JNJ-10280205 and JNJ-10287069: Novel PDE5 inhibitors as clinical candidates for erectile dysfunction.
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.
Qiu
Y
Y
Reproductive Therapeutics, Research & Early Development, Johnson & Johnson Pharmaceutical Research & Development, LLC., Raritan, NJ, USA. yqiu1992@yahoo.com
Bhattacharjee
S
S
Kraft
P
P
Mathew John
T
T
Haynes-Johnson
D
D
Jiang
W
W
Sui
Z
Z
Lundeen
S
S
D015106:3',5'-Cyclic-GMP Phosphodiesterases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004285:Dogs; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use*; D007172:Erectile Dysfunction / Q000188:drug therapy* / Q000201:enzymology*; D051638:Ether-A-Go-Go Potassium Channels / Q000378:metabolism; D000882:Haplorhini; D006801:Humans; D008297:Male; D015363:Quinolones / Q000493:pharmacokinetics / Q000627:therapeutic use*; D051381:Rats
C514864:3-(2,3-dihydro-5-benzofuranyl)-1,2,3,4-tetrahydro-2-(5-(2-pyridinyl)-2-pyrimidinyl)-9H-pyrrolo(3,4-b)quinolin-9-one; C500080:3-(2,3-dihydrobenzofuran-5-yl)-2-pyridin-2-yl-1,2,3,4-tetrahydropyrrolo(3,4-b)quinolin-9-one; D004791:Enzyme Inhibitors; D051638:Ether-A-Go-Go Potassium Channels; D015363:Quinolones; D003577:Cytochrome P-450 Enzyme System; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; C517381:PDE5A protein, human; C517384:Pde5a protein, rat