S. W. Wright et al. / Bioorg. Med. Chem. Lett. 17 (2007) 5638–5642
5641
Table 5. Pharmacokinetic parameters for compound 15b in rat and
dog
Pacini, G.; Foley, J. E.; Schweizer, A. Diabetes Care 2005,
28, 1936.
6. 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. J. Med. Chem. 2003, 46,
2774.
7. 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. J. Med. Chem.
2005, 48, 141.
Species Unbound
CL,
fraction (%) mL/min/kg L/kg h (i.v.) h (p.o.)
Vss, t1/2
,
t1/2
,
F%
Rat
Dog
6
17
6
4.4
4.8
0.67 2.8
1.9
3.3
nda
57
5.1
nda
50b
Human
1.3b
2.0b
a Not determined.
b Projected values based on rat single-species allometric scaling (see
Ref. 19).
8. 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. J. Med. Chem
2005, 48, 5025.
9. Wright, S. W.; Ammirati, M. J.; Andrews, K. M.;
Brodeur, A. M.; Danley, D. E.; Doran, S. D.; Soglia, C.
B.; Lillquist, J. S.; McClure, L. D.; McPherson, R. K.;
Orena, S. J.; Parker, J. C.; Polivkova, J.; Qiu, X.; Soeller,
W. C.; Treadway, J. L.; VanVolkenburg, M. A.; Wilder,
D. C.; Olson, T. V. J. Med. Chem. 2006, 49, 3068.
10. This template was independently discovered at Abbott
Laboratories from a high throughput screening hit, see:
Backes, B. J.; Longenecker, K.; Hamilton, G. L.; Stewart,
K.; Lai, C.; Kopecka, H.; von Geldern, T. W.; Madar, D.
J.; Pei, Z.; Lubben, T. H.; Zinker, B. A.; Tian, Z.;
Ballaron, S. J.; Stashko, M. A.; Mika, A. K.; Beno, D. W.
A.; Kempf-Grote, A. J.; Black-Schaefer, C.; Sham, H. L.;
Trevillyan, J. M. Bioorg. Med. Chem. Lett. 2007, 17, 2005.
11. Miolo, G.; Violaa, G.; Vedaldia, D.; Dall’Acquaa, F.;
Fravolinib, A.; Tabarrinib, O.; Cecchetti, V. Toxicol. In
Vitro 2002, 16, 683.
Figure 1. Compound (+)15b co-crystallized with human DPP4 show-
ing hydrogen bond from Arg 358 to methoxypyridine.
12. Terao, Y.; Kotaki, H.; Imai, N.; Achiwa, K. Chem.
Pharm. Bull. 1985, 33, 2762–2766.
13. Analogs incorporating amides, amines, sulfonamides, and
urea substituents placed on the pyrrolidine ring nitrogen
atom were also evaluated; in general these were less potent
as DPP4 inhibitors.
Supplementary data
Supplementary data associated with this article can be
14. The application disclosing MK-0431 published concur-
rently with our efforts to increase potency by appropriate
substitution of this phenyl ring; for example, a 2,5-
difluorophenyl substitution improved potency to 61 nM
from 790 nM for 10a. We obtained internal co-crystal
structures using compounds similar to 2 and our pyrrol-
idine inhibitors and found a similar aryl binding mode in
these structures. See Edmondson, D. D.; Parmee, E.;
Weber, A. E.; Xu, J. Patent WO 03/000180, 2003; Chem.
Abstr. 2003, 138, 73536.
15. The absolute configuration of (+)12 ([a]D = 61° (c = 1.5,
EtOH) was based upon agreement with protein crystal
structures as well as identity to a sample of (+)12 prepared
by diastereoselective azomethine ylide cycloaddition
to (S)-4-phenyl-3-[(E)-3-(2,4,5-trifluoro-phenyl)-acryloyl]-
oxazolidin-2- one; see U.S. Patent 5,618,949, 1997; Chem.
Abstr. 1997, 126, 330549.
16. All procedures involving animals were reviewed and
approved by the Pfizer Institutional Animal Care and
Use Committee. Oral pharmacokinetic evaluations were
dosed in 0.5% methylcellulose formulation at 5 mg kgÀ1 in
the rat and in sterile saline solutions at 1 mg kgÀ1 in the
dog. Intravenous evaluations were conducted at 1 mg kgÀ1
in sterile saline. Pharmacodynamic determinations were
made by assay of DPP4 activity in plasma samples taken
from the PK study; see reference 7 for plasma DPP4
References and notes
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