Document Detail

Characterization of a novel phosphodiesterase type 5 inhibitor: JNJ-10258859.
MedLine Citation:
PMID:  12860475     Owner:  NLM     Status:  MEDLINE    
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.
Yuhong Qiu; Sheela Bhattacharjee; Patricia Kraft; T Mathew John; Elizabeth Craig; Donna Haynes-Johnson; Jihua Guan; Weiqin Jiang; Mark Macielag; Zhihua Sui; Joanna Clancy; Scott Lundeen
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  European journal of pharmacology     Volume:  472     ISSN:  0014-2999     ISO Abbreviation:  Eur. J. Pharmacol.     Publication Date:  2003 Jul 
Date Detail:
Created Date:  2003-07-15     Completed Date:  2004-04-23     Revised Date:  2007-11-15    
Medline Journal Info:
Nlm Unique ID:  1254354     Medline TA:  Eur J Pharmacol     Country:  Netherlands    
Other Details:
Languages:  eng     Pagination:  73-80     Citation Subset:  IM    
Reproductive Therapeutics, Drug Discovery, R.W. Johnson and Johnson Pharmaceutical Research and Development Institute, LLC. 1000 Route 202, Raritan, NJ 08869, USA.
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MeSH Terms
3',5'-Cyclic-GMP Phosphodiesterases
Blood Platelets / enzymology
Cell Line
Cyclic AMP / metabolism
Cyclic GMP / metabolism
Cyclic Nucleotide Phosphodiesterases, Type 5
Dose-Response Relationship, Drug
Electric Stimulation
Muscle, Skeletal / enzymology
Myocardium / enzymology
Penile Erection / drug effects*
Penis / drug effects,  enzymology,  innervation,  metabolism
Phosphodiesterase Inhibitors / pharmacology*
Phosphoric Diester Hydrolases / isolation & purification,  metabolism*
Piperazines / pharmacology
Quinolones / pharmacology*
Retina / enzymology
Substrate Specificity
Reg. No./Substance:
0/JNJ10258859; 0/Phosphodiesterase Inhibitors; 0/Piperazines; 0/Purines; 0/Quinolones; 0/Sulfones; 139755-83-2/sildenafil; 60-92-4/Cyclic AMP; 7665-99-8/Cyclic GMP; EC 3.1.4.-/Phosphoric Diester Hydrolases; EC',5'-Cyclic-GMP Phosphodiesterases; EC Nucleotide Phosphodiesterases, Type 5; EC protein, human; EC protein, rat

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