Structure-based design and synthesis of benzimidazole derivatives as dipeptidyl peptidase IV inhibitors

Article abstract of DOI:10.1016/j.bmcl.2008.02.071

A novel series of non-covalent, benzimidazole-based inhibitors of DPP-4 has been developed from a small fragment hit using structure-based drug design. A highly versatile synthetic route was created for the development of SAR, which led to the discovery o

Full text of DOI:10.1016/j.bmcl.2008.02.071

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Bioorganic & Medicinal Chemistry Letters 18 (2008) 2362–2367
Structure-based design and synthesis of benzimidazole derivatives
as dipeptidyl peptidase IV inhibitors
Michael B. Wallace,* Jun Feng, Zhiyuan Zhang, Robert J. Skene, Lihong Shi,
Christopher L. Caster, Daniel B. Kassel, Rongda Xu and Stephen L. Gwaltney, II
Takeda San Diego, Drug Discovery, 10410 Science Center Drive, San Diego, CA 92121, USA
Received 13 January 2008; revised 25 February 2008; accepted 27 February 2008
Available online 4 March 2008
Abstract—A novel series of non-covalent, benzimidazole-based inhibitors of DPP-4 has been developed from a small fragment hit
using structure-based drug design. A highly versatile synthetic route was created for the development of SAR, which led to the dis-
covery of potent and selective inhibitors with excellent pharmaceutical properties.
ꢀ 2008 Elsevier Ltd. All rights reserved.
Dipeptidyl peptidase IV (DPP-4) is a serine protease that
cleaves N-terminal dipeptides from polypeptides having
Pro (or Ala) at the penultimate position.1 DPP-4 rapidly
cleaves and inactivates the incretin glucagon-like peptide
1 (GLP-1) in the blood. The active form of GLP-1 en-
hances glucose-stimulated insulin release from beta cells
in the pancreas. Inhibition of DPP-4 can serve as an
indirect way to increase the levels of circulating GLP-
1, and it has been shown to increase insulin secretion
and effectively regulate blood glucose levels.2 DPP-4
inhibitors are highly effective therapeutic agents in the
treatment of type 2 diabetes.3 Clinical validation has
been established with the FDA approval of sitagliptin
(JanuviaTM),4 as well as the progression of several other
candidates through advanced stages of development.5
focused our attention on developing non-covalent inhib-
itors of DPP-4. In addition, we aimed to design inhibi-
tors that would be potent, selective, and orally active.
We began our design of novel, non-covalent DPP-4 inhib-
itors with the aid of a co-crystal structure of DPP-4 with
compound 1, commercially available 2-phenylbenzyl-
amine. Although this fragment was found to be a weak
inhibitor of DPP-4 (IC50 = 30 lM),8 we considered it to
be a very attractive starting point due to its low molecular
weight and functional simplicity. In addition, this frag-
ment is related to the 2-phenyl-aminomethyl-heterocycle
motif contained within other DPP-4 inhibitors.9
NH2
NH2
H
Numerous classes of DPP-4 inhibitors have been re-
ported, most of which are derived from a- and b-amino
acids that mimic the N-terminal dipeptide residues of
natural substrates. Many of the reported DPP-4 inhibi-
tors make a covalent interaction with the Ser630 residue
in the S1 pocket.6 Both sitagliptin and alogliptin (SYR-
322)5e are notable exceptions. In some DPP-4 inhibitors,
the electrophile inherent in a covalent inhibitor in com-
bination with the basic nitrogen necessary for high-affin-
ity binding leads to chemical instability.7 Therefore, we
N
N
1
2
Several important interactions can be observed from the
co-crystal structure of compound 1 in the DPP-4 active
site (Fig. 1).10 The basic nitrogen forms a salt bridge be-
tween both Glu205 and Glu206, as well as a hydrogen
bond with Tyr662; the ortho-phenyl ring occupies the
S1 pocket formed by Tyr666, Trp659, Tyr631, Val656,
Val711, and Tyr662; and a stacking interaction can be
observed between the central phenyl ring and Tyr547.
The catalytic triad of Ser630, His740, and Asp708 does
not interact directly with compound 1.
Keywords: Dipeptidyl peptidase IV; DPP-4; Benzimidazole; Diabetes;
X-ray structure.
*
Corresponding author. Tel.: +1 858 731 3598; fax: +1 858 550
0526; e-mail: michael.wallace@takedasd.com
0960-894X/$ - see front matter ꢀ 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2008.02.071

