Design, synthesis, and biological evaluation of triazolopiperazine-based β-amino amides as potent, orally active dipeptidyl peptidase IV (DPP-4) inhibitors

Article abstract of DOI:10.1016/j.bmcl.2007.07.100

Various β-amino amides containing triazolopiperazine heterocycles have been prepared and evaluated as potent, selective, orally active dipeptidyl peptidase IV (DPP-4) inhibitors. These compounds display excellent oral bioavailability and good overall phar

Full text of DOI:10.1016/j.bmcl.2007.07.100

Bioorganic & Medicinal Chemistry Letters 17 (2007) 5934–5939
Design, synthesis, and biological evaluation of
triazolopiperazine-based b-amino amides as potent, orally
active dipeptidyl peptidase IV (DPP-4) inhibitors
Jennifer E. Kowalchick,a,* Barbara Leiting,b KellyAnn D. Pryor,b Frank Marsilio,b
Joseph K. Wu,b Huaibing He,a Kathryn A. Lyons,a George J. Eiermann,c
Aleksandr Petrov,c Giovanna Scapin,a Reshma A. Patel,c Nancy A. Thornberry,b
Ann E. Webera and Dooseop Kima
aDepartment of Medicinal Chemistry, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA
bDepartment of Metabolic Disorders, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA
cDepartment of Pharmacology, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA
Received 31 May 2007; revised 23 July 2007; accepted 24 July 2007
Available online 23 August 2007
Abstract—Various b-amino amides containing triazolopiperazine heterocycles have been prepared and evaluated as potent, selec-
tive, orally active dipeptidyl peptidase IV (DPP-4) inhibitors. These compounds display excellent oral bioavailability and good
overall pharmacokinetic profiles in preclinical species. Moreover, in vivo efficacy in an oral glucose tolerance test in lean mice is
demonstrated.
Ó 2007 Elsevier Ltd. All rights reserved.
In recent years, glucagon-like peptide 1 (GLP-1) therapy
has emerged as an area of active investigation for the
treatment of type 2 diabetes.1 GLP-1 is an incretin hor-
mone released in the gut upon food ingestion that regu-
lates insulin in a glucose-dependent manner. Elevation
of blood glucose levels causes GLP-1 to trigger insulin
biosynthesis and secretion, inhibit glucagon release,
slow gastric emptying, and induce pancreatic b-cell pro-
liferation. The serine protease dipeptidyl peptidase IV
(DPP-4) rapidly renders GLP-1 inactive through cleav-
age of its N-terminal two amino acids. Inhibition of
DPP-4 prolongs the half life of GLP-1 and thus, leads
to increased levels of active endogenous GLP-1.
Accordingly, DPP-4 inhibition is a promising new
treatment for type 2 diabetes.2
for the treatment of patients with type 2 diabetes.
Because the fused heterocycle moiety of sitagliptin is
recognized as a key pharmacophore that contributes
to its good pharmacokinetic profile, potency, and
selectivity,3 a new series of triazolopiperazines have
been investigated. Moving the nitrogen from the 2-
to the 3-position in the triazolopiperazine bicycle of
sitagliptin brought about a new family of compounds.
Herein, we focus on the evaluation of the following
variations to this new triazolopiperazine structure:
modification at the 2-position as well as the 8-position
of the bicycle 2.
F
F
8
F
F
NH2
O
NH2
O
R2
8
1
1
N
N
2
N
2
N
N
R1
Compound 1, JANUVIATM (sitagliptin), was recently
approved by the U.S. Food and Drug Administration
H3PO4
F
N
F
N
N
3
3
CF3
1 JANUVIATM
2
(sitagliptin phosphate)
DPP-4 IC50 = 18 nM
Keywords: Dipeptidyl peptidase IV; DPP-4; Dipeptidyl peptidase IV
inhibitors; DPP-4 inhibitors; b-Amino amides; Triazolopiperazine;
Triazolopiperazine-based b-amino amides; Type 2 diabetes.
