Dipeptidyl peptidase IV inhibitors derived from β-aminoacylpiperidines bearing a fused thiazole, oxazole, isoxazole, or pyrazole

Article abstract of DOI:10.1016/j.bmcl.2005.03.012

A series of β-aminoacylpiperidines bearing various fused five-membered heterocyclic rings was synthesized as dipeptidyl peptidase IV inhibitors. Potent and relatively selective inhibition could be obtained, depending on choice of heterocycle, regioisomerism, and substitution. In particular, one analog (74, DPP-IV IC₅₀ = 26 nM) exhibited good oral bioavailability and acceptable half-life in the rat, albeit with rather high clearance.

Full text of DOI:10.1016/j.bmcl.2005.03.012

Bioorganic & Medicinal Chemistry Letters 15 (2005) 2253–2258
Dipeptidyl peptidase IV inhibitors derived from
b-aminoacylpiperidines bearing a fused thiazole, oxazole,
isoxazole, or pyrazole
Wallace T. Ashton,a,* Rosemary M. Sisco,a Hong Dong,a Kathryn A. Lyons,a
Huaibing He,a George A. Doss,b Barbara Leiting,c Reshma A. Patel,c Joseph K. Wu,c
Frank Marsilio,c Nancy A. Thornberryc and Ann E. Webera
aDepartment of Medicinal Chemistry, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065-0900, USA
bDepartment of Preclinical Drug Metabolism, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065-0900, USA
cDepartment of Metabolic Disorders, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065-0900, USA
Received 22 February 2005; revised 2 March 2005; accepted 3 March 2005
Abstract—A series of b-aminoacylpiperidines bearing various fused five-membered heterocyclic rings was synthesized as dipeptidyl
peptidase IV inhibitors. Potent and relatively selective inhibition could be obtained, depending on choice of heterocycle, regioiso-
merism, and substitution. In particular, one analog (74, DPP-IV IC50 = 26 nM) exhibited good oral bioavailability and acceptable
half-life in the rat, albeit with rather high clearance.
Ó 2005 Elsevier Ltd. All rights reserved.
In recent years, one of the most active areas of diabetes
research has centered on glucagon-like peptide 1 (GLP-
1), an incretin hormone that stimulates glucose-depen-
dent insulin biosynthesis and secretion, inhibits gluca-
gon secretion, and promotes proliferation of
pancreatic b cells.1 Although GLP-1-based approaches
are attractive for treatment of type 2 diabetes, therapeu-
tic use of GLP-1 itself is limited by lack of oral activity
and rapid degradation by dipeptidyl peptidase IV (DPP-
IV).2 Long-acting peptide GLP-1 analogs are in clinical
development, but these still require injection.2 DPP-IV is
a widely expressed serine peptidase, specific for cleavage
of an Xaa-Pro or Xaa-Ala N-terminal dipeptide from its
natural substrates.3 Orally active DPP-IV inhibitors
have the potential to improve glucose tolerance by sus-
taining the action of endogenous GLP-1.2,4 On the basis
of animal studies and initial clinical trials, it appears that
DPP-IV inhibitors are capable of significantly lowering
fasting and postprandial glucose concentration, as well
as reducing HbA1c levels, with good tolerability and
minimal risk of hypoglycemia.4,5
Novel b-aminoacyl derivatives of triazolo- or imidazolo-
fused piperazines such as MK-0431 (1) have recently
been reported from these laboratories as potent, selec-
tive, orally bioavailable inhibitors of DPP-IV.6 We
now describe the synthesis and biological evaluation of
analogous b-aminoacylpiperidines 2 bearing various
fused five-membered rings (thiazoles, oxazoles, isoxaz-
oles, and pyrazoles).
F
F
NH2
O
N
N
N
F
F
N
1
CF3
NH2
O
X
N
Keywords: Dipeptidyl peptidase IV inhibitors; Diabetes.