M. B. Wallace et al. / Bioorg. Med. Chem. Lett. 18 (2008) 2362–2367
2363
amine appendage to a range that includes the preferred
conformation seen in the crystal structure. Compound
3a showed a 10-fold increase in potency (IC50 = 1.0 lM)
over compound 2, validating our rationale for the de-
sign, while the isomer 3b showed a predicted decrease
in potency (IC50 = 40 lM). Although the N-alkylated
benzimidazole 3a has lost any possibility of gaining
affinity through a hydrogen-bonding interaction with
the backbone carbonyl of Glu205, the gain in affinity
due to conformational restriction more than compen-
sates for this.
Structural information was used to guide us in our SAR
development from compound 3a (Fig. 3). The position
on the phenyl ring that appeared to be most promising
for gaining affinity was the ortho-position, given the
available room to build and possibility for interaction
with nearby Arg125. There also appeared to be a small
hydrophobic pocket at the para-position. Substituents
larger than a methyl group at R1 seemed possible, pro-
vided that these larger groups would be able to pack
along the backbone of Glu206 and Val207 while direct-
ing towards Arg358. Substitution at R2 seemed promis-
ing due to the possibility of creating an interaction with
Ser209. Finally, derivatization at R5 looked highly
promising due to the close proximity of Ser630.
Figure 1. X-ray co-crystal structure of compound 1 bound in the DPP-
4 active site.
Utilizing this structure in molecular modeling, we pre-
dicted that the bicyclic benzimidazole ring of compound
2 would provide an additional p-stacking interaction
with Arg125, while possibly allowing for a hydrogen-
bonding interaction with the backbone carbonyl of
Glu205. In addition, the benzimidazole ring would pro-
vide a drug-like, heterocyclic central scaffold that would
be synthetically tractable in further derivatization and
SAR development.
The synthesis of the initial core compounds 2 and 3a is
outlined in Scheme 1.11 2-Amino-6-chloro-3-nitro-ben-
zonitrile 4a (R1 = H) was prepared according to the
method of Goldberg and coworkers.12 A Suzuki reac-
tion with phenylboronic acid gave compound 5a
(R = H), and subsequent nitro reduction by hydrogena-
tion led to intermediate 6a. Acid catalyzed condensation
with formic acid gave compound 7a (R2 = H), which
was reduced by high-pressure hydrogenation to produce
compound 2. Alkylation of intermediate 7a with dimeth-
ylsulfate followed by hydrogenation yielded compounds
3a and 3b as a 2:1 ratio of isomers.
The prototype compound 2 showed only a modest
improvement in potency (IC50 = 12 lM). We reasoned
that this compound could adopt a low-energy confor-
mation with an internal hydrogen bond between the
benzylic amine and the benzimidazole nitrogen. The
molecule would need to overcome such an interaction
(at significant energy cost) in order to adopt the proper
conformation for optimal binding in the active site of
the protein. The N-methylated compound 3a (Fig. 2)
was designed in order to prevent such an internal hydro-
gen bond, as well as restrict the rotation of the methyl-
The original synthetic scheme was expanded and modi-
fied to allow for SAR development at multiple positions
on the core. The general route outlined in Scheme 1 was
used in the syntheses of compounds 8–24. The R1
groups were installed from the start of the sequence by
the selective SNAr displacement of the C-2 chlorine of
2,6-dichloro-3-nitro-benzonitrile with primary amines.
Subsequent Suzuki reactions with R-substituted arylbo-
ronic acids led to intermediates 5. Nitro reductions were
carried out with hydrogenation as before, or by using
Arg125
NH2
Trp659
Val656
backbone of
Glu206, Val207
Arg358
R1
R
N
N
R2
Ser209
R5
Ser630
Figure 3. SAR strategy for benzimidazole DPP-4 inhibitors.
Figure 2. Benzimidazole conformations leading to the design of
N-methyl benzimidazole isomers 3a and 3b.

