Discovery of Novel Tricyclic Heterocycles as Potent and Selective DPP-4 Inhibitors for the Treatment of Type 2 Diabetes

Article abstract of DOI:10.1021/acsmedchemlett.6b00027

In our efforts to develop second generation DPP-4 inhibitors, we endeavored to identify distinct structures with long-acting (once weekly) potential. Taking advantage of X-ray cocrystal structures of sitagliptin and other DPP-4 inhibitors, such as alogliptin and linagliptin bound to DPP-4, and aided by molecular modeling, we designed several series of heterocyclic compounds as initial targets. During their synthesis, an unexpected chemical transformation provided a novel tricyclic scaffold that was beyond our original design. Capitalizing on this serendipitous discovery, we have elaborated this scaffold into a very potent and selective DPP-4 inhibitor lead series, as highlighted by compound 17c.

Full text of DOI:10.1021/acsmedchemlett.6b00027

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Letter
Discovery of Novel Tricyclic Heterocycles as Potent and
Selective DPP-4 Inhibitors for the Treatment of Type 2 Diabetes
Wen-Lian Wu, Jinsong Hao, Martin Domalski, Duane A Burnett, Dmitri Pissarnitski,
Zhiqiang Zhao, Andrew W Stamford, Giovanna Scapin, Ying Duo Gao, Aileen Soriano,
Terri M Kelly, Zuliang Yao, Mary Ann Powles, Shiying Chen, Hong Mei, and Joyce Hwa
ACS Med. Chem. Lett., Just Accepted Manuscript • DOI: 10.1021/acsmedchemlett.6b00027 • Publication Date (Web): 12 Mar 2016
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Discovery of Novel Tricyclic Heterocycles as Potent and Selective DPP-4 Inhibitors
for the Treatment of Type 2 Diabetes
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WenꢀLian Wu,*,† Jinsong Hao,† Martin Domalski,† Duane A. Burnett,† Dmitri Pissarnitski,† Zhiqiang
Zhao,† Andrew Stamford,† Giovanna Scapin,║ YingꢀDuo Gao,║ Aileen Soriano,‡ Terri M. Kelly,‡
Zuliang Yao,‡ Mary Ann Powles,‡ Shiying Chen,§ Hong Mei,§ Joyce Hwa‡
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†Department of Lead Optimization Chemistry, ║Department of Structural Chemistry, ‡Department of
Pharmacology, and §Department of Pharmacokinetics, Pharmacodynamics, and Drug Metabolism ,
Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States
* To whom correspondence should be addressed.
Phone 908ꢀ740ꢀ3987. Eꢀmail: wenꢀlian.wu@merck.com
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Discovery of Novel Tricyclic Heterocycles as Potent and
Selective DPP-4 Inhibitors for the Treatment of Type 2
Diabetes
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WenꢀLian Wu, Jinsong Hao, Martin Domalski, Duane A.
Burnett, Dmitri Pissarnitski, Zhiqiang Zhao, Andrew
Stamford, Giovanna Scapin, YingꢀDuo Gao, Aileen Soriano,
Terri Kelly, Zuliang Yao, Mary Ann Powers, Shiying Chen,
Hong Mei, Joyce Hwa
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In our efforts to develop second generation DPPꢀ4 inhibitors, we endeavored to identify distinct structures with
longꢀacting (once weekly) potential. Taking advantage of Xꢀray coꢀcrystal structures of sitagliptin and other DPPꢀ4
inhibitors such as alogliptin and linagliptin bound to DPPꢀ4, and aided by molecular modeling, we designed several
series of heterocyclic compounds as initial targets. During their synthesis, an unexpected chemical transformation
provided a novel tricyclic scaffold that was beyond our original design. Capitalizing on this serendipitous discovery,
we have elaborated this scaffold into a very potent and selective DPPꢀ4 inhibitor lead series, as highlighted by
compound 17c.
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Key Words
Diabetes, dipeptidyl peptidase IV (DPP−4), inhibitor, tricyclic heterocycles, crystal structure, OGTT
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Diabetes mellitus remains a challenging health
conformationally restricted analogues of
sitagliptin culminated in discovery,
problem that affects 415 million adults
worldwide as of 2015, with an alarming growth
predicted over the next quarter of century.1
Typeꢀ2 diabetes (T2DM), a chronic disease
characterized by elevated blood sugar levels and
insulin resistance, is the most prevalent form.
