602 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 3
Kim et al.
P. V.; Haemers, A. Inhibitors of Proline-Specific Dipeptidyl Peptidases:
DPP IV Inhibitors as Novel Approach for the Treatment of Type 2
Diabetes. Expert Opin. Ther. Pat. 2005, 15, 1387–1407. (d) von
Geldern, T. W.; Trevillyan, J. M. “The Next Big Thing” in Diabetes:
Clinical Progress on DPP-IV Inhibitors. Drug DeV. Res. 2006, 67,
627–642.
2003, 46, 2774–2789. (b) Magnin, D. R.; Robl, J. A.; Sulsky, R. B.;
Augeri, D. J.; Huang, Y.; Simpkins, L. M.; Taunk, P. C.; Betebenner,
D. A.; Robertson, J. G.; Abboa-Offei, B. E.; Wang, A.; Cap, M.; Xin,
L.; Tao, L.; Sitkoff, D. F.; Malley, M. F.; Gougoutas, J. Z.; Khanna,
A.; Huang, Q.; Han, S.; Parker, R. A.; Hamann, L. G. Synthesis of
Novel Potent Dipeptidyl Peptidase IV Inhibitors with Enhanced
Chemical Stability: Interplay between the N-Terminal Amino Acid
Alkyl Side Chain and the Cyclopropyl Group of R-Aminoacyl-L-cis-
4,5-methanoprolinenitrile-Based Inhibitors. J. Med. Chem. 2004, 47,
2587.
(4) (a) Orsakov, C. Glucagon-Like Peptide 1, a New Hormone of the
Enteroinsular Axis. Diabetologia 1992, 35, 701–711. (b) Zander, M.;
Madsbad, S.; Madsen, J. L.; Holst, J. J. Effect of 6-Week Course of
Glucagon-Like Peptide 1 on Glycaemic Control, Insulin Sensitivity,
and ꢀ-Cell Function in Type 2 Diabetes; a Parallel-Group Study.
Lancet 2002, 359, 824–830.
(5) (a) For recent reviews, see: Knudsen, L. B. Glucagon-Like Peptide 1:
A Basis of a New Class of Treatment for Type 2 Diabetes. J. Med.
Chem. 2004, 47, 4128–4134. (b) Vahl, T. P.; D’Alessio, D. A. Gut
Peptides in the Treatment of Diabetes Mellitus. Expert Opin. InVest.
Drugs 2004, 13, 177–188. (c) Meier, J. J.; Nauck, M. A. Glucagon-
Like Peptide 1 (GLP-1) in Biology and Pathology. Diabetes Metab.
Res. ReV. 2005, 21, 91–117. (d) Drucker, D. J.; Nauck, M. A. The
Inceretin System: Glucagon-Like Peptide-1 Receptor Agonists and
Dipeptidyl Peptidase 4 Inhibitors in Type 2 Diabetes. Lancet 2006,
368, 1696–1705. (e) Combettes, M. M. J. GLP-1 and Type 2 Diabetes:
Physiology and New Clinical Advances. Curr. Opin. Pharm. 2006,
6, 598–605.
(6) (a) Wettergren, A.; Schjoldager, B.; Martensen, P. E.; Myhre, J.;
Christiansen, J.; Holst, J. J. Truncated GLP-1 (Proglucagon 72–107
Amide) Inhibits Gastric and Pancreatic Functions in Man. Dig. Dis.
Sci. 1993, 38, 665–673. (b) Nauck, M. A.; Niedereichholz, U.; Ettler,
R.; Holst, J. J.; Orskov, C.; Ritzel, R.; Schmigel, W. H. Glucagon-
Like Peptide-1 Inhibition of Gastric-Emptying Outweighs Its Insuli-
notropic Effects in Healthy Humans. Am. J. Physiol. 1997, 273, E981–
E988.
(7) Flint, A.; Raben, A.; Ersboll, A. K.; Holst, J. J.; Astrup, A. The Effect
of Physiological Levels of Glucagons-Like Peptide-1 on Appetite,
Gastric Emptying, Energy and Substrate Metabolism in Obesity. Int.