*
Y
F
Corresponding author. Tel.: +1 732 594 4508; fax: +1 732 594
5350; e-mail: wally_ashton@merck.com
Z
2
0960-894X/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2005.03.012

2254
W. T. Ashton et al. / Bioorg. Med. Chem. Lett. 15 (2005) 2253–2258
Using conditions similar to those reported for N-benzyl
analogs,7 1-Boc-piperidin-4-one (3) was converted to its
silyl enol ether 48 and acylated to give the diketone 5
(Scheme 1). Condensation of 5 with hydrazines or
hydroxylamine typically gave a mixture of pyrazolo-
piperidine or isoxazolopiperidine regioisomers 6 and 7,
which were deprotected to give, respectively, the amines
8 and 9. Similarly, the corresponding piperidin-3-one 10
was transformed to the major diketone 11, which was
separated from the minor isomer 12. As above, 11 could
be converted to bicyclic products 13 and 14, which were
deprotected to give, respectively, amines 15 and 16. The
minor diketone isomer 12 (R = CF3) afforded another
pyrazolopiperidine regioisomer 17. It should be noted
that, in some cases (especially where R is perfluo-
roalkyl), condensation of the diketones with hydrazines
or hydroxylamine led to hydrated adducts such as 18
and 19 as major products. Although relatively resistant
to dehydration at this stage, if these hydroxy intermedi-
ates were carried forward, they could be successfully
dehydrated during the EDC- or HATU-mediated cou-
pling with the protected b-amino acid (see Scheme 4).
Isomers 6 and 7 (R = CF3, Y = NMe) were assigned
by NOE experiments. Other pairs of pyrazolopiperidine
regioisomers were assigned by analogy on the basis of
NMR and TLC behavior. Isoxazolopyrimidine regio-
isomers 15 and 16 (R = CF3, Y = O; only 16 obtained
pure) were definitively assigned by 15N, 19F, and 13C
NMR experiments after synthesis from hydroxyl-
amine–15N hydrochloride.
N-Protected piperidin-4-ones 20 were a-brominated to
provide 219 (Scheme 2). Although the Boc group was
lost, the SES [2-(trimethylsilyl)ethylsulfonyl]10 and Cbz
protecting groups were retained. Condensation of 21
with thioamides11 afforded thiazolopiperidines 22, which
were deprotected to give the amines 23. Similarly, piperi-
din-3-ones 24 were brominated to give 25 along with a
minor amount of the isomer 26. As above, 25 was con-
verted to thiazolopiperidine 27 and then deprotected to
provide amine 28. In both series, a Cbz-protected thi-
azolopiperidine 29 bearing a 4-(methylthio)phenyl sub-
stituent could be oxidized to the corresponding sulfone
30. Because, we were unable to prepare oxazolopiper-
idines and some thiazolo derivatives by the pathway in
Scheme 2, an alternative route was developed (Scheme
3). Azido alcohol 3112 was reduced to the amine 32,12b
which was acylated to give 33. Following oxidation of
the alcohol, the resulting ketone 34 was cyclized to a
thiazolopiperidine with Lawessonꢀs reagent or to an
oxazolopiperidine with Burgess reagent. Subsequent
deprotection afforded amines 23 and 35, respectively.
OSiMe3
O
O
O
R
R
Boc
Boc
a
b
c
R
N
N
and/or
N
Y
Y
N
N
N
N
7
Boc
Boc
Boc
6
3
4
5
d
d
R
R
R
O
HN
HN
O
O
O
R
N
Y
a,b
+
Y
N
O
N
N
N
8
9
Boc
Boc
Boc
c,d
10
11 (major)
12 (minor)
F3C
N
c
NH
HN
Y = NR' or O
Boc
Boc
Y
N
N
N
17
and/or
N
Y
R
R
13
14
R
Boc
N
N
OH
Boc
Y
N
d
Y
d
OH
N
R
18
19
Y
N
HN
HN
N
Y
R
R
15
16
Scheme 1. Reagents and conditions: (a) (1) LiHMDS, THF, ꢀ78°C; (2) TMSCl, ꢀ78°C; (b) (1) MeLi, THF, ꢀ10°C; (2) RCOCl or (RCO)2O,
ꢀ78°C; (c) RNHNH2, EtOH or 2-methoxyethanol, D; or HClÆNH2OH, AcOH, D; or HClÆNH2OH, aq NaOH, EtOH, D; (d) anhydrous 4 M HCl/
dioxane.