2364
M. B. Wallace et al. / Bioorg. Med. Chem. Lett. 18 (2008) 2362–2367
R
CN
CN
CN
H
N
H
c
Cl
Cl
Cl
b
N
R1
a
R1
NO2
NO2
NO2
4a-e
5a-o
R
R
R
NH2
R1
CN
CN
H
N
R1
e
d
N
N
N
R1
R2
R2
N
NH2
2, 8-24
7a-r
6a-o
NH2
NH2
CN
H
N
f, e
N
N
N
N
+
N
3b
3a
7a
Scheme 1. Synthesis of compounds 2–24. Reagents and conditions: (a) R1NH2, THF; (b) R-Ph-B(OH)2, Pd2dba3, DavePhos, K3PO4, DMA, 68 ꢁC;
(c) H2, Pd/C, MeOH; or Fe, HOAc; (d) R2CO2H, PPA; (e) H2, Pd/C, HOAc, MeOH, 50 p.s.i.; or 1—BH3ÆTHF, reflux, 1 h; 2—HCl; (f)
dimethylsulfate, K2CO3.
iron in acetic acid in instances with halogen-containing
substrates. The resulting diamine compounds 6 were
NH2
CN
H
a , b
N
heated with carboxylic acids (or esters) in the presence
of a catalytic amount of PPA to give the benzimidazoles
7 with R2 groups in place. Finally, nitrile reductions oc-
curred optimally through either high-pressure hydroge-
nation or borane reduction to yield the final
compounds 8–24.
N
N
N
Cl
Cl
NH2
25
6b
NH2
N
c , b
O
The synthetic scheme was amenable to simple core mod-
ifications as well (Scheme 2). The benzotriazole 25 and
benzimidazolone 26 were synthesized by treatment of
the aniline 6b (R = 2-Cl, R1 = Me) with sodium nitrite
or carbonyldiimidazole, respectively, followed by bor-
ane reduction of the nitrile to give the desired amines.
Cl
N
H
26
Scheme 2. Synthesis of benzotriazole and benzimidazolone com-
pounds 25 and 26. Reagents and conditions: (a) NaNO2, HCl; (b)
1—BH3ÆTHF, reflux, 1 h; 2—HCl; (c) CDI, THF.
Cl
Cl
Cl
CN
CN
CN
H
N
H
N
b, c
d
a
N
N
NO2
Br
NO2
Br
27
5b
28
Cl
NH2
Cl
NH2
Cl
NH2
h
N
N
e, f, g
N
N
O
N
N
Br
NC
29
30
31
NH2
Scheme 3. Synthesis of compounds 29–31. Reagents and conditions: (a) Br2, HOAc, 88 ꢁC; (b) Fe, HOAc; (c) formic acid, PPA; (d) 1—BH3ÆTHF,
reflux; 2—HCl; (e) BOC2O; (f) Zn(CN)2, Pd2dba3, DavePhos, K3PO4, DMA, 92 ꢁC; (g) TFA, CH2Cl2; (h) H2O2, KOH, MeOH.

M. B. Wallace et al. / Bioorg. Med. Chem. Lett. 18 (2008) 2362–2367
Table 1. Selected data for benzimidazole analogues: R and R1-modified compounds
2365
NH2
N
R1
R
N
Compound
R
R1
DPP-4 IC50 (lM)
DPP-8 IC50 (lM)
RLM/HLM t1/2 (min)
3a
8
H
Me
Me
1.0
0.4
63
46/93
2-CH2OH
2-Cl
NT
50
39/100
57/>200
NT/NT
NT/NT
NT/NT
28/183
46/>200
NT/NT
NT/NT
46/129
42/>200
32/>200
4/8
9
Me
Me
0.063
4.0
2.0
10
11
12
13
14
15
16
17
18
19
20
2-CONH2
2-OMe
2-OH
NT
NT
NT
80
Me
Me
1.6
2-Me
Me
Me
0.098
0.062
0.32
0.79
0.63
0.066
0.096
0.102
2,4-Di-Cl
2-Cl, 5-F
2,4-Di-F
2,4-Di-Cl
2,4-Di-Cl
2-Cl
25
Me
Me
NT
NT
32
H
Et
50
20
CH2CH2OH
Bn
2-Cl
>100
NT, not tested.
Table 2. Selected data for benzimidazole analogues: R2 and R5-modified compounds
Cl
NH2
N
X R2
R5
N
Compound
X
R2
R5
DPP-4 IC50 (lM)
DPP-8 IC50 (lM)
RLM/HLM t1/2 (min)
9
21
22
23
24
25
26
29
30
31
C
H
Me
H
0.063
0.160
0.097
0.066
0.011
0.061
0.052
0.050
0.008
0.032
50
57/>200
7/>200
2/>200
11/>200
26/96
C
H
NT
32
C
Et
CH2OCH3
3-Pyridyl
H
C
H
40
4.0
C
H
N
C@O
C
H
40
13/29
76/>200
24/176
H
Br
>100
>100
>100
32
H
H
H
C
CN
CONH2
38/>200
>200/>200
C
NT, not tested.
The synthesis of R5-substituted compounds 29–31 is
illustrated in Scheme 3. Bromination of intermediate
5b selectively produced compound 27. Nitro reduction,
benzimidazole formation, and nitrile reduction were car-
ried out as previously described to produce compound
29. Boc-protection of the resulting amine was necessary
prior to palladium-catalyzed cyanation of the aryl bro-
mide, and subsequent Boc-deprotection gave compound
30. Finally, hydrolysis of the nitrile with basic peroxide
yielded the benzamide compound 31. Compounds 29–31
were determined to exist as diastereomeric mixtures of
atropisomers by chiral SFC analysis.13 Experimental
data were collected for the compound mixtures.
Results of initial SAR development for the series are
shown in Table 1. Substitution at the ortho-position of
the phenyl ring with a methyl or preferably chloro group
(compounds 13 and 9, respectively) provided a substan-
Figure 4. X-ray co-crystal structure of compound 30 in the DPP-4
active site.

