Letters
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 26 6453
cell proliferation and inhibition of apoptosis. Endocrinology 2003, 144,
5145–5148.
(6) (a) Lim, G. E.; Brubaker, P. L. Glucagon-like peptide 1 secretion by
the L-cell. The view from within. Diabetes 2006, 55, S70–S77. (b)
Murphy, K. G.; Dhillo, W. S.; Bloom, S. R. Gut peptides in the
regulation of food intake and energy homeostasis. Endocrine ReV.
2006, 27, 719–727.
(7) (a) Idris, I.; Donnelly, R. Dipeptidyl peptidase-IV inhibitors: a major
new class of oral antidiabetic drug. Diabetes, Obes. Metab. 2007, 9,
153–165. (b) Barnett, A. DPP-4 inhibitors and their potential role in
the management of type 2 diabetes. Int. J. Clin. Pract. 2006, 60, 1454–
1470.
(8) (a) Villhauer, E. B.; Brinkman, J. A.; Naderi, G. B.; Burkey, B. F.;
Dunning, B. E.; Prasad, K.; Mangold, B. L.; Russel, M. E.; Hughes,
T. E. 1-[[(3-Hydroxy-1-adamantyl)amino]acetyl]-2-cyano-(S)-pyrro-
lidine: a potent, selective, and orally bioavailable dipeptidyl peptidase
IV inhibitor with antihyperglycemic properties. J. Med. Chem. 2003,
46, 2774–2789. (b) 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. E. (2R)-4-Oxo-4-[3-
(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-R]pyrazin-7(8H)-yl]-
1-(2,4,5-trifluorophenyl)butan-2-amine: a potent, orally active dipep-
tidyl peptidase IV inhibitor for the treatment of type 2 diabetes. J. Med.
Chem. 2005, 48, 141–151. (c) Augeri, D. J.; Robl, J. A.; Betebenner,
D. A.; Magnin, D. R.; Khanna, A.; Robertson, J. G.; Wang, A.;
Simpkins, L. M.; Taunk, P.; Huang, Q.; Han, S.-P.; Abboa-Offei, B.;
Cap, M.; Xin, L.; Tao, L.; Tozzo, E.; Welzel, G. E.; Egan, D. M.;
Marcinkeviciene, J.; Chang, S. Y.; Biller, S. A.; Kirby, M. S.; Parker,
R. A.; Hamann, L. G. Discovery and preclinical profile of saxagliptin
(BMS-477118): a highly potent, long-acting, orally active dipeptidyl
peptidase IV inhibitor for the treatment of type 2 diabetes. J. Med.
Chem. 2005, 48, 5025–5037. (d) Feng, J.; Zhang, Z.; Wallace, M. B.;
Strafford, J. A.; Kaldor, S. W.; Kassel, D. B.; Navre, M.; Shi, L.;
Skene, R. J.; Asakawa, T.; Takeuchi, K.; Xu, R.; Webb, D. R.;
Gwaltney, S. L. Discovery of alogliptin: a potent, selective, bioavail-
able, and efficacious inhibitor of dipeptidyl peptidase IV. J. Med.
Chem. 2007, 50, 2297–2300.
(9) Himmelsbach, F.; Langkopf, E.; Eckhardt, M.; Mark, M.; Maier, R.;
Lotz, R.; Tadayyon, M. WO 2004018468, 2004.
(10) Compound 2 has also been found and further elaborated in the
following: Kanstrup, A. B.; Christiansen, L. B.; Lundbeck, J. M.; Sams,
C. K.; Kristiansen, M. WO 2002002560, 2002.
(11) Thoma, R.; Loeffler, B.; Stihle, M.; Huber, W.; Ruf, A.; Hennig, M.
Structural basis of proline-specific exopeptidase activity as observed
in human dipeptidyl peptidase-IV. Structure 2003, 11, 947–959.
(12) Engel, M.; Hoffmann, T.; Manhart, S.; Heiser, U.; Chambre, S.; Huber,
R.; Demuth, H.-U.; Bode, W. Rigidity and flexibility of dipeptidyl
peptidase IV: crystal structures of and docking experiments with DPIV.
J. Mol. Biol. 2006, 355, 768–783.
(13) Longenecker, K. L.; Stewart, K. D.; Madar, D. J.; Jakob, C. G.; Fry,
E. H.; Wilk, S.; Lin, C. W.; Ballaron, S. J.; Stashko, M. A.; Lubben,
T. H.; Yong, H.; Pireh, D.; Pei, Z.; Basha, F.; Wiedeman, P. E.; von
Geldern, T. W.; Trevillyan, J. M.; Stoll, V. S. Crystal structures of
DPP-IV (CD26) from rat kidney exhibit flexible accommodation of
peptidase-selective inhibitors. Biochemistry 2006, 45, 7474–7482.
(14) Sheehan, S. M.; Mest, H.-J.; Watson, B. M.; Klimkowski, V. J.; Timm,
D. E.; Cauvin, A.; Parsons, S. H.; Shi, Q.; Canada, E. J.; Wiley, M. R.;
Ruehter, G.; Evers, B.; Petersen, S.; Blaszczak, L. C.; Pulley, S. R.;
Margolis, B. J.; Wishart, G. N.; Renson, B.; Hankotius, D.; Mohr,
M.; Zechel, J.-C.; Kalbfleisch, J. M.; Dingess-Hammond, E. A.;
Boelke, A.; Weichert, A. G. Discovery of non-covalent dipeptidyl
peptidase IV inhibitors which induce a conformational change in the
active site. Bioorg. Med. Chem. Lett. 2007, 17, 1765–1768.
