JNJ-10280205 and JNJ-10287069: novel PDE5 inhibitors as clinical candidates for erectile dysfunction
| Autor: | Zhihua Sui, T. Mathew John, Patricia Kraft, Weiqin Jiang, Sheela Bhattacharjee, Donna Haynes-Johnson, Scott G. Lundeen, Yuhong Qiu |
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| Rok vydání: | 2006 |
| Předmět: |
Male
medicine.medical_specialty Sildenafil Urology hERG Quinolones Pharmacology chemistry.chemical_compound Dogs Cytochrome P-450 Enzyme System Erectile Dysfunction Pharmacokinetics 3' 5'-Cyclic-GMP Phosphodiesterases Internal medicine medicine Animals Humans Enzyme Inhibitors Cyclic Nucleotide Phosphodiesterases Type 5 chemistry.chemical_classification biology business.industry Cytochrome P450 Haplorhini medicine.disease Ether-A-Go-Go Potassium Channels Rats Bioavailability Endocrinology Enzyme Erectile dysfunction chemistry cGMP-specific phosphodiesterase type 5 biology.protein business |
| Zdroj: | International Journal of Impotence Research. 18:477-483 |
| ISSN: | 1476-5489 0955-9930 |
| Popis: | Phosphodiesterase 5 (PDE5) inhibitors are efficacious in treating patients with erectile dysfunction. New PDE5 inhibitors with different selectivity and pharmacokinetic profiles have been vigorously pursued. Here we report two novel, potent, and selective PDE5 inhibitors, JNJ-10280205 and JNJ-10287069, with Ki values of 0.05 and 0.12 nM, respectively. Both compounds displayed superior selectivity against PDE1-4 and -6 when compared to sildenafil. In the anesthetized dogs, JNJ-10280205 and JNJ-10287069 exhibited similar efficacy as sildenafil in enhancing erectile functions, with no significant effect on cardiovascular parameters. Pharmacokinetic studies showed that JNJ-10287069 had better oral bioavailability than JNJ-10280205 in several animal species. In vitro study suggested that cytochrome P450 (CYP) 3A4 played a major role in the metabolism of both compounds. The compounds inhibited some of the CYP450 enzymes and the human ether-a-go-go (HERG) channel at much higher concentrations than that required to inhibit PDE5, thus, no cross inhibition would be expected at therapeutic doses. Both compounds are suitable clinical candidates. |
| Databáze: | OpenAIRE |
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