title: Characterization of a novel phosphodiesterase type 5 inhibitor: JNJ-10258859.
abstract: We have characterized a novel, potent, and selective phosphodiesterase type 5 inhibitor, JNJ-10258859 ((R)-(-)-3-(2,3-dihydro-benzofuran-5-yl)-2-[5-(4-methoxy-phenyl)-pyrimidin-2-yl]-1,2,3,4-tetrahydro-pyrrolo[3,4-b]quinolin-9-one). Its inhibitory effects on phosphodiesterase 1-6 were determined using enzymes partially purified from human tissues. The compound inhibited phosphodiesterase type 5 with a K(i) of 0.23 nM and displayed excellent selectivity versus phosphodiesterase types 1-4 (>/=22,000 fold compared to phosphodiesterase type 5). It had 27-fold selectivity over phosphodiesterase type 6 as well. In a cell-based assay, JNJ-10258859 was more potent than sildenafil in potentiating nitric oxide (NO) induced accumulation of intracellular cGMP. The in vivo effect of JNJ-10258859 was evaluated in an anesthetized dog model via intravenous administration. The compound had similar efficacy to sildenafil in enhancing both the amplitude and duration of intracavernosal pressure increase induced by electrical stimulation to the pelvic nerve. No significant effects on either mean aortic pressure or heart rate were observed during the course of the experiments. This data suggests that JNJ-10258859 could be a useful treatment for erectile dysfunction.
authors.affiliation: Reproductive Therapeutics, Drug Discovery, R.W. Johnson and Johnson Pharmaceutical Research and Development Institute, LLC. 1000 Route 202, Raritan, NJ 08869, USA. yqiu@prdus.jnj.com
authors.forename: Yuhong
authors.initials: Y
authors.lastname: Qiu
authors.forename: Sheela
authors.initials: S
authors.lastname: Bhattacharjee
authors.forename: Patricia
authors.initials: P
authors.lastname: Kraft
authors.forename: T Mathew
authors.initials: TM
authors.lastname: John
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Craig
authors.forename: Donna
authors.initials: D
authors.lastname: Haynes-Johnson
authors.forename: Jihua
authors.initials: J
authors.lastname: Guan
authors.forename: Weiqin
authors.initials: W
authors.lastname: Jiang
authors.forename: Mark
authors.initials: M
authors.lastname: Macielag
authors.forename: Zhihua
authors.initials: Z
authors.lastname: Sui
authors.forename: Joanna
authors.initials: J
authors.lastname: Clancy
authors.forename: Scott
authors.initials: S
authors.lastname: Lundeen
mesh_terms: D015106:3',5'-Cyclic-GMP Phosphodiesterases; D000818:Animals; D001792:Blood Platelets / Q000201:enzymology; D002460:Cell Line; D000242:Cyclic AMP / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D006801:Humans; D008297:Male; D018482:Muscle, Skeletal / Q000201:enzymology; D009206:Myocardium / Q000201:enzymology; D010410:Penile Erection / Q000187:drug effects*; D010413:Penis / Q000187:drug effects / Q000201:enzymology / Q000294:innervation / Q000378:metabolism; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D010727:Phosphoric Diester Hydrolases / Q000302:isolation & purification / Q000378:metabolism*; D010879:Piperazines / Q000494:pharmacology; D011687:Purines; D015363:Quinolones / Q000494:pharmacology*; D051381:Rats; D012160:Retina / Q000201:enzymology; D000068677:Sildenafil Citrate; D013379:Substrate Specificity; D013450:Sulfones
chemical_list: C483959:JNJ10258859; D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D011687:Purines; D015363:Quinolones; D013450:Sulfones; D000068677:Sildenafil Citrate; D000242:Cyclic AMP; D010727:Phosphoric Diester Hydrolases; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; C517381:PDE5A protein, human; C517384:Pde5a protein, rat; D006152:Cyclic GMP