Corresponding author. Tel.: +1 570 594 2569; e-mail:
jennifer_kowalchick@yahoo.com
The DPP-4 inhibitors in this report were prepared by
standard peptide coupling of b-amino acids with fused
*
0960-894X/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2007.07.100

J. E. Kowalchick et al. / Bioorg. Med. Chem. Lett. 17 (2007) 5934–5939
5935
heterocycles as reported earlier.3 The synthesis of non-
commercially available b-amino acid (13) has already
been reported.3 Four different approaches to novel substi-
tuted triazolopiperazines are described in Scheme 1.
F
F
Boc
F
N
N
NH
O
a
HN
R
N
N
N
N
R
N
F
F
6, 7, 9, 12
14
F
Boc
Following the procedures analogous to those reported in
the literature, the target triazolopiperazine heterocycles
were each prepared in four to five steps.4–7 Aminopyr-
azine (3) was acylated with trifluoroacetic anhydride,
cyclopropane carbonyl chloride, and benzoyl chloride
to give acetamides 4, 8, and 10, respectively.4 The triflu-
oromethyl and benzyl acetamides were then treated with
phosphorous pentachloride followed by hydroxylamine
to afford their respective hydroxyimideamides, 5 and
11.5 Condensation in polyphosphoric acid (PPA) or
superphosphoric acid at elevated temperatures followed
by catalytic hydrogenation gave piperazine intermedi-
ates 6 and 12.6 The cyclopropyl acetamide 8 was subse-
quently treated with O-mesitylenesulfonyl hydroxyl
amine, giving the aminopyrazinium salt,7 which was
then cyclized and reduced using the aforementioned
method, to afford 9. Heterocycle 7 was prepared from
aminopyrazine using procedures outlined in the
literature.6
NH
O
OH
b
13
F
F
F
NH2
HCl
O
N
N
N
.
R
N
25, 26, 27, 28
Scheme 2. Reagents and conditions: (a) 13, HOBT, EDC, DMF, rt,
16 h; (b) satd HCl in CH3OH, rt, 1 h.
22. Treatment of 19 with 1,1-thiocarbonyldiimidazole
resulted in elimination, which, followed by reduction
and deprotection, gave 21. Coupling of the triazolopip-
erazines 16, 18, 20–22 with b-amino acid 13, followed by
separation of the diastereomers on OD chiralcel or AS
and AD chiral pak columns, and deprotection provided
desired compounds 29a–b, 30a–b, 31a–b, 32a–b, 33a–d,
34a–d, 35, 36, 37, and 37a–b. In general, the slower elut-
ing diastereomers on the OD and AS chiral columns and
the faster eluting diastereomers on the AD chiral col-
umn were the more potent diastereomers, and are listed
in Table 2.
As shown in Scheme 2, coupling of b-amino acid 13 with
the respective piperazines, followed by deprotection of
the amine, provided the desired compounds 25–28 in
Table 1.
With piperazine analogs, a-substitution on the pipera-
zine heterocycle has been shown to increase DPP-4 po-
tency.8 To boost the potency of compounds in the
triazolopiperazine series of current focus, various sub-
stituents were added to the a-position of the fused
bicycle. Several approaches to obtain a-substitution on
the triazolopiperazine heterocycle are described in
Scheme 3.