J. Obes. 2001, 25, 781–792.
(8) (a) Ahren, B. E. Enhancement or Prolongation of GLP-1 Activity as
a Strategy for Treatment of Type 2 Diabetes. Drug DiscoVery Today
2004, 1, 207–212. (b) Deacon, C. F. Therapeutic Strategies Based on
Glucagon-Like Peptide 1. Diabetes 2004, 53, 2181–2189. (c) Deacon,
C. F.; Holst, J. J. Glucagon-Like Peptide 1 and Inhibitors of Dipeptidyl
Peptidase IV in the Treatment of Type 2 Diabetes Mellitus. Curr. Opin.
Pharmacol. 2004, 4, 589–596. (d) Mentlein, R. Therapeutic Assess-
ment of Glucagon-Like Peptide-1 Agonists Compared with Dipeptidyl
Peptidase IV Inhibitors as Potential Antidiabetic Drugs. Expert Opin.
InVest. Drugs 2005, 14, 57–64. (e) Nielsen, L. L. Incretin Mimetics
and DPP-4 Inhibitors for the Treatment of Type 2 Diabetes. Drug
DiscoVery Today 2005, 10, 703–710. (f) Gautier, J. F.; Fetita, S.;
Sobngwi, E.; Salaun-Martin, C. Biological Actions of the Incretins
GIP and GLP-1 and Therapeutic Perspectives in Patients with Type 2
Diabetes. Diabetes Metab. 2005, 31, 233–242.
(12) Kim, D.; Kowalchick, J. E.; Edmondson, S. D.; Mastracchio, A.; Xu,
J. M.; Eiermann, G. J.; Leiting, B.; Wu, J. K.; Pryor, K.; Patel, R. A.;
He, H.; Lyons, K. A.; Thornberry, N. A.; Weber, A. E. Triazolopip-
erazine-amides as dipeptidyl peptidase IV inhibitors: close analogues
of JANUVIA (sitagliptin phosphate). Bioorg. Med. Chem. Lett. 2007,
17, 3373.
(13) (a) Xu, J.; Ok, H. O.; Gonzalez, E. J.; Colwell, L. F., Jr.; Habulihaz,
B.; He, H.; Leiting, B.; Lyona, K. A.; Marsilio, F.; Patel, R. A.; Wu,
J. K.; Thornberry, N. A.; Weber, A. E.; Parmee, E. R. Discovery of
Potent and Selective ꢀ-Homophenylalanine Based Dipeptidyl Peptidase
IV Inhibitors. Bioorg. Med. Chem. Lett. 2004, 14, 4759–4762. (b)
Brockunier, L.; He, J.; Colwell, Jr., L. F.; Habulihaz, B.; He, H.;
Leiting, B.; Lyons, K. A.; Marsilio, F.; Patel, R.; Teffera, Y.; Wu,
J. K.; Thornberry, N. A.; Weber, A. E.; Parmee, E. R. Substituted
Piperazines as Novel Dipeptidyl Peptidase IV Inhibitors. Bioorg. Med.
Chem. Lett. 2004, 14, 4763–4766.
(14) Coppola, G. M. Alkylation of N-Boc-1,2,3,4-tetrahydroisoquinolines
in the 1-Position and its Application to the Synthesis of Isoquinoline
Alkaloids. J. Heterocycl. Chem. 1991, 28 (7), 1769–1772.
(15) Balsells, J.; DiMichele, L.; Liu, J.; Kubryk, M.; Hansen, K.; Armstrong,
J. D. Synthesis of [1,2,4]Triazolo[4,3-a]piperazines via Highly Reactive
Chloromethyloxadiazoles. Org. Lett. 2005, 7 (6), 1039.
(16) For assay conditions. see: Leiting, B.; Pryor, K. D.; Wu, J. K.; Marsilio,
F.; Patel, R. A.; Craik, C. S.; Ellman, J. A.; Cummings, R. T.;
Thornberry, N. A. Catalytic Properties and Inhibition of Proline-
Specific Dipeptidyl Peptidases II, IV and VII. Biochem. J. 2003, 371,
525–532.
(17) Abbot, C. A.; Yu, D. M.; Woollatt, E.; Sutherland, G. R.; McCaughan,
G. W.; Gorrell, M. D. Cloning, Expression and Chromosomal
Localization of a Novel Human Dipeptidyl Peptidase (DPP) IV
Homolog, DPP8. Eur. J. Biochem. 2000b, 267, 6140–6150.
