5128
M. Sakairi et al. / Bioorg. Med. Chem. Lett. 22 (2012) 5123–5128
2. Tahrani, A. A.; Bailey, C. J.; Del Prato, S.; Barnett, A. H. Lancet 2011, 378, 182.
3. For recent reviews: (a) Jones, R. M.; Leonard, J. N. Annu. Rep. Med. Chem. 2009,
44, 149; (b) Jones, R. M.; Leonard, J. N.; Buzard, D. J.; Lehmann, J. Expert Opin.
Ther. Patents 2009, 19, 1339; (c) Shah, U. Curr. Opin. Drug Disc. Dev. 2009, 12,
519; (d) Fyfe, M. C. T.; McCormack, J. G.; Overton, H. A.; Procter, M. J.; Reynet, C.
Expert Opin. Drug Disc. 2008, 3, 403.
4. (a) Soga, T.; Ohishi, T.; Matsui, T.; Saito, T.; Matsumoto, M.; Takasaki, J.;
Matsumoto, S.; Kamohara, M.; Hiyama, H.; Yoshida, S.; Momose, K.; Ueda, Y.;
Matsushime, H.; Kobori, M.; Furuichi, K. Biochem. Biophys. Res. Commun. 2005,
326, 744; (b) Sakamoto, Y.; Inoue, H.; Kawakami, S.; Miyawaki, K.; Miyamoto,
T.; Mizuta, K.; Itakura, M. Biochem. Biophys. Res. Commun. 2006, 351, 474.
5. Chu, Z.; Carroll, C.; Alfonso, J.; Gutierrez, V.; He, H.; Lucman, A.; Pedraza, M.;
Mondala, H.; Gao, H.; Bagnol, D.; Chen, R.; Jones, R. M.; Behan, D. P.; Leonard, J.
Endocrinology 2008, 149, 2038.
of fluorescence intensity of each well at 620 and 665 nm. The sigmoidal dose–
response equation was used to determine EC50 and Emax values. These values
represent the relative efficacy that was defined as the ratio of the response of
test compound to the maximum response of AR231453 (7.4 nM for hEC50 and
20 nM for mEC50).
12. Semple, G.; Ren, A.; Fioravanti, B.; Pereira, G.; Calderon, I.; Choi, K.; Xiong, Y.;
Shin, Y. J.; Gharbaoui, T.; Sage, C. R.; Morgan, M.; Xing, C.; Chu, Z. L.; Leonard, J.
N.; Grottick, A. J.; Al-Shamma, H.; Liang, Y.; Demarest, K. T.; Jones, R. M. Bioorg.
Med. Chem. Lett. 2011, 21, 3134.
13. (a) Atkinson, F. L.; Barker, M. D.; Campos, S. A.; Parp, N. J.; Patel, V. K. PCT Int.
Appl. WO/2006129100, 2006.; (b) Diedrichs, N.; Fahrig, T.; Gerlach, I.; Ragot, J.;
Schuhmacher, J.; Thede, K.; (DE). Horvath, E. PCT Int. Appl. WO/2005113529,
2005.; (c) Bursavich, M. G.; Nowak, P. W.; Malwitz, D.; Lombardi, S.; Gilbert, A.
M.; Zhang, N.; Ayral-Kaloistian, S.; Anderson, J. T.; Brooijmans, N. PCT Int. Appl.
WO/2010011620, 2010.; (d) Tsou, H. R.; MacEwan, G.; Birnberg, G.; Zhang, N.;
Brooijmans, N.; Toral-Barza, L.; Hollander, I.; Ayral-Kaloustian, S.; Yu, K. Bioorg.
Med. Chem. Lett. 2010, 20, 2259; (e) Greenblatt, L. P. PCT Int. Appl. WO/
200503780, 2005.; (f) Wurtz, N. R.; Priestley, E. S.; Cheney, D. L.; Glunz, P. W.;
Zhang, X.; Ladziata, V.; Parkhurst, B.; Mueller, L. PCT Int. Appl. WO/
2008079759, 2008.
14. Fang, J.; Tang, J.; Carpenter, A. J.; Peckham, G.; Conlee, C. R.; Du, K. S.;
Katamreddy, S. R. PCT Int. Appl. WO/2008079692, 2008.
15. LogP was calculated with ACD/PhysChem History. ACD/Labs, ver. 10.00,
Advanced Chemistry Development, Inc.: Toronto, Canada, 2006.
16. (a) Szewczyk, J. W.; Acton, J.; Adams, A. D.; Chicchi, G.; Freeman, S.; Howard, A.