The compounds listed in Tables 1 and 2 underwent
in vitro evaluation for inhibition of DPP-4.12 To screen
for off-target activity, the analogs were also tested
against homologs of DPP-4 in the same gene family as
well as other proline-specific enzymes. Homologs tested
include DPP-8,13 DPP-9,14 and fibroblast activation
protein (FAP).15 Other proline-specific enzymes that
were tested include quiescent cell proline dipeptidase
(QPP, also known as DPP-2),12,16 prolidase, and amino
peptidase P (APP). None of the compounds in this re-
port showed any significant inhibition against FAP, pro-
lidase, and APP (IC50s > 50,000 nM), thus those data
are not reported. Previous DPP-8/9 selective inhibitor
studies suggest that DPP-8 and/or DPP-9 inhibition is
associated with profound toxicity in preclinical spe-
cies.17 Furthermore, monkeys treated with a non-selec-
tive DPP-4, DPP-8, and DPP-9 inhibitor displayed
Boc-protection of amine 6 followed by alkylation at the
a-position with the appropriate alkyl halides and subse-
quent deprotection gave 16.9 Alkylation of 15 with
benzyl chloromethyl ether, followed by debenzylation,
conversion to the mesylate (17),10 and displacement with
the desired heterocycle gave heteroaryl-substituted pip-
erazines 18. Reaction of 15 with cyclopropane carboxal-
dehyde gave hydroxyl intermediate 19. Deprotection of
19 gave 20, whereas fluorination with diethylaminosul-
fur trifluoride (DAST)11 followed by deprotection gave
H
H
NH2
N
CF3
OH
N
CF3
a
N
N
d,e
b,c
N
N
f, g, d, e
N
HN
N
HN
N
CF3
N
N
N
N
N
N
O
h
j
3
4
7
6
5
H
N
H
H
N
N
N
N
N
N
N
k,e
b,c
i,d,e
HN
N
N
HN
N
O
N
N
N
N
10
O
N
OH
8
11
12
9
Scheme 1. Reagents and conditions: (a) (CF3CO)2O, Et3N, CH2Cl2, 0 °C–rt, 2h; (b) PCl5, dichloroethane, reflux, 5 h; (c) 50% aq NH2OH, THF, rt,
2 h; (d) polyphosphoric acid, 150 °C, 18 h; (e) H2, 10% Pd/C, EtOH, rt, 18 h; (f) N,N-dimethylformamide dimethyl acetal, reflux, 2 h; (g) 50% aq
NH2OH, THF, reflux, 1.5 h; (h) cyclopropane carbonyl chloride, pyridine, chloroform, rt, 2 h; (i) O-mesitylenesulfonyl hydroxyl amine,6 CH2 Cl2,
0 °C–rt, 1.5 h; (j) benzoyl chloride, pyridine, 0 °C–rt, 18 h; (k) superphosphoric acid, 110 °C, 3 h.

5936
J. E. Kowalchick et al. / Bioorg. Med. Chem. Lett. 17 (2007) 5934–5939
Table 1. Inhibitory properties of fused heterocycle-derived DPP-4 inhibitors with varied 2-position substituents
F
F
NH2
O
N
N
N
R
F
N
Compound
R
DPP-4 IC50, nM
QPP IC50, nM
DPP-8 IC50, nM
DPP-9 IC50, nM
25
26
CF3
H
59
100
54,000
>100,000
62,000
>100,000
>100,000
>100,000
27
71
68
>100,000
4000
>100,000
44,000
>100,000
28
>100,000
R1
N
N
HN
CF3
N
16
F
O
F
R2
O
HO
N
HO
S
R1
NH
O
b,c
CH3
O
Boc
Boc
Boc
N
N
N
N
N
N
N
N
N
HN
N
CF3
CF3
CF3
CF3
CF3
N
N
N
N
N
N
N
F
i
c
d
N
e,f,g
17
20
15
19
23 R2 = Boc
j,c
h,c
c
24 R2 = H (HCl salt)
a
Het.