W. T. Ashton et al. / Bioorg. Med. Chem. Lett. 15 (2005) 2253–2258
2255
O
O
Br
G'
S
N
a
b
c
S
N
N
HN
R
R
N
G
N
G'
22
23
20
21
G = Boc, SES, Cbz
G' = H.HBr, SES, Cbz
Br
O
O
O
a
S
N
+
n
N
G
N
N
Br
Cbz
N
SMe
G'
G'
m
24
25 (major)
26 (minor)
29
b
d
G'
N
c
S
N
N
R
S
N
HN
n
R
Cbz
N
SO2Me
S
m
27
28
30
Scheme 2. Reagents and conditions: (a) Br2, CHCl3, 5–20 °C; (b) RCSNH2, DMF, 100 °C; (c) For Boc: anhydrous 4 M HCl/dioxane; for SES: CsF,
DMF, 95 °C; for Cbz: anhydrous 30% HBr/AcOH; (d) MCPBA, DMF.
A similar sequence from the azido alcohol 3612 led to the
isomeric bicyclic products 40 and 41.
the target DPP-IV inhibitors 45–77 (corresponding to
general structure 2) upon Boc removal (Scheme 4).
Finally, the Boc-protected b-amino acid 426 was coupled
with the fused piperidines 43 to furnish 44, which yielded
As previously reported,13 compounds were determined
as inhibitors of human recombinant DPP-IV using the
OH
OH
OH
O
H
H
N3
NH2
N
R
N
R
a
b
c
d,e
S
N
HN
HN
R
R
O
O
N
N
N
N
Boc
Boc
Boc
Boc
23
35
31
32
33
34
O
N
f,e
O
O
N3
NH2
R
NH
R
NH
OH
OH
OH
O
a
b
c
N
S
d,e
HN
R
R
N
N
N
N
Boc
Boc
Boc
Boc
40
36
37
38
39
f,e
N
O
HN
41
Scheme 3. Reagents and conditions: (a) Ph3P , HO, THF; (b) RCOCl or (RCO)2O, Et3N, CH2Cl2; (c) Dess–Martin periodinane, CH2Cl2; or
2
(ClCO)2, DMSO, Et3N, CH2Cl2, ꢀ60 °C; (d) Lawessonꢀs reagent, toluene, D; (e) anhydrous 4 M HCl/dioxane; (f) Burgess reagent, THF, D.

2256
W. T. Ashton et al. / Bioorg. Med. Chem. Lett. 15 (2005) 2253–2258
F
F
F
F
Boc
Boc
X
Z
b
a
HN
O
NH2 O
HN
O
HN
+
Y
X
Z
X
Z
N
N
OH
Y
Y
F
F
42
43
44
2 (45-77)
Scheme 4. Reagents and conditions: (a) EDC, HOBT, iPr2NEt, CH2Cl2; or HATU, HOAT, iPr2NEt, CH2Cl2; (b) anhydrous 4 M HCl/dioxane.
substrate Gly-Pro-AMC, which is cleaved to release the
fluorescent leaving group, 7-amino-4-methylcoumarin.
In addition, the compounds were counter-screened
against human peptidases structurally or functionally re-
lated to DPP-IV,14 including quiescent cell proline
dipeptidase (QPP),15 DPP8, and DPP9. Although these
enzymes share some general substrate preferences with
DPP-IV, their physiological function is unclear. In con-
trast to DPP-IV, they are localized intracellularly14 and
are not known to be involved in the metabolism of GLP-
1. Inhibition of DPP8 and/or DPP9 is reported to be
associated with significant toxicity.16
peptidases. The isoxazolopiperidine 59 was similar in
activity to the corresponding pyrazolopiperidine 46.
The ring fusion ꢁBꢀ pyrazolo- and isoxazolopiperidine
derivatives (those derived from diketones 11), 60–64,
tended to be somewhat more potent DPP-IV inhibitors
than their ring fusion ꢁAꢀ counterparts (60 vs 46, 61 vs
47, 64 vs 59), although this was not accompanied by
an improvement in selectivity (Table 2). Analog 65 with
ring fusion ꢁCꢀ (derived from diketone 12) was 5-fold and
15-fold less potent on DPP-IV than corresponding ana-
logs 46 (ring fusion ꢁAꢀ) and 60 (ring fusion ꢁBꢀ),
respectively.
