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.