the treatment of cognitive disorders","volume":"55","author":"Verhoest","year":"2012","journal-title":"J. Med. Chem."},{"key":"2026090218172543000_cit23","doi-asserted-by":"crossref","first-page":"7946","DOI":"10.1021\/jm9015334","article-title":"Identification of a\nbrain penetrant PDE9A inhibitor utilizing prospective design and chemical\nenablement as a rapid lead optimization strategy","volume":"52","author":"Verhoest","year":"2009","journal-title":"J. Med. Chem."},{"key":"2026090218172543000_cit24","doi-asserted-by":"crossref","first-page":"8549","DOI":"10.1021\/jm301189c","article-title":"Structure-based discovery of highly selective phosphodiesterase-9A\ninhibitors and implications for inhibitor design","volume":"55","author":"Meng","year":"2012","journal-title":"J. Med. Chem."},{"key":"2026090218172543000_cit25","doi-asserted-by":"crossref","first-page":"908","DOI":"10.1016\/j.neuropharm.2008.07.005","article-title":"The novel selective\nPDE9 inhibitor BAY 73-6691 improves learning and memory in rodents","volume":"55","author":"van der Staay","year":"2008","journal-title":"Neuropharmacology"},{"key":"2026090218172543000_cit26","doi-asserted-by":"crossref","first-page":"665","DOI":"10.1016\/j.neuropharm.2011.05.009","article-title":"The selective phosphodiesterase 9 (PDE9) inhibitor\nPF-04447943(6-[(3S,4S)-4-methyl-1-(pyrimidin-2-\nylmethyl)pyrrolidin-3-yl]-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one) enhances\nsynaptic plasticity and cognitive function in rodents","volume":"61","author":"Hutson","year":"2011","journal-title":"Neuropharmacology"},{"key":"2026090218172543000_cit27","doi-asserted-by":"crossref","first-page":"120","DOI":"10.3109\/01677063.2011.630494","article-title":"The selective phosphodiesterase\n9 (PDE9) inhibitor PF-04447943 attenuates a scopolamine-induced deficit\nin a novel rodent attention task","volume":"25","author":"Vardigan","year":"2011","journal-title":"J. Neurogenet."},{"key":"2026090218172543000_cit28","doi-asserted-by":"crossref","first-page":"1375","DOI":"10.1177\/0269881112447991","article-title":"The effect of phosphodiesterase inhibitors on extinction\nof cocaine-induced conditioned place preference in mice","volume":"26","author":"Liddie","year":"2012","journal-title":"J. Psychopharmacol."},{"key":"2026090218172543000_cit29","doi-asserted-by":"crossref","first-page":"1964","DOI":"10.1016\/j.neuropharm.2011.12.021","article-title":"Inhibition of acetylcholinesterase and phosphodiesterase-9A\nhas differential effects on hippocampal early and late LTP","volume":"62","author":"Kroker","year":"2012","journal-title":"Neuropharmacology"},{"key":"2026090218172543000_cit30","doi-asserted-by":"crossref","first-page":"396","DOI":"10.1124\/jpet.111.191353","article-title":"Phosphodiesterase 9A regulates central\ncGMP and modulates responses to cholinergic and monoaminergic perturbation\nin vivo","volume":"341","author":"Kleiman","year":"2012","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"2026090218172543000_cit31","doi-asserted-by":"crossref","first-page":"9055","DOI":"10.1021\/jm3009635","article-title":"Application of structure-based drug design and parallel chemistry\nto identify selective, brain penetrant, in vivo active phosphodiesterase\n9A inhibitors","volume":"55","author":"Claffey","year":"2012","journal-title":"J. Med. Chem."},{"key":"2026090218172543000_cit32","doi-asserted-by":"crossref","first-page":"1726","DOI":"10.1021\/jm901519f","article-title":"Insight into binding of phosphodiesterase-9A\nselective inhibitors by crystal structures and mutagenesis","volume":"53","author":"Wang","year":"2010","journal-title":"J. Med. Chem."},{"key":"2026090218172543000_cit33","doi-asserted-by":"crossref","first-page":"391","DOI":"10.2174\/156802607779941242","article-title":"Crystal structures\nof phosphodiesterases and implications on substrate specificity and\ninhibitor selectivity","volume":"7","author":"Ke","year":"2007","journal-title":"Curr. Top. Med. Chem."},{"key":"2026090218172543000_cit34","volume-title":"Drug Disposition and Pharmacokinetics: From Principles to Applications","author":"Stephen","year":"2011"},{"key":"2026090218172543000_cit35","unstructured":"Accelrys Discovery Studio, version 2.5.5; Accelrys Software Inc.: San Diego, CA, 2010."},{"key":"2026090218172543000_cit36","doi-asserted-by":"crossref","first-page":"1549","DOI":"10.1002\/jcc.10306","article-title":"Detailed analysis of\ngrid-based molecular docking: a case study of CDOCKER\u2500A CHARMm-based\nMD docking algorithm","volume":"24","author":"Wu","year":"2003","journal-title":"J. Comput. Chem."},{"key":"2026090218172543000_cit37","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1016\/S1093-3263(02)00164-X","article-title":"LigandFit: a novel method for the shape-directed rapid\ndocking of ligands to protein active sites","volume":"21","author":"Venkatachalam","year":"2003","journal-title":"J. Mol. Graphics Modell."