Characterization of a novel phosphodiesterase type 5 inhibitor: JNJ-10258859.
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.
Qiu
Yuhong
Y
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
Bhattacharjee
Sheela
S
Kraft
Patricia
P
John
T Mathew
TM
Craig
Elizabeth
E
Haynes-Johnson
Donna
D
Guan
Jihua
J
Jiang
Weiqin
W
Macielag
Mark
M
Sui
Zhihua
Z
Clancy
Joanna
J
Lundeen
Scott
S
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
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