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JNJ-10280205 and JNJ-10287069: novel PDE5 inhibitors as clinical candidates for erectile dysfunction

International Journal of Impotence Research volume 18, pages 477–483 (2006)Cite this article

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 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.

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References

  1. Aboseif SR, Lue TF . Haemodynamics of penile erection. Urol Clin N Am 1988; 15: 1–7.

    CAS  Google Scholar 

  2. Ignarro LJ, Bush PA, Buga GM, Wood KS, Fukuto J, MRajfer J . Nitric oxide and cyclic GMP formation upon electrical field stimulation cause relaxation of corpus cavernosum smooth muscle. Biochem Biophys Res Comm 1990; 170: 843–850.

    Article  CAS  Google Scholar 

  3. Kim N, Azadzoi KM, Goldstein I, Saenz de Tejada I . A nitric oxide-like factor mediates nonadrenergic–noncholinergic neurogenic relaxation of penile corpus cavernosum smooth muscle. J Clin Invest 1991; 88: 112–118.

    Article  CAS  Google Scholar 

  4. Burnett AL, Lowenstein CJ, Bredt DS, Chang TS, Snyder SH . Nitric oxide: a physiologic mediator of penile erection. Science 1992; 257: 401–403.

    Article  CAS  Google Scholar 

  5. Corbin JD, Francis SH . Cyclic GMP phosphodiesterase-5: target of sildenafil. J Biol Chem 1999; 274: 13729–13732.

    Article  CAS  Google Scholar 

  6. Maggi M, Filippi S, Ledda F, Magini A, Forti G . Erectile dysfunction: from biochemical pharmacology to advances in medical therapy. Eur J Endocrinol 2000; 143: 143–154.

    Article  CAS  Google Scholar 

  7. Francis SH, Turko IV, Corbin JD . Cyclic nucleotide phosphodiesterases: relating structure and function. Prog Nucleic Acid Res Mol Biol 2001; 65: 1–52.

    CAS  Google Scholar 

  8. O'Donnell JM . William Harvey Research Conference on PDE inhibitors: drugs with an expanding range of therapeutic uses. Exp Opin Invest Drugs 2000; 9: 621–625.

    Article  CAS  Google Scholar 

  9. Boolell M, Allen MJ, Ballard SA, Gepi-Attee S, Muirhead GJ, Naylor AM et al. Sildenafil: an orally active type 5 cyclic GMP-specific phosphodiesterase inhibitor for the treatment of penile erectile dysfunction. IntJ Impot Res 1996; 8: 47–52.

    CAS  Google Scholar 

  10. Goldenberg MM . Safety and efficacy of sildenafil citrate in the treatment of male erectile dysfunction. Clin Ther 1998; 20: 1033–1048.

    Article  CAS  Google Scholar 

  11. Eardley I . New oral therapies for the treatment of erectile dysfunction. Br J Urol 1998; 81: 122–127.

    Article  CAS  Google Scholar 

  12. Briganti A, Salonia A, Gallina A, Sacca A, Montorsi P, Rigatti P et al. Drug insight: oral phosphodiesterase type 5 inhibitors for erectile dysfunction. Nat Clin Pract Urol 2005; 2: 239–247.

    Article  CAS  Google Scholar 

  13. Sui Z . Phosphodiesterase-5 inhibitors for male erectile dysfunction. Expert Opin Ther Patents 2003; 13: 1371–1388.

    Article  Google Scholar 

  14. Jiang W, Guan J, Macielag M, Sui Z, Qiu Y, Kraft P et al. Pyrroloquinolone PDE5 inhibitors with improved pharmaceutical profiles for clinical studies on erectile dysfunction. J Med Chem 2005; 48: 2126–2133.

    Article  CAS  Google Scholar 

  15. Qiu Y, Bahattacharjee S, Kraft P, John TM, Craig E, Haynes-Johnson D et al. Characterization of a novel phosphodiesterase type 5 inhibitor: JNJ-10258859. Eur J Pharm 2003; 472: 73–80.

    Article  CAS  Google Scholar 

  16. D'Andrea MR, Qiu Y, Haynes-Johnson D, Bhattacharjee S, Kraft P, Lundeen S . Expression of PDE11A4 in normal and malignant human tissues. J Histochem Cytochem 2005; 53: 895–903.

    Article  CAS  Google Scholar 

  17. Yan Z, Rafferty B, Caldwell GW, Masucci J . Rapidly distinguishing reversible and irreversible CYP450 inhibitors by using fluorometric kinetic analyses. Eur J Drug Metab Pharmacokinet 2002; 27: 281–287.