Dipeptidyl peptidase IV (DPPꢀ4), a serine
protease in blood, regulates glucose metabolism
through degradation of the incretins glucagonꢀ
like peptide 1 (GLPꢀ1) and glucoseꢀdependent
insulinotropic polypeptide (GIP) that are
secreted following a meal. Inhibition of DPPꢀ4
thus increases the levels of GLPꢀ1 and GIP,
which inhibits glucagon release and in turn
stimulates insulin secretion thereby reducing
blood glucose levels.2 Indeed, the usefulness of
DPPꢀ4 inhibitors for treatment of T2DM has
been demonstrated by the successful launch of
JANUVIA® (sitagliptin, 1, Figure 1), the first
DPPꢀ4 inhibitor approved by the U.S. Food and
Drug Administration.3 Systematic structureꢀ
activity relationship (SAR) studies of
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development, and launch of MARIZEV®
(omarigliptin, 2) as a onceꢀweekly treatment for
T2DM.4 Over the last decade, several other
DPPꢀ4 inhibitors with distinct structures have
also been developed, such as 3 (alogliptin),5 and
4 (linagliptin).6
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Figure 1 Representative DPPꢀ4 inhibitors
In our continued efforts to develop second
generation DPPꢀ4 inhibitors, we endeavored to
identify distinct structures with longꢀacting
(once weekly, QW) potential. Taking advantage
of available Xꢀray coꢀcrystal structures of
sitagliptin and other DPPꢀ4 inhibitors under
lateꢀstage development such as alogliptin and
linagliptin bound to DPPꢀ4, and assisted by
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molecular modeling, we designed several series
should give intermediate 8, and activation of the
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7
8
of heterocyclic compounds as initial synthetic
targets (Figure 2).7 Over the course of the
hydroxy of 8 would result in ring closure to
provide the tricyclic guanine scaffold.
However, treatment of 7 with 2ꢀaminoethanol in
DMF under microwave heating conditions did
not give any expected product 8 as judged by
LCꢀMS, although the starting material was
consumed. Instead, an amidine compound 9
was isolated and its structure has been verified
rigorously.9
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synthesis,
an
unexpected
chemical
transformation provided a novel tricyclic
scaffold. Capitalizing on this serendipitous
discovery, we elaborated the scaffold into a very
potent and selective DPPꢀ4 inhibitor lead series.
In this communication, we report our
preliminary findings and results of initial SAR
exploration.
Scheme 1 Synthesis of cyclic guanines
Figure 2 Design of cyclic guanine scaffold
As depicted in Scheme 1, we planned to
construct the tricyclic guanine scaffold starting
from the readily available 2,6ꢀdichloropurine
derivative 5.8 Compound 5 was hydrolyzed
selectively to give 6, which in turn was
alkylated under basic conditions to afford
intermediate 7. At this stage, we reasoned that
substitution of a βꢀaminoalcohol for the chlorine
Reagents and conditions: (a) NaOH, 90%; (b)
BrCH2CN,
DIEA,
DMF,
55%;
(c)
HOCH2CH2NH2, DMF, 120 oC, 65%.
Although our plan did not work out, we were
curious to explore the reaction at lower
temperatures using simple methylamine, as
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outlined in Scheme 2. Mixing compound 7 with
With identification of the compelling novel
5
6
7
8
an excess amount of methylamine as a solution
in 1,4ꢀdioxane at room temperature, or even at 0
oC, brought about a fast reaction (in less than 10
min.) to give amidine 10 as the major product
along with some lactam 11. This result was
quite surprising because amidine formation
from a nitrile usually occurs under harsh
conditions or in the presence of catalysts.10
What was more striking was identification of
lactam 11 as a minor product, presumably
through hydrolysis of 10, hinting that the
amidine moiety might be easily converted to the
more stable lactam. To our great pleasure, a
mixture of compounds 10 and 11 was refluxed
in 6 N HCl to give compound 12, with
migration of the NꢀPMB group from N3 to
N1.11 Lactams 11 and 12 can be differentiated
by LCꢀMS and TLC, but their difference in
protection regiochemistry is inconsequential
because the PMB group was removed by TFA
in the next step to give tricyclic core 13.
tricyclic scaffold of compound 13, we
endeavored to scale up this structure and
elaborate it to generate tricyclic targets as DPPꢀ
4 inhibitors. The stability of the tricyclic core
under the above harsh acidic hydrolysis
conditions further augmented our confidence in
its usefulness. After bromination at the C2
position of intermediate 13, Nꢀalkylation of the
imidazole moiety of 14 gave a mixture of
substituted regioisomers 15aa-15ea and 15ab-
15eb. Finally, displacement of the C2ꢀbromide
of the isolated N1ꢀalkylated compound 15ca
with the (R)ꢀ3ꢀaminopiperidine moiety, an
optimized structural feature in both alogliptin
and linagliptin, gave intermediate 16c, and
removal of NꢀBoc group furnished target 17c.
