5122
M. M. Stec et al. / Bioorg. Med. Chem. Lett. 18 (2008) 5118–5122
Ognyanov, V. I.; Pettus, L.; Rzasa, R. M.; Stec, M.; Surapaneni, S.; Tamir, R.; Zhu,
J.; Treanor, J. J. S.; Norman, M. H. J. Med. Chem. 2007, 50, 3515.
solubility relative to AMG 517, yet maintained good potency to-
ward TRPV1 and good pharmacokinetic properties.
14. Wang, H.-L.; Katon, J.; Balan, C.; Bannon, A. W.; Bernard, C.; Doherty, E. M.;
Dominguez, C.; Gavva, N. R.; Gore, V.; Ma, V.; Nishimura, N.; Surapaneni, S.; Tang,
P.; Tamir, R.; Thiel, O.; Treanor, J. J. S.; Norman, M. H. J. Med. Chem. 2007, 50, 3528.
15. Wang, X.; Chakrabarti, P. P.; Ognyanov, V. I.; Pettus, L. H.; Tamir, R.; Tan, H.;
Tang, P.; Treanor, J. J. S.; Gavva, N. R.; Norman, M. H. Bioorg. Med. Chem. Lett.
2007, 17, 6539.
16. Doherty, E. M.; Fotsch, C.; Bo, Y.; Chakrabarti, P. P.; Chen, N.; Gavva, N.; Han, N.;
Kelly, M. G.; Kincaid, J.; Klionsky, L.; Liu, Q.; Ognyanov, V. I.; Tamir, R.; Wang,
X.; Zhu, J.; Norman, M. H.; Treanor, J. J. S. J. Med. Chem. 2005, 48, 71.
17. Norman, M. H.; Zhu, J.; Fotsch, C.; Bo, Y.; Chen, N.; Chakrabarti, P.; Doherty, E.
M.; Gavva, N. R.; Nishimura, N.; Nixey, T.; Ognyanov, V. I.; Rzasa, R. M.; Stec,
M.; Surapaneni, S.; Tamir, R.; Viswanadhan, V. N.; Treanor, J. J. S. J. Med. Chem.
2007, 50, 3497.
References and notes
1. Szallasi, A.; Blumberg, P. M. Pharmacol. Rev. 1999, 51, 159.
2. Caterina, M. J.; Schumacher, M. A.; Tominaga, M.; Rosen, T. A.; Levine, J. D.;
Julius, D. Nature 1997, 389, 816.
3. Tominaga, M.; Caterina, M. J.; Malmberg, A. B.; Rosen, T. A.; Gilbert, H.; Skinner,
K.; Raumann, B.; Basbaum, A. I.; Julius, D. Neuron 1998, 21, 531.
4. Smart, D.; Gunthorpe, M. J.; Jerman, J. C.; Nasir, S.; Gray, J.; Muir, A. I.;
Chambers, J. K.; Randall, A. D.; Davis, J. B. Br. J. Pharmacol. 2000, 129, 227.
5. Ji, R.-R.; Samad, T. A.; Jin, S.-X.; Schmoll, R.; Woolf, C. J. Neuron 2002, 36, 57.
6. Caterina, M. J.; Leffler, A.; Malmberg, A. B.; Martin, W. J.; Trafton, J.; Petersen-
Zeitz, K. R.; Koltzenburg, M.; Basbaum, A. I.; Julius, D. Science 2000, 288, 306.
7. Davis, J. B.; Gray, J.; Gunthorpe, M. J.; Hatcher, J. P.; Davey, P. T.; Overend, P.;
Harries, M. H.; Latcham, J.; Clapham, C.; Atkinson, K.; Hughes, S. A.; Rance, K.;
Grau, E.; Harper, A. J.; Pugh, P. L.; Rogers, D. C.; Bingham, S.; Randall, A.;
Sheardown, S. A. Nature 2000, 405, 183.