F
N
N
N
HN
HN
CF3
CF3
N
N
N
N
N
N
N
HN
HN
CF3
CF3
6
21
N
N
18
22
Scheme 3. Reagents and conditions: (a) (Boc)2O, DIPEA, CH2Cl2, rt, 18 h; (b) TMEDA, n-BuLi, R–X, À78 °C–rt, 1.5 h; (c) satd HCl in CH3OH,
1 h; (d) 13, HOAT, HATU, DIPEA, DMF, rt, 18 h, followed by chiral separation on Chiral OD, AD, or AS columns; (e) TMEDA, n-BuLi, benzyl
chloromethyl ether, À78 °C–rt, 1.5 h; (f) H2 (1 atm) 10% Pd/C, EtOH, rt, 29 h, followed by H2 (42 psi) 12 h; (g) MsCl, Et3N, CH2Cl2, 0 °C–rt, 4 h10
;
(h) heterocycle (imidazole, pyrazole, or 1,2,4-triazole) K2CO3, DMF, 50 °C or NaH (60%), DMF, rt, 0.6 h; (i) sec-BuLi, cyclopropane
carboxaldehyde, À78 °C–rt, 1 h; (j) DAST, CH2Cl2, À78 °C–rt, 17 h; (k) 1,1-thiocarbonyldiimidazole, DMAP, CH2Cl2, reflux, 17 h; (l) H2 (1 atm)
10% Pd/C, EtOH, rt, 18 h.
treatment-related dermatological toxicity.18 Also, earlier
b-amino acid-derived DPP-4 inhibitors were associated
with significant QPP off-target activity.19 Thus, activities
against these three enzymes are reported in Tables 1 and
2.
observed by the 2-trifluoromethyl group. Deletion of
the trifluoromethyl substituent in compound 25
resulted in a twofold decrease in the DPP-4 potency
(26). Cyclopropyl and phenyl-substituted compounds
27 and 28 both displayed decreased DPP-4 potency
and selectivity and, thus, offered no advantage over
compound 25. Of those explored, the trifluoromethyl
group was accepted as the optimal 2-position substitu-
ent, and this substituent was thus used in further SAR
studies examining other modifications in the piperazine
heterocycle.
In vitro inhibitory activity for the selected triazolopiper-
azine-based DPP-4 inhibitors is listed in Tables 1 and 2,
while Table 3 exhibits the pharmacokinetic properties of
selected compounds with high DPP-4 potency.
Variation of the substituent at the triazolopiperazine
2-position is reported in Table 1. Exchanging the 2-posi-
tion nitrogen of compound 1 with its 3-position substitu-
ent produces a threefold decrease in DPP-4 potency, as
seen in compound 25 (DPP-4 IC50 = 59 nM vs 18 nM
for compound 1). However, isomer 25 exhibits 100% oral
bioavailability and a half life of 3.6 h in the rat (Table 3).
Aiming to boost DPP-4 potency in the series, various
substituents were added to the a-position of the fused
bicycle. In Table 2, simple addition of an R-methyl
group to the a-position of the triazolopiperazine (con-
firmed by X-ray analysis) increased DPP-4 potency
twofold (DPP-4 IC50 = 25 nM) in comparison to 25.
This compound (29b) displayed outstanding oral
bioavailability and a lengthened half life in rat, dog,
and rhesus monkey models (Table 3). Notably, the half
life of 29b in the dog model was an exceptional 26 h.
In an attempt to increase DPP-4 potency, the 2-posi-
tion substituent was both varied and deleted; however,
no substituent produced potency greater than that

J. E. Kowalchick et al. / Bioorg. Med. Chem. Lett. 17 (2007) 5934–5939
5937
Table 2. Inhibitory properties of fused heterocycle-derived DPP-4 inhibitors with varied 8-position substituents
F
F
NH2
O
R
N
N
N
CF3
F
N
Compound
R
DPP-4 IC50 (nM)
QPP IC50 (nM)
DPP-8 IC50 (nM)
DPP-9 IC50 (nM)
25
H
59
274
25
54,000
72,000
25,000
62,000
>100,000
>100,000
>100,000
>100,000
>100,000
29a
29b
CH3(S)
CH3(R)
F
30ba
31ba
32ba
4
4
7
60,000
15,000
7400
25,000
16,000
71,000
27,000
27,000
54,000
CF3
33ba,c
33da,c
12
14
33,000
18,000
86,000
>100,000
>100,000
>100,000
HO
F
34ca,d
34da,d
18
11
5767
4100
>100,000
>100,000
77,000
63,000
N
35b
36b
37b
37aa
2
4
5
2
26,000
9600
>100,000
>100,000
>100,000
>100,000
27,000
N
N
>100,000
>100,000
>100,000
N
N
49,000
22,000
N
N
N
N
N
a Tentatively assigned R-stereochemistry.
b Mixture of diastereomers.
c Single diastereomer, configuration at OH unknown.
d Single diastereomer, configuration at F unknown.