Pyrazolopiperidines with ring fusion ꢁAꢀ (i.e., those de-
rived from diketones 5), 45–58, exhibited moderate po-
tency (generally 100–300 nM) against DPP-IV,
frequently with >100-fold selectivity versus the other
peptidases (Table 1). No pronounced structure–activity
relationships were evident, although the combination
of alkyl and bulky 4-fluorophenyl substituents at distal
positions on the pyrazole ring (isomer A-1, compounds
51 and 57) appeared unfavorable for DPP-IV inhibition,
whereas the same substituents at proximal ring positions
(isomer A-2, compounds 52 and 58) were associated
with increased potency at one or more of the off-target
A striking effect of regioisomerism was observed in the
thiazolopiperidines and, to a lesser extent, the oxazolo-
piperidines. Those designated as ring fusion ꢁDꢀ, 66–72,
were only modest inhibitors of DPP-IV (Table 3). In
addition, several of these, especially those bearing an
aryl substituent, were poorly selective relative to other
peptidases. In contrast, Table 4 shows that 73–77, desig-
nated as ring fusion ꢁEꢀ, had marked gains in DPP-IV
potency compared to their ring fusion ꢁDꢀ analogs
(e.g., 5-fold for 73 vs 67, 14-fold for 74 vs 68, 20-fold
for 75 vs 69, and 90-fold for 76 vs 71). The 1.4 nM
Table 1. Inhibition of DPP-IV and other peptidases by pyrazolo- and isoxazolopiperidines (ring fusion ꢁAꢀ)
F
NH2
O
R
R
N
N
and
N
Y
F
Y
N
Isomer A-1
Isomer A-2
Compd
Y
R
Isomer
IC50 (lM)
DPP-IV
QPP
DPP8
DPP9
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
NH
NH
Me
CF3
A-1/A-2
A-1/A-2
A-1
0.25
0.11
0.13
0.15
0.18
0.15
0.35
0.16
0.16
0.22
0.30
0.27
0.78
0.15
0.13
71
71
38
51
16
18
17
24
21
63
65
NMe
NMe
CF3
CF3
68
>100
71
>100
>100
>100
>100
24
A-2
A-1
NCH2CF3
NCH2CF3
NPh-4-F
NPh-4-F
NH
CF3
CF3
A-2
A-1
>100
18
Me
Me
A-2
5.5
9.4
27
CF2CF3
CF2CF3
CF2CF3
Ph-4-F
Ph-4-F
Ph-4-F
CF3
A-1/A-2
A-1
A-2
67
40
92
43
26
72
56
>100
>100
>100
50
NMe
NMe
>100
22
62
NH
NMe
A-1/A-2
A-1
A-2
>100
>100
>100
NMe
O
4.0
54
58
>100
A-2

W. T. Ashton et al. / Bioorg. Med. Chem. Lett. 15 (2005) 2253–2258
2257
Table 2. Inhibition of DPP-IV and other peptidases by pyrazolo- and isoxazolopiperidines (ring fusion ꢁBꢀ and ꢁCꢀ)
F
R
N
NH2
O
Y
Y
N
N
N
N
N
Y
, and
,
F
R
R
Isomer B-1
Isomer B-2
Isomer C
IC50 (lM)
Compd
Y
R
Isomer
DPP-IV
QPP
DPP8
DPP9
60
61
62
63
64
65
NH
NMe
NMe
NH
O
CF3
CF3
CF3
B-1/B-2
B-1
B-2
0.039
0.072
0.13
30
67
10
32
65
11
13
26
85
43
>100
34
36
Cyclopropyl
CF3
CF3
B-1/B-2
B-2
0.16
0.085
0.59
>100
31
5.8
>100
NH
C
>100
Table 3. Inhibition of DPP-IV and other peptidases by thiazolo- and
oxazolopiperidines (ring fusion ꢁDꢀ)
Table 4. Inhibition of DPP-IV and other peptidases by thiazolo- and
oxazolopiperidines (ring fusion ꢁEꢀ)
F
F
NH2
O
NH2 O
Y
N
N
Y
N
N
R
R
F
F
Compd
Y
R
IC50 (lM)
DPP-IV QPP DPP8 DPP9
Compd
Y
R
IC50 (lM)
DPP-IV QPP DPP8 DPP9
66
67
68
69
70
71
72
S
S
S
S
S
S
O
Me
CF3
0.48
0.31
0.36
0.26
0.38
80
63
15
11
7.1
29
20
41
73
74
75
76
77
S
S
S
S
O
CF3
Ph-4-F
Ph-4-CF3
0.057
0.026
0.013
95 63
11 16
>100
43
28
Ph-4-F
Ph-4-CF3
Ph-4-SMe
4.3
3.0
3.3
3.2
7.8
15
51
7.9
8.6
9.6
5.1
6.5
Ph-4-SO2Me 0.0014
Cyclopropyl 0.18
25
>100
1.9
>100 51
Ph-4-SO2Me 0.13
Cyclopropyl 0.29
35
56
28
30
inhibitors. Among the pyrazolopiperidines, ring fusion
ꢁBꢀ tended to give more potent DPP-IV inhibition than
ring fusion ꢁAꢀ, and ring fusion ꢁCꢀ was least effective.
