1370
W. S. Park et al. / Bioorg. Med. Chem. Lett. 21 (2011) 1366–1370
2D6), and exhibited less than 50% inhibition toward 5 subtypes at
10 M. Compound 2da showed no hERG binding with an EC50 va-
lue of 408 M. Compound 2da is not cytotoxic up to 100 M in a
Supplementary data
l
l
l
Supplementary data associated with this article can be found, in
cell cytotoxicity assay with two cell lines (HepG2 and WI-38 cells).
We investigated a binding mode of compound 2da with molec-
ular modeling and X-ray co-crystallization. Calculations for dock-
ing were carried out using LigandFit13 interfaced with Accelrys
DiscoveryStudio 2.5, using our previous complex (pdb entry;
2OLE) as a reference structure. We set the O atoms of carboxylic
group in side chain of E205 and E206 as interaction sites with de-
fault parameters in LigandFit. As can be seen by viewing the bind-
ing site region in Figure 4, the b-aminoacyl group has a similar
conformation to that of MK-0431,8 and the carbonyl moiety in ami-
no acyl group is possible to form the water-bridged hydrogen
bonding with Y547, as shown in our previous literature.10 Also, car-
boxylic moiety forms the strong ionic interaction with guanidium
group in R125 residue, inducing the most favorable activity. The
X-ray co-crystal structure of human DPP-IV complexed with 2da
showed the same result with modeling study.
In order to evaluate in vivo efficacy in rat and dog model, we
used compound 2db as a prodrug, which is very rapidly converted
to 2da in plasma, to increase absorption after oral administration.
The compound 2db showed good in vivo DPP-IV inhibitions in rat
and dog model as shown in Figure 5.
Oral administration of compound 2db at 10 mpk in CD rats re-
sulted in ca 90% inhibition of plasma DPP-IV activity up to 12 h.
Also, 2db exhibited ꢀ80% DPP-IV inhibition at 3 mg/kg after 12 h
in beagle dogs.
In conclusion, we have identified a series of b-aminoacyl con-
taining thiazolidine derivatives as DPP-IV inhibitors. Several thia-
zolidine derivatives with acid moiety were found to be potent
DPP-IV inhibitors. Among them, the compound 2da is the most ac-
tive in this series with an IC50 value of 1 nM. The compound 2da
showed excellent selectivity toward DPP-IV related enzymes
including DPP-2, DPP-8, and DPP-9. The compound 2da is chemi-
cally and metabolically stable, also showed no CYP inhibition,
hERG binding, and cytotoxicity. From the modeling and co-crystal
structure of 2da with DPP-IV, 2da bound the active pocket of DPP-
IV and showed additional binding of side chain of 2da. The in vivo
efficacy of 2db as a prodrug of 2da showed good DPP-IV inhibition
after oral administration in rat and dog model.
References and notes
1. Knudsen, L. B. J. Med. Chem. 2004, 47, 4128.
2. Drucker, D. J. Endocrinology 2001, 142, 521.
3. (a) Holst, J. J.; Deacon, E. F. Curr. Opin. Pharmacol. 2004, 4, 589; (b) Drucker, D. J.
Gastroenterology 2002, 122, 531.
4. (a) Kieffer, T. J.; McIntosh, C. H. S.; Pederson, T. A. Endocrinology 1995, 136,
3585; (b) Deacon, C. F.; Nauck, M. A.; Toft-Nielson, M.; Pridal, L.; Willms, B.;
Holst, J. J. Diabetes 1995, 44, 1126.
5. Mentlein, R. Regul. Pept. 1999, 85, 9.
6. (a) Ahren, B.; Holst, J. J.; Martensson, H.; Balkan, B. Eur. J. Pharmacol. 2000, 404,
239; (b) Deacon, C. F.; Hughes, T. E.; Joist, J. J. Diabetes 1998, 47, 764; (c)
Pospisilik, J. A.; Stafford, S. G.; Demuth, H.-U.; Brownsey, R.; Parkhous, W.;
Finegood, D. T.; McIntosh, D. H.; Pederson, R. A. Diabetes 2002, 51, 943.
7. (a) Brigance, R. P.; Meng, W.; Fura, A.; Harrity, T.; Wang, A.; Zahler, R.; Kirby, M.