    Article  CAS  Google Scholar 

  18. Hellstrom WJG, Overstreet JW, Yu A, Saikali K, Shen W, Beasley CMJ et al. Tadalafil has no detrimental effect on human spermatogenesis or reproductive hormones. J Urol 2003; 170: 887–891.

    Article  CAS  Google Scholar 

  19. Saenz de Tejada I, Angulo J, Cuevas P, Fernandez A, Moncada I, Allona A et al. The phosphodiesterase inhibitory selectivity and the in vitro and in vivo potency of the new PDE5 inhibitor vardenafil. Int J Impotence Res 2001; 13: 282–290.

    Article  CAS  Google Scholar 

  20. Daugan A, Grondin P, Ruault C, Le Monnier de Gouville AC, Coste H et al. The discovery of tadalafil: a novel and highly selective PDE5 inhibitor. 2: 2,3,6,7,12,12a-hexahydropyrazino[1′,2′:1,6]pyrido[3,4-b]indole-1,4-dione analogue. J Med Chem 2003; 46: 4533–4542.

    Article  CAS  Google Scholar 

  21. Montorsi F, Salonia A, Briganti A, Barbieri L, Zanni G, Suardi N et al. Vardenafil for the treatment of erectile dysfunction: a critical review of the literature based on personal clinical experience. Eur Urol 2005; 47: 612–621.

    Article  CAS  Google Scholar 

  22. Ormrod D, Easthope SE, Figgitt DP . Vardenafil. Drugs Aging 2002; 19: 217–227.

    Article  CAS  Google Scholar 

  23. Fawcett L, Baxendale R, Stacey P, McGrouther C, Harrow I, Soderling S et al. Molecular cloning and characterization of a distinct human phosphodiesterase gene family: PDE11A. Proc Natl Acad Sci USA 2000; 97: 3702–3707.

    Article  CAS  Google Scholar 

  24. Hetman JM, Robas N, Baxendale R, Fidock M, Phillips SC, Soderling SH et al. Cloning and characterization of two splice variants of human phosphodiesterase 11A. Proc Natl Acad Sci USA 2000; 97: 12891–12895.

    Article  CAS  Google Scholar 

  25. Yuasa K, Kotera J, Fujishige K, Michibata H, Sasaki T, Omori K . Isolation and characterization of two novel phosphodiesterase PDE11A variants showing unique structure and tissue-specific expression. J Biol Chem 2000; 275: 31469–31479.

    Article  CAS  Google Scholar 

  26. Maw GN, Allerton CMN, Gbekor E, Million WA . Design, synthesis and biological activity of [beta]-carboline-based type-5 phosphodiesterase inhibitors. Bioorg Med Chem Lett 2003; 13: 1425–1428.

    Article  CAS  Google Scholar 

  27. Weeks JL, Zoraghi R, Beasley A, Sekhar KR, Francis SH, Corbin JD . High biochemical selectivity of tadalafil, sildenafil and vardenafil for human phosphodiesterase 5A1 (PDE5) over PDE11A4 suggests the absence of PDE11A4 cross-reaction in patients. Int J Impot Res 2005; 17: 5–9.

    Article  CAS  Google Scholar 

  28. Walker DK, Ackland MJ, James GC, Muirhead GJ, Rance DJ, Wastall P et al. Pharmacokinetics and metabolism of sildenafil in mouse, rat, rabbit, dog and man. Xenobiotica 1999; 29: 297–310.

    Article  CAS  Google Scholar 

  29. Pryor J . Vardenafil: update on clinical experience. Int J Impot Res 2002; 14(Suppl 1): S65–S69.

    Article  Google Scholar 

  30. Padma-Nathan H . Efficacy and tolerability of tadalafil, a novel phosphodiesterase 5 inhibitor, in treatment of erectile dysfunction. Am J Cardiol 2003; 92: 19–25.

    Article  Google Scholar 

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Acknowledgements

We thank the JJPRD Chemical and Biological Support Teams in Raritan and Spring House, and the Drug Metabolism Team in Spring House for their excellent technical support.

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  1. T Mathew John

    Present address: Center for Biomaterials & Advanced Technologies, Ethicon, Somerville, NJ, USA

Authors and Affiliations

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

    Y Qiu, S Bhattacharjee, P Kraft, T Mathew John, D Haynes-Johnson, W Jiang, Z Sui & S Lundeen

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  1. Y Qiu
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  2. S Bhattacharjee
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  7. Z Sui
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  8. S Lundeen
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Correspondence to Y Qiu.

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Qiu, Y., Bhattacharjee, S., Kraft, P. et al. JNJ-10280205 and JNJ-10287069: novel PDE5 inhibitors as clinical candidates for erectile dysfunction. Int J Impot Res 18, 477–483 (2006). https://doi.org/10.1038/sj.ijir.3901462

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