(18) Olsen, C.; Wagtmann, N. Identification and Characterization of Human
DPP9, a Novel Homologue of Dipeptidyl Peptidase IV. Gene 2002,
299, 185–193.
(19) Scallan, M. J.; Raj, B. K. M.; Calvo, B.; Garin-Chesa, P.; Sanz-
Moncasi, M. P.; Healey, J. H.; Old, L. J.; Rettig, W. J. Molecular
Cloning of Fibroblast Activation Protein Alpha, a Member of the
Serine Protease Family Selectively Expressed in Stromal Fibroblast
of Epithelical Cancers. Proc. Natl. Acad. Sci. U.S.A. 1994, 91, 5657–
5661.
(20) McDonald, J. K.; Leibach, F. H.; Grindeland, R. E.; Ellis, S.
Purification of Dipeptidyl Aminopeptidase II (Dipeptidyl Arylamidase
II) of the Anterior Pituitary Gland. J. Biol. Chem. 1968, 243, 4143–
4150.
(21) Lankas, G; Leiting, B.; Sinha Roy, R.; Eiermann, G.; Beconi, M. G.;
Biftu, T.; Chan, C.-C.; Edmonson, S.; Freeney, W. P.; He, H.; Ippolito,
D. E.; Kim, D.; Lyons, K. A.; Ok, H.; 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 Peptidase 8 and 9. Diabetes
2005, 54, 2988–2994.
(22) It should be noted that the % inhibition as determined using the in
vitro assay underestimates the % inhibition achieved in vivo, as
compound 34b is a competitive, rapidly reversible inhibitor, and assay
of plasma DPP-4 activity requires (1) the dilution of plasma, which
results in a dilution of the total inhibitor, and (2) the presence of
substrate, which competes with inhibitor for binding to the enzyme.
(23) Marguet, D.; Baggio, L.; Kobayashi, T.; Bernard, A.-M.; Pierres, M.;
Nielsen, P. F.; Ribel, U.; Watanabe, T.; Drucker, D. J.; Wagtmann,
N. Enhanced Insulin Secretion and Improved Glucose Tolerance in
Mice Lacking CD26. Proc. Natl. Acad. Sci. U.S.A. 2000, 97,
6864–6879.
(9) (a) Kieffer, T. J.; McIntosh, C. H. S.; Pederson, T. A. Degradation of
Glucose-Dependent Insulinotropic Polypeptide and Truncated Gluca-
gon-Like Peptide 1 In Vitro and In Vivo by Dipeptidyl Peptidase IV.
Endocrinology 1995, 136, 3585–3596. (b) Deacon, C. F.; Nauck,
M. A.; Toft-Nielson, M.; Pridal, L.; Willms, B.; Holst, J. J. Both
Subcutaneously and Intravenously Administered Glucagons-Like Pep-
tide 1 Are Rapidly Degraded from the NH2-Terminus in Type II
Diabetic Patients and in Healthy Subjects. Diabetes 1995, 44, 1126–
1131.
(10) (a) 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.; Sinha Roy, R.; Wu, J. K.; Wyvratt, M. J.; Zhang, B. B.;
Zhu, L.; Thornberry, N. A.; Weber, A. E. (2R)-4-Oxo-4-[3-(trifluoro-
methyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-tri-
fluorophenyl)butan-2-amine: A Potent, Orally Active Dipeptidyl
Peptidase IV Inhibitor for the Treatment of Type 2 Diabetes. J. Med.
Chem. 2005, 48, 141–151. (b) Edmondson, S. E.; Fisher, M. H.; Kim,
D.; Maccoss, M.; Parmee, E. R.; Weber, A. E.; Xu, J. U.S. Patent
6,699,871 B2, Mar. 2, 2004.
(11) (a) Villhauer, E. B.; Brinkman, J. A.; Naderi, G. B.; Burkey, B. F.;
Dunning, B. E.; Prasad, K.; Mangold, B. L.; Russell, M. E.; Hughes,
T. E. 1-[[(3-Hydroxy-1-adamantyl)amino]acetyl]-2-cyano-(S)-pyrro-
lidine: A Potent Selective, and Orally Bioavailable Dipeptidyl Pep-
tidase IV Inhibitor with Antihyperglycemic Properties. J. Med. Chem.
JM070330V