Compound 29b also displayed selectivity over QPP,
DPP-8, and DPP-9. Compound 29a, the S-diastereo-
mer of 29b, was significantly less active (DPP-4
IC50 = 274 nM) than the R-diastereomer. This 10-fold
decrease in potency was observed in all other less po-
tent diastereomers, which were assumed to be the S-
diastereomers (not included in Table 2). The biological
results of 29b suggested that a-substitution could be
used for enhancement of both DPP-4 potency as well
as pharmacokinetic properties.
compounds were the benzyl, cyclopropyl, and heteroa-
ryl-substituted triazolopiperazines shown in Table 2.
Benzyl substitution, as seen in compounds 30b and
31b, greatly enhanced DPP-4 potency (DPP-4
IC50 = 4 nM) when compared to compound 29b; con-
versely, oral bioavailability (30b) suffered (%F = 32).
Cyclopropyl substitution at the triazolopiperazine a-po-
sition was evaluated next. As compared to lead com-
pound 29b, potent diastereomers of the series cause a
definite boost in DPP-4 potency and retain selectivity
against DPP-8 and DPP-9. Upon further evaluation in
pharmacokinetic studies, 33b and 33d did not show
improvement relative to 29b. Further efforts to improve
pharmacokinetics then focused on heteroaryl incorporation
Following the lead of a-methyl-substituted triazolopip-
erazine compound 29b, a number of other analogs
containing a-substitution were evaluated. Among these

5938
J. E. Kowalchick et al. / Bioorg. Med. Chem. Lett. 17 (2007) 5934–5939
Table 3. Pharmacokinetic properties of fused heterocycle-derived DPP-4 inhibitors
Compound
Species
Clp (mL/min/kg)
t1/2 (h)
AUCnorm (lM h kg mgÀ1
)
F (%)
1
Rat
60
6.0
28
1.7
4.9
3.7
3.6
4.0
26
0.523
8.3
1.0
76
100
68
Dog
Monkey
Rat
25
29b
60
68
1.143
0.432
30.240
1.640
0.146
0.199
0.271
0.027
0.151
0.035
100
74
Rat
Dog
Monkey
Rat
1.0
16
67
65
7.7
2.7
5.1
3.9
9.0
2.3
2.8
30b
33b
33d
35
76
91
32
51
Rat
Rat
97
97
63
Rat
Rat
7.1
62
36
37
142
129
Rat
13
at the a-position of the bicycle. Diastereomeric separa-
tion could only be achieved for the 1-methyl-1H-1,2,4-
triazole analog (37), so biological data is reported for
the (R) and (S) diastereomeric mixtures of the heterocy-
clic analogs. These compounds displayed increased
DPP-4 potencies of 5- to 10-fold over lead compound
29b and good selectivity over other proline-specific en-
zymes. Further in vivo testing of 35 and 37 revealed
an overall decrease in oral bioavailability (%F = 7.1
and 13, respectively), as well as diminished oral exposure
in 35, 36, and 37 (po AUCnorm = 0.027, 0.151, and 0.035,
respectively).
occupying a relatively open area of the DPP-4 binding
site, and thus, providing further surface complementar-
ity to the Phe375 side chain. Since having an (S)-methyl
group at the a-position would cause a clash with
Phe357, a 10-fold decrease in potency is observed with
its diastereomer, 29a (DPP-4 IC50 = 274 nM).