There were no pronounced substituent effects, and the
isoxazolopiperidines were similar in activity to their pyr-
azolo counterparts. A clear structure–activity trend was
evident in the thiazolopiperidine series. Here ring fusion
ꢁEꢀ was strongly preferred over ring fusion ꢁDꢀ with re-
spect to DPP-IV inhibitory potency and selectivity. A les-
ser effect was observed for the oxazolopiperidines.
Excellent DPP-IV inhibitory potency (IC50 = 1.4 nM
for 76) and selectivity over other peptidases (>1000-fold
for 76 and 73) could be achieved in the thiazolopiperi-
dines with ring fusion ꢁEꢀ. Compound 74 (DPP-IV
IC50 = 26 nM; selectivity >400-fold vs other peptidases),
despite rather high clearance, had good oral bioavailabil-
ity (55%) and an acceptable half-life (3.3 h) in rats.
IC50 for 76 demonstrates a remarkable activity enhance-
ment attributable to the methanesulfonyl substituent in
this series. This compound was >6000-fold selective
for DPP-IV over the other peptidases. Although less
potent, the trifluoromethyl thiazole derivative 73 was
also notable for its very high selectivity (>1000-fold).
Selected compounds were evaluated for pharmacokinet-
ics in male Sprague–Dawley rats (typically dosed at
1 mg/kg iv and 2 mg/kg po). Trifluoromethyl thiazole
derivative 73 had moderate half-life (2.0 h) but very high
clearance (250 mL/min/kg) and low oral bioavailability
(16%). The 4-(methanesulfonyl)phenyl analog 76 had re-
duced clearance (60 mL/min/kg) but no improvement in
half-life (1.5 h), and oral bioavailability was only 20%.
However, the corresponding 4-fluorophenyl analog 74
displayed improved half-life (3.3 h) and oral bioavail-
ability (55%), albeit with rather high clearance (91 mL/
min/kg).
Acknowledgements
We are grateful to Dr. Charles G. Caldwell (Medicinal
Chemistry) for helpful suggestions and synthetic proce-
dures. We are also indebted to Mr. Christian N. Nunes,
Mr. James C. Hausamann, Mr. Kenneth G. Vakerich,
In conclusion, a series of b-aminoacyl amides derived
from piperidines bearing a fused pyrazole, isoxazole, thi-
azole, or oxazole was prepared and evaluated as DPP-IV

2258
W. T. Ashton et al. / Bioorg. Med. Chem. Lett. 15 (2005) 2253–2258
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.
and Dr. Judith E. Fenyk-Melody (Laboratory Animal
Resources) as well as to Ms. Ida Ita (Medicinal Chemis-
try) for valuable assistance in the pharmacokinetics
experiments.
7. Boumendjel, A.; Roberts, J. C.; Hu, E.; Pallai, P. V.;
Rebek, J., Jr. J. Org. Chem. 1996, 61, 4434.
8. Irie, T.; Fukushi, K.; Namba, H.; Iyo, M.; Ikota, N.;
Nagatsuka, S.; Ueda, T.; Nishiura, M.; Takatoku, K;
Yomoda, I. U.S. Patent 6,306,882, 2001. Chem. Abstr.
1999, 130, 81402.
9. Preparation of compound 21 (G0 = HÆHBr) by a similar
route: Gangjee, A.; Elzein, E.; Queener, S. F.; McGuire,
J. J. J. Med. Chem. 1998, 41, 1409.
References and notes
1. (a) Kieffer, T. J.; Habener, J. F. Endocrine Rev. 1999, 20,
876; (b) Holst, J. J.; Gromada, J. Am. J. Physiol.