8. Gavva, N. R.; Tamir, R.; Qu, Y.; Klionsky, L.; Zhang, T. J.; Immke, D.; Wang, J.;
Zhu, D.; Vanderah, T. W.; Porreca, F.; Doherty, E. M.; Norman, M. H.; Wild, K. D.;
Bannon, A. W.; Louis, J.-C.; Treanor, J. J. S. J. Pharmacol. Exp. Ther. 2005, 313, 474.
9. Gomtsyan, A.; Bayburt, E. K.; Schmidt, R. G.; Zheng, G. Z.; Perner, R. J.;
Didomenico, S.; Koenig, J. R.; Turner, S.; Jinkerson, T.; Drizin, I.; Hannick, S. M.;
Macri, B. S.; McDonald, H. A.; Honore, P.; Wismer, C. T.; Marsh, K. C.; Wetter, J.;
Stewart, K. D.; Oie, T.; Jarvis, M. F.; Surowy, C. S.; Faltynek, C. R.; Lee, C.-H.
J. Med. Chem. 2005, 48, 744.
10. Honore, P.; Wismer, C. T.; Mikusa, J.; Zhu, C. Z.; Zhong, C.; Gauvin, D. M.;
Gomtsyan, A.; El Kouhen, R.; Lee, C.-H.; Marsh, K.; Sullivan, J. P.; Faltynek, C. R.;
Jarvis, M. F. J. Pharmacol. Exp. Ther. 2005, 314, 410.
11. Pomonis, J. D.; Harrison, J. E.; Mark, L.; Bristol, D. R.; Valenzano, K. J.; Walker, K.
J. Pharmacol. Exp. Ther. 2003, 306, 387.
12. Rami, H. K.; Gunthorpe, M. J. Drug Discov. Today 2004, 1, 97.
13. For a discussion of AMG 517 and examples of compounds that were selective
toward capsaicin or acid activation, see: Doherty, E. M.; Fotsch, C.; Bannon, A.
W.; Bo, Y.; Chen, N.; Dominguez, C.; Falsey, J.; Gavva, N. R.; Katon, J.; Nixey, T.;
18. As a comparison, the pharmacokinetic properties of AMG 517 are as follows:
CL = 190 mL/h/kg, t = 6.3 h, VSS = 1.6 L/kg, Foral = 32%, and AUC0–1 = 5400 ng h/
½
mL.
19. Boisnard, S.; Carbonnelle, A.-C.; Zhu, J. Org. Lett. 2001, 3, 2061.
20. Hewawasam, P.; Meanwell, N. A. Tetrahedron Lett. 1994, 35, 7303.
21. Coste, J.; Frerot, E.; Jouin, P.; Castro, B. Tetrahedron Lett. 1991, 32, 1967.
22. Tamayo, N.; Liao, H.; Stec, M. M.; Wang, X.; Chakrabarti, P.; Retz, D.; Doherty, E.
M.; Surapaneni, S.; Tamir, R.; Bannon, A. W.; Gavva, N.; Norman, M. H. J. Med.
Chem. 2008, 51, 5744.
23. Tan, H.; Semin, D.; Wacker, M.; Cheetham, J. JALA 2005, 10, 364.
24. Compounds dosed intravenously at 1 mg/kg in DMSO into fed male Sprague–
Dawley rats with sampling time up to 6 h. n = 2 animals per study. Interanimal
variability was less than or equal to 30%.
25. Freshly isolated rat hepatocytes at 1 million cells per mL were incubated at
37 °C with 10 lM of the test compound with humidity control and 5% CO2 for 1
or 2 h. The reaction was stopped by the addition of acetonitrile or methanol.
After vortexing and centrifugation, the supernatant was analyzed by LC/MS.
26. ACD/pKa DB, Version 8.07; Advanced Chemistry Development Inc., Toronto,
Ontario, Canada, 2004.
27. Compounds dosed orally at 5 mg/kg as a suspension in 5% Tween 80/Oraplus
into fasted male Sprague–Dawley rats with sampling time up to 8 h. n = 2
animals per study. Interanimal variability was less than or equal to 30%.