Through variation of the heterocyclic moiety found in
sitagliptin by exchanging the 2-position nitrogen with
the 3-position substituent, a novel series of potent triazolo-
piperazine-based DPP-4 inhibitors have been discov-
ered. These triazolopiperazine analogs are potent,
selective DPP-4 inhibitors, and exhibit an excellent oral
bioavailability and good overall pharmacokinetic profile,
as demonstrated by isomer 25. Introduction of alkyl,
heteroaryl, and benzyl substitution at the a-position re-
sulted in a pronounced boost in DPP-4 potency. Com-
pound 29b, the (R)-diastereomer, exhibited greater
DPP-4 potency than its (S) counterpart. Due to its in-
creased DPP-4 potency over compound 25, good selec-
tivity over other proline-specific enzymes, and both a
long half life and excellent oral bioavailability in all pre-
clinical species tested, compound 29b was selected for
further in vivo development. An OGTT revealed that
when administered to lean mice, compound 29b showed
a dose-dependent inhibition of glucose excursion maxi-
mal at 1 mg/kg. As in sitagliptin, the fused heterocycle
moiety of this series played a positive key role in
Of the compounds examined, compound 29b displayed
the best overall profile with regard to in vitro potency,
selectivity, and pharmacokinetics, and thus, was selected
for further biological evaluation in vivo. The ability of
compound 29b to reduce glucose levels in lean mice
was assessed in an oral glucose tolerance test (OGTT).3a
Single oral doses of 29b administered 60 min prior to
dextrose challenge reduced the blood glucose excursion
in a dose-dependent manner from 0.1 mg/kg (14% inhi-
bition) to 3.0 mg/kg (44% inhibition). Dose-dependent
inhibition of glucose excursion appeared maximal at
1.0 mpk (39% inhibition) (Fig. 1).
X-ray crystal structure determination of compound 29b
(the more potent diastereomer) in complex with the
DPP-4 enzyme demonstrates that the absolute stereo-
chemistry at the triazolopiperazine a-position is (R)
(Fig. 2).20 In a similar manner to that shown in the
crystal structure of sitagliptin, the S1 hydrophobic
pocket in the DPP-4 enzyme is fully occupied by com-
pound 29b’s 2,4,5-trifluorophenyl moiety. Also, the
(R)-b-amino group interacts with glutamate residues
Glu205 and Glu206 through four hydrogen bonding
interactions.3a The carboxylic oxygen and the hydroxyl
of Tyr547 are bridged by a water molecule, and several
other water-mediated interactions are also present be-
tween the nitrogen atoms of the triazolopiperazine
and protein atoms. The triazolopiperazine is stacked
against the side chain of Phe357.
300
vehicle
250
glucose
Compound 29b:
0.1 mg/kg
200
150
100
50
0.3 mg/kg
1 mg/kg
3 mg/kg
control
0
pre
0
20 40 60
120
time (min)
Figure 1. The effect of compound 29b on glucose levels following an
oral glucose tolerance test in lean mice. Single oral doses of 29b
administered 60 min prior to dextrose challenge, reduced the blood
glucose excursion in a dose-dependent manner from 0.1 mg/kg (14%
inhibition) to 3.0 mg/kg (44% inhibition).
The enhanced potency of 29b (DPP-4 IC50 = 25 nM) in
comparison to 25 (DPP-4 IC50 = 59 nM) corresponds
to the (R)-a-methyl group of the triazolopiperazine

J. E. Kowalchick et al. / Bioorg. Med. Chem. Lett. 17 (2007) 5934–5939
5939
6. Polanc, S.; Vercek, B.; Stanovnik, B.; Tisler, M. Tetrahe-
dron Lett. 1973, 14, 1677.
7. Tamura, Y.; Minamikawa, J.; Sumoto, K.; Fujii, S.;
Ikeda, M. J. Org. Chem. 1973, 38, 1239.
8. Brockunier, L.; He, J.; Colwell, L. F., Jr.; 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. Bioorg. Med. Chem. Lett.