2366
M. B. Wallace et al. / Bioorg. Med. Chem. Lett. 18 (2008) 2362–2367
Table 3. Selected PK parameters for compounds 14, 26, and 30
Compound
Dose iv/oral (mg/kg)
iv t1/2 (h)
Oral t1/2 (h)
AUCpo (lg h/mL)
Vdss (mL/kg)
F (%)
14
26
30
0.8/8
0.7/8.4
1.0/11.6
7.0
4.2
3.8
4.4
4.0
2.9
11.5
9.0
4808
1137
1073
100
49
22.1
122
tial (>10·) boost in potency. Larger or more polar
groups were not as well tolerated. The addition of a
chlorine at the para-position had little effect. SAR at
the R1 position demonstrated that groups larger than
methyl could be tolerated, but no additional improve-
ment in activity was observed.
Acknowledgments
The authors appreciate the drug-discovery expertise of
Jeffrey Stafford and Stephen Kaldor. We thank G. Sri-
dhar Prasad, Gyorgy Snell, Melinda Manuel, Lu Zeng,
and Derek B. Laskar for their valuable experimental
assistance. We also thank Andrew Jennings for technical
assistance in computational chemistry. The X-ray crys-
tallography data reported here are based on research
conducted at the Advanced Light Source (ALS). ALS
is supported by the Director, Office of Science, Office
of Basic Energy Sciences, Materials Sciences Division,
of the U.S. Department of Energy (DOE) under Con-
tract No. DE-AC03-76SF00098 at Lawrence Berkeley
National Laboratory. We thank the staff at ALS for
their excellent support in the use of the synchrotron
beam lines.
Once the R and R1 groups were optimized (R = 2-Cl,
R1 = Me), we turned our attention to SAR work at R2
and R5 (Table 2). Substitution at R2 with a 3-pyridyl
group (compound 24) resulted in a sixfold increase in
potency (IC50 = 11 nM), demonstrating the utility in
optimal engagement of Ser209. In addition, the central
core could be modified to the benzotriazole 25 or the
benzimidazolone 26 without significant change in activ-
ity. Substitution at R5 proved to be highly productive,
with the 5-cyano group (compound 30) imparting the
greatest
improvement
in
enzyme
inhibition
(IC50 = 8 nM). This low molecular weight compound
also displayed excellent selectivity over the related S9B
protease DPP-8.
References and notes
1. (a) Yaron, A.; Naider, F. Crit. Rev. Biochem. Mol. Biol.
1993, 28, 31; (b) Heins, J.; Welker, P.; Scho¨nlein, C.; Born,
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Biochim. Biophys. Acta 1988, 954, 161.
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3. (a) Gwaltney, S. L.; Stafford, J. A. Ann. Rep. Med. Chem.
2005, 40, 149; (b) Green, B. D.; Flatt, P. R.; Bailey, C. J.
Diabetes Vasc. Dis. Res. 2006, 3, 159; (c) Drucker, D. J.;
The co-crystal structure of compound 30 in the DPP-4
active site is shown in Figure 4.14 A single atropisomer
of the compound preferentially co-crystallizes with the
enzyme. In addition to the interactions described for
compound 1, the benzimidazole ring displays a p-stack-
ing interaction with Arg125. The chlorine on the phenyl
ring favorably increases the dihedral angle of the bicyclic
system and also makes an electrostatic interaction with
Arg125. The 5-cyano group favorably interacts with
neighboring residues and locks the orthogonal confor-
mation of the bicyclic system.
´
Nauck, M. A. Lancet 2006, 368, 1696; (d) Ahren, B.
Diabetes Care 2007, 30, 1344.
4. (a) Herman, G. A.; Bergman, A.; Liu, F.; Stevens, C.;
Wang, A. Q.; Zeng, W.; Chen, L.; Snyder, K.; Hilliard, D.;
Tanen, M.; Tanaka, W.; Meehan, A. G.; Lasseter, K.;
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McCann, M. E.; Patel, R. A.; Petrov, A.; Scapin, G.;
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B. B.; Zhu, L.; Thornberry, N. A.; Weber, A. E. J. Med.
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After acceptable enzymatic activity and microsomal
stability were demonstrated for compounds 14, 26,
and 30, the pharmacokinetic properties of these
compounds were determined in rats (Table 3). Com-
pound 14 showed long half-life, low clearance, and
excellent oral bioavailability. Compounds 26 and 30
showed moderate half-lives, low clearance, and mod-
erately high volume of distribution. The oral bio-
availability was determined to be 49% for
compound 26 and in excess of theoretical 100%
for compound 30.
´
5. (a) Ahren, B.; Gomis, R.; Standl, E.; Mills, D.; Schweizer,
A. Diabetes Care 2004, 27, 2874; (b) Ahren, B. Expert
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Opin. Investig. Drugs 2006, 15, 431; (c) 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; (d) Augeri, D. J.;
Robl, J. A.; Betebenner, D. A.; Magnin, D. R.; Khanna,
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P.; Huang, Q.; Han, S.-P.; Abboa-Offei, B.; Cap, M.; Xin,
L.; Tao, L.; Tozzo, E.; Welzel, G. E.; Egan, D. M.;
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A.; Kaldor, S. W.; Kassel, D. B.; Navre, M.; Shi, L.;
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In summary, we have utilized structure-based design to
build a novel series of non-covalent benzimidazole-
based DPP-4 inhibitors from a small fragment lead.
SAR development led to the discovery of multiple com-
pounds which are potent and selective while maintaining
excellent physical properties and drug-like characteris-
tics. We have developed highly versatile synthetic
schemes for the rapid development of SAR around this
core.