},{"key":"2026090218172543000_cit38","doi-asserted-by":"crossref","first-page":"636","DOI":"10.1016\/j.bmcl.2009.11.051","article-title":"Novel purine and pyrazolo[3,4-d]pyrimidine\ninhibitors of PI3 kinase-alpha: hit to lead studies","volume":"20","author":"Gilbert","year":"2010","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"2026090218172543000_cit39","doi-asserted-by":"crossref","first-page":"9624","DOI":"10.1073\/pnas.0401120101","article-title":"Crystal structure of phosphodiesterase 9 shows orientation variation\nof inhibitor 3-isobutyl-1-methylxanthine binding","volume":"101","author":"Huai","year":"2004","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"2026090218172543000_cit40","doi-asserted-by":"crossref","first-page":"e18092","DOI":"10.1371\/journal.pone.0018092","article-title":"Structural asymmetry\nof phosphodiesterase-9, potential protonation of a glutamic acid,\nand role of the invariant glutamine","volume":"6","author":"Hou","year":"2011","journal-title":"PLoS One"},{"key":"2026090218172543000_cit41","doi-asserted-by":"crossref","first-page":"21469","DOI":"10.1074\/jbc.M512527200","article-title":"Multiple conformations of phosphodiesterase-5:\nimplications for enzyme function and drug development","volume":"281","author":"Wang","year":"2006","journal-title":"J. Biol. Chem."},{"key":"2026090218172543000_cit42","doi-asserted-by":"crossref","first-page":"30949","DOI":"10.1074\/jbc.M504398200","article-title":"Multiple elements jointly\ndetermine inhibitor selectivity of cyclic nucleotide phosphodiesterases\n4 and 7","volume":"280","author":"Wang","year":"2005","journal-title":"J. Biol. Chem."},{"key":"2026090218172543000_cit43","doi-asserted-by":"crossref","first-page":"12760","DOI":"10.1021\/bi801487x","article-title":"Kinetic and structural studies of\nphosphodiesterase-8A and implication on the inhibitor selectivity","volume":"47","author":"Wang","year":"2008","journal-title":"Biochemistry"},{"key":"2026090218172543000_cit44","doi-asserted-by":"crossref","first-page":"5782","DOI":"10.1073\/pnas.0700279104","article-title":"Structural\ninsight into substrate specificity of phosphodiesterase 10","volume":"104","author":"Wang","year":"2007","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"2026090218172543000_cit45","doi-asserted-by":"crossref","first-page":"865","DOI":"10.1016\/S0969-2126(03)00123-0","article-title":"Three-dimensional structures of PDE4D in complex with roliprams and\nimplication on inhibitor selectivity","volume":"11","author":"Huai","year":"2003","journal-title":"Structure"},{"key":"2026090218172543000_cit46","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1016\/S0076-6879(97)76066-X","article-title":"Processing of X-ray\ndiffraction data collected in oscillation mode","volume":"276","author":"Otwinowski","year":"1997","journal-title":"Methods Enzymol."},{"key":"2026090218172543000_cit47","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1107\/S0108767390010224","article-title":"Improved methods\nfor building protein models in electron density maps and the location\nof errors in these models","volume":"A47","author":"Jones","year":"1991","journal-title":"Acta Crystallogr."},{"key":"2026090218172543000_cit48","first-page":"905","article-title":"Crystallography\nand NMR system: a new software suite for macromolecular structure\ndetermination","volume":"D54","author":"Bru\u0308nger","year":"1998","journal-title":"Acta Crystallogr."},{"key":"2026090218172543000_cit49","doi-asserted-by":"crossref","first-page":"306","DOI":"10.2337\/db07-0381","article-title":"Metformin inhibits hepatic gluconeogenesis\nthrough AMP-activated protein kinase-dependent regulation of the orphan\nnuclear receptor SHP","volume":"57","author":"Kim","year":"2008","journal-title":"Diabetes"},{"key":"2026090218172543000_cit50","doi-asserted-by":"crossref","first-page":"9089","DOI":"10.1021\/jm401047q","article-title":"Synthesis and evaluation of multi-target-directed ligands against\nAlzheimer\u2019s disease based on the fusion of donepezil and ebselen","volume":"56","author":"Luo","year":"2013","journal-title":"J. Med. Chem."}],"container-title":["Journal of Medicinal Chemistry"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pubs.acs.org\/doi\/pdf\/10.1021\/jm500836h","content-type":"application\/pdf","content-version":"vor","intended-application":"unspecified"},{"URL":"https:\/\/pubs.acs.org\/jmcmar\/article-pdf\/57\/24\/10304\/15128230\/jm500836h.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pubs.acs.org\/jmcmar\/article-pdf\/57\/24\/10304\/15128230\/jm500836h.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T22:18:27Z","timestamp":1788387507000},"score":1,"resource":{"primary":{"URL":"https:\/\/pubs.acs.org\/jmcmar\/article\/57\/24\/10304\/1436220\/Discovery-of-a-Phosphodiesterase-9A-Inhibitor-as-a"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2014,11,28]]},"references-count":50,"journal-issue":{"issue":"24","published-online":{"date-parts":[[2014,11,28]]},"published-print":{"date-parts":[[2014,12,26]]}},"URL":"https:\/\/doi.org\/10.1021\/jm500836h","relation":{"has-review":[{"id-type":"doi","id":"10.3410\/f.725249728.793502040","asserted-by":"object"}]},"ISSN":["0022-2623","1520-4804"],"issn-type":[{"value":"0022-2623","type":"print"},{"value":"1520-4804","type":"electronic"}],"subject":[],"published":{"date-parts":[[2014,11,28]]}}}