S.; Hamann, L. G. Bioorg. Med. Chem. 2010, 20, 4395; (b) Mattei, P.; Boehringer,
M.; Giorgio, P. D.; Fischer, H.; Hennig, M.; Huwyler, J.; Kocer, B.; Kuhn, B.;
Loeffler, B. M.; MacDonald, A.; Narquizian, R.; Rauber, E.; Sebokova, E.;
Sprecher, U. Bioorg. Med. Chem. 2010, 20, 1109; (c) Edmondson, S. D.;
Mastracchio, A.; Cox, J. M.; Eiermann, G. J.; He, H.; Lyons, K. A.; Patel, R. A.;
Patel, S. B.; Petrov, A.; Scapin, G.; Wu, J. K.; Xu, S.; Zhu, B.; Thornberry, N. A.;
Roy, R. S.; Weber, A. E. Bioorg. Med. Chem. 2009, 19, 4097; (d) Idris, I.; Donnelly,
R. Diabetes, Obesity and Metabolism 2007, 9, 153; (e) Kim, D.; Kowalchick, J. E.;
Brockunier, L. L.; Parmee, E. R.; Eiermann, G. J.; Fisher, M. H.; He, H.; Leiting, B.;
Lyons, K.; Scapin, G.; Pater, S. B.; Petrov, A.; Pryor, K. D.; Roy, R. S.; Wu, J. K.;
Zhang, X.; Wyvratt, M. J.; Zhang, B. B.; Zhu, L.; Thornberry, N. A.; Weber, A. E. J.
Med. Chem. 2008, 51, 589; (f) Kondon, T.; Nekado, T.; Sugimoto, I.; Ochi, K.;
Takai, S.; Kinoshita, A.; Hatayama, A.; Yamamoto, S.; Kawabata, K.; Nakai, H.;
Toda, M. Bioorg. Med. Chem. 2008, 16, 190; (g) Kondo, T.; Nekado, T.; Sugimoto,
I.; Ochi, K.; Takai, S.; Kinnoshita, A.; Hatayama, A.; Yamamoto, S.; Kishikawa, K.;
Nakai, H.; Toda, M. Bioorg. Med. Chem. 2008, 16, 1613; (h) Wallace, M. B.; Feng,
J.; Zhang, Z.; Skene, R. J.; Shi, L.; Caster, C. L.; Kassel, D. B.; Xu, R.; Gwaltney, S. L.
Bioorg. Med. Chem. Lett. 2008, 18, 2362; (i) Edmondson, S. D.; Wei, L.; Xu, J.;
Shang, J.; Xu, S.; Pang, J.; Chaudhary, A.; Dean, D. C.; He, H.; Leiting, B.; Lyons, K.
A.; Patel, R. A.; Patel, S. B.; Scapin, G.; Wu, J. K.; Beconi, M. G.; Thornberry, N. A.;
Weber, A. E. Bioorg. Med. Chem. 2008, 18, 2409.
8. Kim, D.; Wang, L.; Beconi, M.; Eiermann, G. J.; Fisher, M. H.; He, H.; Hickey, G. J.;
Kowalchick, J. E.; Leiting, B.; Lyons, K.; Marsilio, F.; McCann, M. E.; Patel, R. A.;
Petrov, A.; Scapin, G.; Patel, S. B.; Roy, R. S.; Wu, J. K.; Wyvratt, M. J.; Zhang, B.
B.; Zhu, L.; Thornberry, N. A.; Weber, A. J. Med. Chem. 2005, 48, 141.
9. Edmondson, S. D.; Mastracchio, A.; Beconi, M.; Colwell, L. F.; Habulihaz, B.; He,
H.; Kumar, S.; Leiting, B.; Lyons, K. A.; Mao, A.; Marsilio, F.; Patel, R. A.; Wu, J. K.;
Zhu, L.; Thornberry, N. A.; Weber, A. E.; Parmee, E. R. Bioorg. Med. Chem. Lett.
2004, 14, 5151.
10. Ahn, J. H.; Shin, M. S.; Jung, S. H.; Kang, S. K.; Kim, K. R.; Rhee, S. D.; Kang, N. S.;
Kim, S. Y.; Sohn, S. K.; Kim, S. G.; Jin, M. S.; Lee, J. O.; Cheon, H. G.; Kim, S. S.
Bioorg. Med. Chem. Lett. 2007, 17, 2622.
11. Jun, M. A.; Park, W. S.; Kang, S. K.; Kim, K. Y.; Kim, K. R.; Rhee, S. D.; Bae, M. A.;
Kang, N. S.; Sohn, S. K.; Kim, S. G.; Lee, J. O.; Lee, D. H.; Cheon, H. G.; Kim, S. S.;
Ahn, J. H. Eur. J. Med. Chem. 2008, 43, 1889.
Acknowledgments
12. Kang, S. K.; Park, W. S.; Thopate, T. S.; Ahn, J. H. Bull. Korean Chem. Soc. 2010, 31,
2709.
13. Venkatachalam, C. M.; Jiang, X.; Oldfield, T.; Waldman, M. J. Mol. Graphics
Modell. 2003, 21, 289.
This research was supported by the Center for Biological
Modulators of the 21st Century Frontier R&D Program, Ministry
of Education, Science and Technology, Korea. We thank the staff
of the 4A and 6B beam lines of Pohang Accelerator Laboratory.