¹Reproductive Therapeutics, Research & Early Development, Johnson & Johnson Pharmaceutical Research & Development, LLC., Raritan, NJ, USA

Correspondence: Dr Y Qiu, Johnson & Johnson Pharm. Res. & Dev., 1000 Route 202 South, Raritan, NJ 08869, USA. E-mail: yqiu1992@yahoo.com

²Current address: Center for Biomaterials & Advanced Technologies, Ethicon, Somerville, NJ, USA.

Received 29 December 2005; Revised 19 January 2006; Accepted 2 February 2006; Published online 9 March 2006.

Abstract

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 K_i 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.