S. Y. Sit et al. / Bioorg. Med. Chem. Lett. 20 (2010) 1272–1277
1277
4. Sit, S. Y.; Conway, C.; Bertekap, R.; Xie, K.; Bourin, C.; Burris, K.; Deng, H. Bioorg.
Med. Chem. Lett. 2007, 17, 3287.
10. a The crystal structure of 1MT5 has been used by many researchers in the field.
The exact technique used to generate useful information varies from group to
group. For example: methods for modeling study can be found in the
Supplementary data to Ref. 10.; (b) Guimarães, C. R. W.; Boger, D. L.;
Jorgensen, W. L. J. Am. Chem. Soc. 2005, 127, 17377; (c) Boger, D. L.;
Miyauchi, H.; Du, W.; Hardouin, C.; Fecik, R. A.; Cheng, H.; Hwang, I.;
Hedrick, M. P.; Leung, D.; Acevedo, O.; Guimaraes, C. R. W.; Jorgensen, W. L.;
Cravatt, B. F. J. Med. Chem. 2005, 48, 1849; (d) Keith, J. M.; Apodaca, R.; Xiao, W.;
Seierstad, M.; Pattabiraman, K.; Wu, J.; Webb, M.; Karbarz, M. J.; Brown, S.;
Wilson, S.; Scott, B.; Tham, C.-S.; Luo, L.; Palmer, J.; Wennerholm, M.; Chaplan,
S.; Breitenbucher, J. G. Bioorg. Med. Chem. Lett. 2008, 18, 4838.
11. Dockingwithmultiple ligandorientations hasbeenreported, for instance Ref. 10b.
12. Met191 hydrogen bond formation with carbamate NH has been implicated in
FAAH inhibition: Saario, Ref. 10b; and more recently in: Saario, S. M.; Poso, A.;
Juvonen, R. O.; Jaervinen, T.; Salo-Ahen, O. M. H. J. Med. Chem. 2006, 49, 4650.
13. (a) Dirig, D. M.; Salami, A.; Rathbun, M. L.; Ozaki, G. T.; Yaksh, T. L. J. Neurosci.
Methods 1997, 76, 183; (b) Hargreaves, K.; Dubner, R.; Brown, F.; Flores, C.;
Joris, J. Pain 1988, 32, 77.
5. (a) Meanwell, N. A.; Rosenfeld, M. J.; Wright, J. J. K.; Brassard, C. L.; Buchanan, J.
O.; Federici, M. E.; Fleming, J. S.; Gamberdella, M.; Hartl, K. S.; Zavoico, G. B.;
Seiler, S. M. J. Med. Chem. 1993, 36, 3871; (b) Seiler, S. M.; Brassard, C. L.;
Federici, M. E.; Romine, J.; Meanwell, N. A. Prostaglandins 1997, 53, 21; (c). J.
Med. Chem. 1994, 37, 560; (d) Magnin, D. R.; Biller, S. A.; Wetterau, J.; Robl, J. A.;
Dickson, J. K.; Taunk, P.; Harrity, T. W.; Lawrence, R. M.; Sun, C.-Q.; Wang, T.;
Logan, J.; Fryszman, O.; Connolly, F.; Jolibois, K.; Kunselman, L. Bioorg. Med.
Chem. Lett. 2003, 13, 1337; (e) Sharpe, T. R.; Cherkofsky, S. C.; Hewes, W. E.;
Smith, D. H.; Gregory, W. A.; Haber, S. B.; Leadbetter, M. R.; Whitney, J. G. J. Med.
Chem. 1985, 28, 1188; (f) Kahlon, D. K.; Lansdell, T. A.; Fisk, J. S.; Hupp, C. D.;
Friebe, T. L.; Hovde, S.; Jones, A. D.; Dyer, R. D.; Henry, R. W.; Tepe, J. J. J. Med.
Chem. 2009, 52, 1302.
6. Previous results obtained by others showed that meta-oriented biphenyls and
phenoxyphenyls analogs on
a different core demonstrated potent FAAH
inhibitors: (a) Mor, M.; Lodola, A.; Rivara, S.; Vacondio, F.; Duranti, A.;
Tontini, A.; Sanchini, S.; Piersanti, G.; Clapper, J. R.; King, A. R.; Tarzia, G.;
Piomelli, D. J. Med. Chem. 2008, 51, 3487; (b) Mor, M.; Rivara, S.; Lodola, A.;
Plazzi, P. V.; Tarzia, G.; Duranti, A.; Tontini, A.; Piersanti, G.; Kathuria, S.;
Piomelli, D. J. Med. Chem. 2004, 47, 4998; (c) Tarzia, G.; Duranti, A.; Gatti, G.;
Piersanti, G.; Tontini, A.; Rivara, S.; Lodola, A.; Plazzi, P. V.; Mor, M.; Kathuria, S.;
Piomelli, D. Chem. Med. Chem. 2006, 1, 130.
14. Given the observed reversible inhibition, the statement is
a form of the
Hammond’s Postulate. Hence whatever carbonyl interactions oxime carbamate
might have such as those with Ser241, the hydroxy oxygen atom is not close
enough to get past the energy barrier to establish a covalent bond.
15. The Km and Vmax for each substrate–velocity curve was calculated through non-
7. Sit, S. Y.; Xie, K.; Deng, H. (Bristol-Myers Squibb Co., USA), (Oxime)carbamoyl
fatty acid amide hydrolase inhibitors, US Patent 6,949,574, September 25,
2005.
8. Bracey, M.; Hanson, M. A.; Masuda, K. R.; Stevens, R. C.; Cravatt, B. F. Science
2002, 298, 1793; McKinney, M. K.; Cravatt, B. F. Annu. Rev. Biochem. 2005, 74,
411.
linear regression of the Michaelis–Menten equation,
m
¼ ðVꢄmax½SꢅÞ=ðKm þ ½SꢅÞ,
using GraphPad Prism, with R2 P 0.94 for all curves. The inset plot of the
double-reciprocal (Lineweaver–Burke) plot was created by constructing and
plotting each line using the calculated Km and Vmax values from the non-linear
regression and was produced to visually show the constant Vmax values with
increasing inhibitor concentration.
9. For comparison purposes, a subset of selected ‘simple carbamate’ analogs were
screened, and results can be found in the Supplementary data.
16. H4 cells that express transfected human FAAH were used for all in vitro
experiments. See Ref. 4 for details.