2004, 14, 4763.
9. Cappola, G. M. J. Heterocycl. Chem. 1991, 28, 1769.
10. Liu, L. T.; Lin, Y.; Wang, C. J.; Lin, M.; Yen, S.; Chen, H.
Bioorg. Med. Chem. Lett. 1996, 6, 1335.
´
11. (a) Fernandez, R.; Matheu, M. I.; Echarri, R.; Castillon,
S. Tetrahedron 1998, 54, 3523; (b) Demange, L.; Mendez,
´
´
A.; Dugave, C. Tetrahedron Lett. 1998, 39, 1169.
12. 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. Biochem. J. 2003,
371, 525.
13. Abbot, C. A.; Yu, D. M.; Woollatt, E.; Sutherland, G. R.;
McCaughan, G. W.; Gorrell, M. D. Eur. J. Biochem. 2000,
267, 6140.
14. Olsen, C.; Wagtmann, N. Gene 2002, 299, 185.
15. 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. Proc. Natl. Acad. Sci. U.S.A. 1994, 91, 5657.
16. McDonald, J. K.; Leibach, F. H.; Grindeland, R. E.; Ellis,
S. J. Biol. Chem. 1968, 243, 4143.
17. Lankas, G. R.; Leiting, B.; Sinha Roy, R.; 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, X.; Zhu, L.; Weber, A. E.; Thornberry, N. A.
Diabetes 2005, 54, 2988.
18. Sami, T. The Pink Sheet DAILY, Jan. 22, 2007.
19. For earlier studies, see: (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. Bioorg.
Med. Chem. Lett. 2004, 14, 4759; (b) Brockunier, L.;
He, J.; Colwell, L. F., Jr.; 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.
Bioorg. Med. Chem. Lett. 2004, 14, 4763; (c) Edmondson,
S. D.; Mastracchio, A.; Beconi, M.; Colwell, L., Jr.;
Habulihaz, H.; He, H.; Kumar, S.; Leiting, B.; Lyons, K.;
Mao, A.; Marsilio, F.; Patel, R. A.; Wu, J. K.; Zhu, L.;
Thornberry, N. A.; Weber, A. E.; Parmee, E. R. Bioorg.
Med. Chem. Lett. 2004, 14, 5151.
Figure 2. The binding of compound 29b to the DPP-4 enzyme. Red
dotted lines portray the interactions with 29b with DPP-4. For clarity
purposes, the extensive hydrogen bonding network between water
molecules, compound 29b, and protein atoms has been omitted.
DPP-4 potency, selectivity, and pharmacokinetics; how-
ever, due to unacceptable muscarinic receptor binding
activities (M2 Ki = 0.470 lM: and M4 Ki = 0.800 lM),
further development of compound 29b was
discontinued.
References and notes
1. For recent GLP-1 references, see: (a) Holst, J. J. Curr.
Opin. Endocrin. Diabetes 2005, 12, 56; (b) Knudsen, L. B.
J. Med. Chem. 2004, 47, 4128; (c) Vahl, T. P.; D’Alessio,
D. A. Expert Opin. Invest. Drugs 2004, 13, 177.
2. For recent reviews see (a) Weber, A. E. J. Med. Chem.
2004, 47, 4135; (b) von Geldern, T. W.; Trevillyan, J. M.
Drug Dev. Res. 2006, 67, 627; (c) Augustyns, K.; der
Veken, P. V.; Haemers, A. Expert Opin. Ther. Patents
2005, 15, 1387.
3. (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) U.S. Patent 6,699,871 B2, 2004.
4. Sambaiah, T.; Reddy, K. K. Indian J. Chem., Sect. B 1992,
31b, 444.
5. Fink, D.; Kurys, B. Tetrahedron Lett. 1996, 37, 995.
20. The structure of DPP-4 in complex with a triazolopiper-
azine-based beta amino acid inhibitor has been assigned
the RCSB code rcsb043852 and PDB ID code 2QOE.