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420 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 21
Brief Articles
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2) (a) Orsakov, C. Glucagon-Like Peptide 1, a New Hormone of the
Enteroinsular Axis. Diabetologia 1992, 35, 701-711. (b) Knudsen,
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of Saxagliptin (BMS-477118): A Highly Potent, Long-Acting, Orally
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3) Rachman, J.; Barrow, B. A.; Levy, J. C.; Turner, R. C.; Near-
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(10) (a) Madar, D. J.; Pei, Z.; Pireh, D.; Djuric, S. W.; Wiedeman, P. E.;
Yong, H.; Feenstra, M. J.; Kopecka, H.; Li, X.; Longenecker, K.;
Sham, H.; Stewart, K. D.; Szczepankiewicz, B. G. Pharmaceutical
Compositions as Inhibitors of Dipeptidyl Peptidase-IV (DPP-IV)
World Pat. Appl. 2004/026822, April 1, 2004. (b) While this
manuscript was in preparation, an article describing 2,5-dicyanopy-
rrolidines as DPP-IV appeared: Wright, S. W.; Ammirati, M. J.;
Andrews, K. M.; Brodeur, A. M.; Danley, D. E.; Doran, S. D.,
Lillquist, J. S.; McClure, L. D.; McPherson, R. K.; Orena, S. J.;
Parker, J. C.; Polivkova, J.; Qiu, X.; Soeller, W. C.; Soglia, C. B.;
Treadway, J. L.; VanVokenberg, M. A.; Wang, H.; Wilder, D. C.;
Olson, T. V. cis-2,5-Dicyanopyrrolidine Inhibitors of Dipeptidyl
Peptidase IV: Synthesis and in Vitro, in Vivo, and X-ray Crystal-
lographic Characterization J. Med. Chem. 2006, 49, 3068-3076. (c)
Several groups have highlighted the ability to prepare fluorinated
cyanopyrrolidines that either maintained or even showed potency
improvements. See, for instance: Fukushima, H.; Hiratate, A.;
Takahashi, M.; Saito, M.; Munetomo, E.; Kitano, K.; Saito, H.;
Takaoka, Y.; Yamamoto, K. Synthesis and Structure-Activity
Relationships of Potent 3- or 4-Substituted-2-cyanopyrrolidine Dipep-
tidyl Peptidase IV Inhibitors. Bioorg. Med. Chem. Lett. 2004, 12,
6053-6061.
(11) Beal, L. M.; Liu, B.; Chu, W.; Moeller, K. D. Anodic Amide
Oxidation/Olefin Metathesis Strategies: Developing a Unified Ap-
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Tetrahedron 2000, 56, 10113-10125.
(12) DPP-IV activity was determined by measuring the rate of hydrolysis
of a surrogate substrate Gly-Pro-7-amido-methylcoumarin. For full
details, see Supporting Information.
(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 Accommoda-
tion of Peptidase-Selective Inhibitors. Biochemistry 2006, 45, 7474-
7482.
(
4) (a) Mentlein, R.; Gallwitz, B.; Schmidt, W. E. Dipeptidyl-Peptidase
IV Hydrolyses Gastric Inhibitory Polypeptide, Glucagon-Like Pep-
tide-1(7-36) Amide, Peptide Histidine Methionine and is Responsible
for their Degradation in Human Serum. Eur. J. Biochem. 1993, 15,
8
29-835. (b) Kieffer, T. J.; McIntosh, C. H.; Pederson, R. A.
Degradation of Glucose-Dependent Insulinotropic Polypeptide and
Truncated Glucagon-Like Peptide 1 in Vitro and in Vivo by
Dipeptidyl Peptidase IV. Endocrine 1995, 136, 3585-3596.