(15) Lankas, G. R.; Leiting, B.; Roy, R. S.; Eiermann, G. J.; Beconi, M. G.;
Biftu, T.; Chan, C.-C.; Edmondson, S.; Feeney, W. P.; He, H.; Ippolito,
D. E.; Kim, D.; Lyons, K. A.; Ok, H. O.; Patel, R. A.; Petrov, A. N.;
Pryor, K. A.; Qian, X.; Reigle, L.; Woods, A.; Wu, J. K.; Zaller, D.;
Zhang, X.; Zhu, L.; Weber, A. E.; Thornberry, N. A. Dipeptidyl
peptidase IV inhibition for the treatment of type 2 diabetes: potential
importance of selectivity over dipeptidyl peptidases 8 and 9. Diabetes
2005, 54, 2988–2994.
key characteristics of 1 and, in combination with its high potency
and good oral bioavailability, are thought to contribute to the
strong and long-lasting inhibitory effect on DPP-4 observed in
vivo.
Compound 1 was further characterized in vivo in diabetic
mice (Figure 3). Single oral administration of 1 to db/db mice
45 min prior to an oral glucose tolerance test reduced plasma
glucose excursion in a dose-dependent manner from 0.1 mg/kg
(15% inhibition) to 1 mg/kg (66% inhibition). The improvement
of oral glucose tolerance correlated with the DPP-4 activity in
plasma, which was inhibited by 76% with the 1 mg/kg dose 30
min after the glucose load was administered.
Compound 1 exhibits no interaction with CYP-450 enzymes
up to 50 µM. Because inhibition of DPP-8 and DPP-9, which
are closely related to DPP-4, has been associated with toxicities
in animals, it is important to note that 1 displays a more than
10000-fold selectivity against both of these enzymes.15
In summary, a new chemical class of highly potent DPP-4
inhibitors structurally based on the xanthine scaffold has been
discovered. The 3-aminopiperidine attached to C-8 proved to
be a crucial constituent for high inhibitory activity, and but-2-
ynyl on N-7 was essential to eliminate interaction with the hERG
channel and M1 receptor. Further optimization led to 1 bearing
a quinazolin-2-ylmethyl at N-1. 1 represents a highly potent,
selective, and long-acting DPP-4 inhibitor of a novel chemotype
that shows promise for once-daily treatment of type 2 diabetic
patients. Compound 1 is currently undergoing clinical phase
IIb trials.
Acknowledgment. The authors are indebted to their associ-
ates for their dedicated and excellent technical assistance.
Supporting Information Available: Experimental details, ana-
lytical data of the compounds, and X-ray crystallograpic data of 1.
This material is available free of charge via the Internet at http://
pubs.acs.org.
References
(2) (a) Lambeir, A. M.; Durinx, C.; Scharpe, S.; de Meester, I. Dipeptidyl-
peptidase IV from bench to bedside: an update on structural properties,
functions, and clinical aspects of the enzyme DPP IV. Crit. ReV. Clin.
Lab. Sci. 2003, 40, 209–294. (b) Augustyns, K.; Van der Veken, P.;
Senten, K.; Haemers, A. The therapeutic potential of inhibitors of
dipeptidyl peptidase IV (DPP IV) and related proline specific dipeptidyl
aminopeptidases. Curr. Med. Chem. 2005, 12, 971–998.
(3) (a) Mentlein, R.; Gallwitz, B.; Schmidt, W. E. Dipeptidyl-peptidase
IV hydrolyzes gastric inhibitory polypeptide, glucagon-like peptide-1
(7-36)amide, peptide histidine methionine and is responsible for their
degradation in human serum. Eur. J. Biochem. 1993, 214, 829–835.
(b) Kieffer, T. J.; McIntosh, C. H. S.; Pederson, R. A. Degradation of
glucose-dependant insulinotropic polypeptide and truncated glucagon-
like peptide-1 in vitro and in vivo by dipeptidyl peptidase IV.
Endocrinology 1995, 136, 3585–3596.
(4) (a) Thorens, B. Glucagon-like peptide-1 and control of insulin
secretion. Diabetes Metab. 1995, 21, 311–318. (b) Meier, J. J.; Nauck,
M. A.; Schmidt, W. E.; Gallwitz, B. Gastric inhibitory polypeptide:
the neglected incretin revisited. Regul. Pept. 2002, 107, 1–13.
(5) (a) Pospisilik, J. A.; Stafford, S. G.; Demuth, H.-U.; Brownsey, R.;
Parkhouse, W.; Finegood, D. T.; McIntosh, C. H. S.; Pederson, R. A.
Long-term treatment with the dipeptidyl peptidase IV inhibitor P32/
98 causes sustained improvements in glucose tolerance, insulin
sensitivity, hyperinsulinemia, and ꢀ-cell glucose responsiveness in
VDF (fa/fa) Zucker rats. Diabetes 2002, 51, 943–950. (b) Drucker,
D. J. Glucagon-like peptide-1 and the islet ꢀ-cell: augmentation of
JM701280Z