Endocrinol. Metab. 2004, 287, E199; (c) Perry, T.; Greig,
N. H. Trends Pharmacol. Sci. 2003, 24, 377.
10. Weinreb, S. M.; Demko, D. M.; Lessen, T. A.; Demers,
J. P. Tetrahedron Lett. 1986, 27, 2099.
2. (a) Holst, J. J. Exp. Opin. Emerg. Drugs 2004, 9, 155; (b)
Mentlein, R. Exp. Opin. Investig. Drugs 2005, 14, 57; (c)
´
11. Noncommercial thioamides were prepared by reaction of
the corresponding amides with Lawessonꢀs reagent or P2S5
or from the nitrile by the method of Ohkawa, S.; Naruo,
K.; Miwatashi, S.; Kimura, H. PCT Int. Patent Appl. WO
01/74811, 2001. Chem. Abstr. 2001, 135, 303878.
12. (a) Caldwell, C. G. Unpublished work from Merck
Research Laboratories; (b) Sheppeck, J. E.; Duan, J.;
Xue, C.-B.; Wasserman, Z. PCT Int. Patent Appl. WO 02/
096426, 2002. Chem. Abstr. 2002, 138, 14059.
13. 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.
14. (a) Rosenblum, J. S.; Kozarich, J. W. Curr. Opin. Chem.
Biol. 2003, 7, 1; (b) Chen, T.; Ajami, K.; McCaughan, G.
W.; Gorrell, M. D.; Abbott, C. A. In Dipeptidyl Peptidases
in Health and Disease; Hildebrandt, M., Klapp, B. F.,
Hoffman, T., Demuth, H.-U., Eds.; Kluwer Academic/
Plenum: New York, 2003; pp 79–86.
Ahren, B.; Schmitz, O. Horm. Metab. Res. 2004, 36, 867;
(d) Holst, J. J.; Deacon, C. F. Curr. Opin. Pharmacol.
2004, 4, 589; (e) Knudsen, L. B. J. Med. Chem. 2004, 47,
4128; (f) DꢀAlessio, D. A.; Vahl, T. P. Am. J. Physiol.
Endocrinol. Metab. 2004, 286, E882.
´
3. (a) Lambeir, A. M.; Durinx, C.; Scharpe, S.; De Meester,
I. Crit. Rev. Clin. Lab. Sci. 2003, 40, 209; (b) Demuth, H.-
U.; Heins, J.. In Dipeptidyl Peptidase IV (CD26) in
Metabolism and the Immune Response; Fleischer, B., Ed.;
Landes: Austin, 1995, pp 1–35; (c) Mentlein, R. Int. Rev.
Cytol. 2004, 235, 165; (d) Boonacker, E.; Van Noorden, J.
F. Eur. J. Cell Biol. 2003, 82, 53; (e) Chen, T.; Smyth, D.;
Abbott, C. A. J. Biol. Regul. Homeost. Agents 2004, 18,
47.
4. (a) Weber, A. E. J. Med. Chem. 2004, 47, 4135; (b)
´
Deacon, C. F.; Ahren, B.; Holst, J. J. Exp. Opin. Investig.
Drugs 2004, 13, 1091; (c) Drucker, D. J. Exp. Opin.
Investig. Drugs 2003, 12, 87; (d) Augustyns, K.; Van der
Veken, P.; Senten, K.; Haemers, A. Exp. Opin. Ther.
Patents 2003, 13, 499; (e) Wiedeman, P. E.; Trevillyan, J.
M. Curr. Opin. Investig. Drugs 2003, 4, 412.
15. QPP is also known as dipeptidyl peptidase VII and is very
similar, if not identical, to dipeptidyl peptidase II. See Ref.
13.
16. Lankas, G.; Leiting, B.; Sinha Roy, R.; Eiermann, G.;
Biftu, T.; Kim, D.; Ok, H.; Weber, A. E.; Thornberry, N.
A. Abstracts of Papers, 64th Annual Scientific Sessions of
the American Diabetes Association, Orlando, FL, 4–8
June 2004; Abstract 7-OR.
5. (a) Barlocco, D. Curr. Opin. Investig. Drugs 2004, 5, 1094;
(b) McIntyre, J. A.; Castan˜er, J. Drugs Future 2004, 29,
887.
6. Kim, D.; Wang, L.; Beconi, M.; Eiermann, G. J.; Fisher,
M. H.; He, H.; Hickey, G. J.; Kowalchick, J. E.; Leiting,