D.; Huang, Y.; Li, C.; Meinke, P. T.; Mosely, R.; Murphy, E.; Samuel, R.; Santini,
C.; Yang, M.; Zhang, Y.; Zhao, K.; Wood, H. b. Bioorg. Med. Chem. Lett. 2011, 21,
2665; (b) Xia, Y.; Chackalamannil, S.; Greenlee, W. J.; Jayne, C.; Neustadt, B.;
Stamford, A.; Vaccaro, H.; Xu, X.; Baker, H.; O’Neil, K.; Woods, M.; Hawes, B.;
Kowalski, T. Bioorg. Med. Chem. Lett. 2011, 21, 3290.
6. Semple, G.; Fioravanti, B.; Pereira, G.; Calderon, I.; Uy, J.; Choi, K.; Xiong, Y.; Ren,
A.; Morgan, M.; Dave, V.; Thomsen, W.; Unett, D. J.; Xing, C.; Bossie, S.; Carroll,
C.; Chu, Z. L.; Grottick, A. J.; Hauser, E. K.; Leonard, J.; Jones, R. M. J. Med. Chem.
2008, 51, 5172.
7. (a) Drug reports are available from Thomson PharmÒ.; (b) Semple, G.;
Lehmann, J.; Wong, A.; Ren, A.; Bruce, M.; Shin, Y.-J.; Sage, C. R.; Morgan, M.;
Chen, W.-C.; Sebring, K.; Chu, Z.-L.; Leonard, J. N.; Al-Shamma, H.; Grottick, A. J.;
Du, E.; Liang, Y.; Demarest, K.; Jones, R. M. Bioorg. Med. Chem. Lett. 2012, 22,
1750.
8. Metabolex Press Release, Oct 13, 2009, Hayward, California.
9. Shah, U.; Kowalski, T. J. Vitam. Horm. 2010, 84, 415.
10. Zambias, R. A.; Hammond, M. L. Synth. Commun. 1991, 21, 959.
11. Cell-based cAMP functional assay: Cellular cAMP was measured using HTRF
cAMP HiRange reagent (CISBIO, Cedex, France). CHO-K1 cells expressing
hGPR119 receptors were obtained from Applied Cell Sciences and were grown
in flasks containing F-12 medium supplemented with 10% FBS, 1% non
essential amino acids (NEAA), 20 mM HEPES, 50 units/ml penicillin, 50
l
l/ml
17. oGTT and scGTT: Male 8-week-old C57BL/6J (Charles River Japan) were fasted
overnight and then received orally administrated vehicle (20% HPbCD) or
compound 2 at 3 or 10 mg/kg (n = 8). After 30 min, glucose was given orally or
subcutaneously at 2 g/kg, and blood samples were collected from tail veins at
0, 20, 40, 60 and 120 min. Blood glucose level was measured using Glutest Pro
R (Sanwa Kagaku Kenkyusyo).
18. GLP-1 secretion: Male 10-week-old C57BL/6J were fasted for 5 h and received
orally administered vehicle (5% DMSO, 0.1% Tween 80 and 0.5%
methylcellulose) or compound 2 at 30 mg/kg (n = 10). Plasma total GLP-1
(both intact GLP-1 (7–36) amide and its primary metabolite) levels at 30 min
after the administration were measured by ELISA using anti-GLP-1 monoclonal
antibodies.
streptomycin, and 400 g/ml geneticin. CHO-K1 cells expressing mGPR119
l
receptors were prepared in house and were grown in flasks containing F-12
medium supplemented with 10% FBS, 1% non essential amino acids (NEAA),
20 mM HEPES, 50 units/ml penicillin, 50 ll/ml streptomycin, and 400 lg/ml
geneticin. For the hGPR119 or mGPR119 functional assay, cells expressing
hGPR119 or mGPR119 were harvested, resuspended in incubation buffer (F-12
medium, 20 mM HEPES, 1 mM IBMX), and dispensed into 384-well plates at a
density of 1.5 Â 104 cells/well in the presence or absence of test compounds.
Cells were incubated at 37 °C for 30 min, and the cAMP-d2-conjugated
antibody and the anti-cAMP-cryptase-conjugated antibody were added to
the plate. After incubation for 60 min at room temperature, measurements
were made using a HTRFÒ (TR-FRET) Microplate Reader ARTEMIS (Furuno
Electric Co., Ltd, Tokyo, Japan). Data analysis was performed based on the ratio
19. Lan, H.; Lin, H. V.; Wang, C. F.; Wright, M. J.; Xu, S.; Kang, L.; Juhl, K.; Hedrick, J.
A.; Kowalski, T. J. Br. J. Pharmacol. 2012, 165, 2799.