(
5) (a) Ahr e´ n, B.; Simonsson, E.; Larsson, H.; Landin-Olsson, M.;
Torgeirsson, H.; Jansson, P.-A.; Sandqvist, M.; Bavenholm, P.;
Efendic, S.; Eriksson, J. W.; Dickinson, S.; Holmes, D. Inhibition
of Dipeptidyl Peptidase IV Improves Metabolic Control over a
4
8
-Week Study Period in Type 2 Diabetes. Diabetes Care 2002, 25,
69-875. (b) Ahr e´ n, B.; Gomis, R.; Standl, E.; Mills, D.; Schweizer,
A. Twelve- and 52-Week Efficacy of the Dipeptidyl Peptidase IV
Inhibitor LAF237 in Metformin Treated Patients with Type 2
Diabetes. Diabetes Care 2004, 27, 2874-2880. (c) Ahr e´ n, B.;
Landing-Olsson, L.; Jansson, P.-A.; Sevensson, M.; Holmes, D.;
Schweizer, A. Inhibition of Dipeptidyl Peptidase-4 Reduces Glyce-
mia, Sustains Insulin Levels, and Reduces Glucagon Levles in Type
2
Diabetes. J. Clin. Endocrinol. Metab. 2004, 89, 2078-2084. (d)
Ahr e´ n, B.; Pacini, Giovanni; Foley, J. E.; Schweizer, A. Improved
Meal-Related â-Cell Function and Insulin Sensitivity by the Dipep-
tidyl Peptidase-IV Inhibitor Vildagliptin in Metformin-Treated
Patients with Type 2 Diabetes over 1 Year. Diabetes Care 2005, 28,
1936-1940.
(
6) Larsen, J.; Hylleberg, B.; Ng, K.; Damsbo, P. Glucagon-Like
Peptide-1 Infusion Must Be Maintained for 24 h/day to Obtain
Acceptable Glycemia in Type 2 Diabetic Patients Who Are Poorly
Controlled on Sulphonylurea Treatment. Diabetes Care 2001, 24,
1416-1421.
(
7) 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, Z.; 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 Pep-
tidases 8 and 9. Diabetes 2005, 54, 2988-2994.
(14) When compound 16 was heated in phosphate buffer at 37 °C, it was
found to have a half-life of approximately 2 h.
15) (a) Abbott, C. A.; Yu, D. M.; Woollatt, E.; Sutherland, G. R.;
McCaughan, G. W.; Gorell, M. D. Cloning, Expression, and
Chromosomal Localization of a Novel Human Dipeptidyl Peptidase
(
(
(
DPP) IV Homolog, DPP8. Eur. J. Biochem. 2000, 267, 6140-6150.
(
8) (a) Ashworth, D. M.; Atrash, B.; Baker, G. R.; Baxter, A. J.; Jenkins,
P. D. 2-Cyanopyrrolidides as Potent, Stable Inhibitors of Dipeptidyl
Peptidase IV. Bioorg. Med. Chem. Lett. 1996, 6, 1163-1166. (b)
Villhauer, E. B.; Brinkman, J. A.; Naderi, G. B.; Dunning, B. E.;
Mangold, B. L.; Mone, M. D.; Russell, M. E.; Weldon, S. C.; Hughes,
T. E. 1-[2-[(5-Cyanopyridin-2-yl)amino]-ethylamino]acetyl-2-(S)-
pyrrolidine-carbonitrile: A potent, Selective, and Orally Bioavailable
Dipeptidyl Peptidase IV inhibitor with Anithyperglycemic Properties.
J. Med. Chem. 2002, 45, 2362-2365. (c) Li, J.; Wilk, E.; Wilk, S.
Aminoacylpyrrolidine-2-nitriles: Potent and Stable Inhibitors of
Dipeptidyl-Peptidase IV (CD26). Arch. Biochem. Biophys. 1995, 323,
b) Olsen, C.; Wagtmann, N. Identification and Characterization of
Human DPP9, a Novel Homologue of Dipeptidyl Peptidase IV. Gene
002, 299, 185-193.
2
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16) (a) 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 Fibroblasts
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5
661. (b) Mcdonald, J. K.; Leibach, F. H.; Grindeland, R. E.; Ellis,
S. Purification of Dipeptidyl Aminopeptidase II (Dipeptidyl Aryla-
midase II) of the Anterior Pituitary Gland. J. Biol. Chem. 1968, 243,
148-154.
4
143-4150. (c) Fulop, V.; Bocskei, Z.; Polgar, L. Prolyl Oligopep-
(
9) (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
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Betebenner, D. A.; Magnin, D. R.; Khanna, A.; Robertson, J. G.;
tidase: an Unusual Beta-Propellar Domain Regulates Proteolysis. Cell
1998, 94, 161-170.
(
17) The des-alkynyl version of 42 has the following selectivity profile:
KiDPP-IV ) 1.0 nM, KiDPP8 ) 5.2 µM; KiDPP9 ) 1.76 µM.
18) The Ki for rat DPP-IV is 1.0 nM.
(
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