M. B. Wallace et al. / Bioorg. Med. Chem. Lett. 18 (2008) 2362–2367
2367
6. (a) Engel, M.; Hoffmann, T.; Wagner, L.; Wermann, M.;
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from the enzyme progress curves using standard mathe-
matical models.
9. (a) Peters, J.-U.; Weber, S.; Kritter, S.; Weiss, P.; Wallier,
A.; Boehringer, M.; Hennig, M.; Kuhn, B.; Loeffler, B.-M.
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8. DPP-4 Assay: Solutions of test compounds in varying
concentrations (610 mM final concentration) were pre-
pared in DMSO and then diluted into assay buffer
comprising: 20 mM Tris, pH 7.4; 20 mM KCl; and
0.1 mg/mL BSA. Human DPP-4 (0.1 nM final concentra-
tion) was added to the dilutions and pre-incubated for
10 min at ambient temperature before the reaction was
initiated with A-P-7-amido-4-trifluoromethylcoumarin
(AP-AFC; 10 lM final concentration). The total volume
of the reaction mixture was 10–100 lL depending on assay
formats used (384 or 96 well plates). The reaction was
followed kinetically (excitation k = 400 nm; emission
k = 505 nm) for 5–10 min or an end-point was measured
after 10 min. Inhibition constants (IC50) were calculated
S.; Muller, A.; Wallier, A.; Ricklin, F.; Boehringer, M.;
¨
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10. Protein Data Bank code is 3CCB.
11. Full experimental procedures for all syntheses are con-
tained within the following patent application: Feng, J.;
Gwaltney, S. L.; Wallace, M. B.; Zhang, Z. PCT Int.
Patent Appl. WO 05/118555, 2005.
12. Goldberg, D. R.; Butz, T.; Cardozo, M. G.; Eckner, R. J.;
Hammach, A.; Huang, J.; Jakes, S.; Kapadia, S.; Kashem,
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14. Protein Data Bank code is 3CCC.