1886
P. Chen et al. / Bioorg. Med. Chem. Lett. 21 (2011) 1880–1886
Table 6
Table 7
N-substitution piperidine derivatives
Pharmacokinetic properties of selected inhibitors in rat (1/2 mpk iv/p.o)
Entry
Clp (ml/min/kg)
t1/2 (h)
Cmax
(lM)
F%
F
20g
20k
20q
24a
38f
53g
53l
204
180
116
177
201
154
171
nd
0.019
0.19
0.032
0.12
0.024
0.069
0.019
13
25
2.2
9.7
24
22
4.5
3.5
3.0
1.0
2.1
2.8
0.92
NH2
H
F
N
R3
Entry
R3
DPP-4
IC50
QPP
IC50
DPP-8
IC50
DPP-9
IC50 (lM)
(
l
M)
(lM)
(
l
M)
1
53a
53b
Sitagliptin
CH3CO
CH3SO2
0.018
0.45
0.13
>100
66
65
69
>100
95
>100
>100
59
Acknowledgments
We thank colleagues Jacqueline Hicks and Robert Wilkening for
their valuable discussions and revisions regarding this manuscript.
We also thank Tesfaye Biftu for insight and guidance during the
manuscript preparation.
N
N
53c
53d
0.45
0.11
19
37
29
30
19
16
N
53e
53f
0.43
34
39
5.5
46
4.2
18
References and notes
N
0.077
CN
1. (a) Holst, J. J. Diabetologia 2006, 491, 253; (b) Baggio, L. L.; Drucker, D. J.
Gastroenterology 2007, 132, 2131.
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Expert Opin. Investig. Drugs 2004, 13, 177.
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E. J. Pharmacol. Ther. 2009, 124, 113.
4. Havale, S. H.; Pal, M. Bioorg. Med. Chem. 2009, 17, 1783.
N
53g
53h
0.071
0.11
28
52
19
32
3.1
7.2
F
N
5. (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. J. Med. Chem. 2005, 48, 141;
(b) Thornberry, N. A.; Weber, A. E. Curr. Top. Med. Chem. 2007, 7, 557.
6. (a) Gallwitz, B. Drugs Today 2007, 43, 13; (b) Deacon, C. F. Expert Opin. Investig.
Drugs 2007, 16, 533.
7. Parmee, E. R.; He, J.; Mastracchio, A.; Edmondson, S. D.; Colwell, L.; Eiermann,
G.; Feeney, W. P.; Habulihaz, B.; He, H.; Kilburn, R.; Leiting, B.; Lyons, K.;
Marsilio, F.; Patel, R. A.; Retrov, A.; Salvo, J. D.; Wu, J. K.; Thornberry, N. A.;
Weber, A. E. Bioorg. Med. Chem. Lett. 2004, 14, 43.
N
53i
53j
53k
53l
0.082
0.018
0.67
11
22
30
35
37
18
31
35
25
CO2Et
N
27
24
16
CO2NH2
N
N
N
0.075
N
8. 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.; Leigle, L.;
Lyons, K. A.; Ok, H. O.; Patel, R. A.; Petrov, A. N.; Pryor, K. A.; Qian, X.; Woods, A.;
Wu, J. K.; Zaller, D.; Zhang, X.; Zhu, L.; Weber, A. E.; Thornberry, N. A. Diabetes
2005, 54, 2988.
9. (a) Whitehead, C. W.; Traverso, J. J.; Marshall, F. J.; Morrison, D. E. J. Org. Chem.
1961, 26, 2809; (b) White, J. D.; Kawasaki, M. J. Org. Chem. 1992, 57, 5292; (c)
Eckenberg, P.; Groth, U.; Huhn, T.; Richter, N.; Schmeck, C. Tetrahedron 1993,
49, 1619.
10. (a) Lu, Y.; Schiller, P. W. Synthesis 2001, 11, 1639; (b) Gage, J. R.; Evans, D. A.
Org. Synth. 1990, 68, 83.
11. 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. Biochem. J. 2003, 371, 525.
12. Abbott, C. A.; Yu, D. M.; Woollatt, E.; Sutherland, G. R.; McCaughan, G. W.;
Gorrell, M. D. Eur. J. Biochem. 2000, 267, 6140.
N
53m
53n
OCH3
OH
0.078
0.072
42
48
47
26
23
12
N
N
N
O
56
58
60
0.054
0.051
0.021
13
85
23
39
72
58
28
23
19
OCH3
OH
O
O
13. Olsen, C.; Wagtmann, N. Gene 2002, 299, 185.
NH2
14. Rosenblum, J. S.; Kozarich, J. W. Curr. Opin. Chem. Biol 2003, 7, 496.
15. At the time of this study, X-ray structural analysis was limited to complexation
of analog 24a in the DPP-4 enzyme cavity as discussed previously (Ref. 5a).
Two key interactions were identified from this complex: a salt bridge between
the free amino group and Glu205 and/or Glu206 and weak a hydrogen bond
between the amide carbonyl oxygen and the hydroxyl of Tyr547 through a
bridging water molecule in active site.
life (t1/2 = 3.5 h) and modest oral bioavailability (25% F), but the
clearance was unacceptably high.