Analogues 17a, 17b, 17d, and 17e were
prepared from the corresponding mixtures of
regioisomers 15 using the above twoꢀstep
procedures. Ethyl substituted analogues 25a-
25c were prepared accordingly using ethylamine
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instead of methylamine in the first step of
at N1. Replacement of the butyꢀ2ꢀnyl group
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5
6
7
8
Scheme 2.
with a 2ꢀcyanobenzyl moiety improved potency
significantly (17b, IC50 = 10.6 nM), comparable
to that of alogliptin (3, IC50 = 7.6 nM). Further
improvement was achieved with an additional 5ꢀ
fluoro substituent on the benzyl ring (17c, IC50
= 1.7 nM). Electron withdrawing replacements
of the cyano group (17d and 17e) decreased
potency. N5ꢀEthyl substituted analogs are
similarly potent (25b vs. 17d) or less potent
(25a vs. 17c and 25c vs. 17e) than the
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Scheme 2 Identification of a novel scaffold and
elaboration to tricyclic DPPꢀ4 inhibitors
O
O
O
N
N
a
b
NC
R
N
N
N
N
N
N
+
N
O
N
N
N
N
N
Cl
N
R
PMB
R
PMB
PMB
7
10 R = Me
R = Et
11 R = Me
R = Et
18
19
O
N
O
N
O
PMB
H
N
H
N
N
N
c
d
N
N
N
O
Br
O
O
N
R
N
N
N
N
N
R
R
12 R = Me
13 R = Me
21
14 R = Me
22
R = Et
20
R = Et
R = Et
O
N
O
R1
e
f
N
N
N
N
N
+
O
Br
O
Br
N
N
R
N
N
R1
15ab-15eb
R = Me
23ab-23cb R = Et
R
15aa-15ea
23aa-23ca R = Et
R = Me
O
N
O
R1
N
R1
g
N
N
N
corresponding
Nꢀmethyl
substituted
O
N
O
N
N
N
N
N
N
R
NHBoc
R
NH2
+ N3-R1 regioisomers
16a-16e
counterparts. The most active analogues 17b,
17c, 17d, 25a and 25b (IC50 < 100 nM) were
also counterscreened against other related
enzymes12 such as QPP,13 DPP8,14 DPP9,15 and
FAP.16 All analogs except 25a showed no
activity against QPP, DPPꢀ8 and DPPꢀ9 (>100
ꢀM, data not reported in Table 1) and great
17a-17e
R = Me
24a-24c R = Et
R = Me
25a-25c R = Et
Reagents and conditions: (a) MeNH2 or EtNH2,
1,4ꢀdioxane, room temperature; (b) 6 N HCl,
reflux, ~100% over 2 steps; (c) TFA, ~ 90%; (d)
Br2, 50ꢀ60%; (e) R1Br, NaH, 40ꢀ60%; (f) (R)ꢀ
3ꢀ(Bocꢀamino)piperidine; (g) TFA, DCM, ~20ꢀ
40% over two steps.
Analogues were evaluated for their in vitro
inhibition of human DPPꢀ4, and the results are
summarized in Table 1. Analogue 17a (IC50 =
123 nM) bearing a butꢀ2ꢀynyl group on N1 is
much less potent than linagliptin (4, IC50 = 0.10
nM), which has an extra quinazoline substituent
selectivity against FAP.
Compound 25a
showed no activity against QPP but modest
activity against DPPꢀ8 and DPPꢀ9 (IC50
21,163 nM and 15,828 nM, respectively).
=
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Table 1 In vitro biological dataa
3
4
activity with an IC50 of 40 ꢀM. It had no PXR
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9
inhibition (IC50 > 30 ꢀM). Compound 17c also
exhibited low hepatocyte clearance across
species (human, rat, cyno monkey, dog = 0.1,
0.3, <1, <1 ꢀL minꢀ1 106 cellꢀ1, respectively).17
On the basis of its favorable in vitro profile,
compound 17c was evaluated in lean mice for
its ability to improve glucose tolerance (Figure
3). In an oral glucose tolerance test (OGTT), a
single dose of compound 17c (0.3, 1, 3 and 10
mg/kg) was given orally to C57BL/6 mice 1 h
prior to dextrose challenge. Compound 17c
significantly reduced blood glucose excursion in
a doseꢀdependent manner from 0.3 mg/kg to 3
mg/kg with a plateau between 3 and 10 mpk.
The observed reduction of glucose in AUC was
consistent with the measured plasma inhibitor
concentration (0.3 mg/kg, 38% reduction in
glucose AUC, plasma concentration 2 nM; 1
mg/kg, 52% reduction, 10 nM; 3 mg/kg, 64%
reduction, 70 nM; 10 mg/kg, 63% reduction,
235 nM). The maximum efficacy of glucose
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Compd
R
R1
IC50 (nM)
DPPꢀ4
7.6
IC50 (nM)
FAP
>100,000
3
0.1
123.0
10.6
70.8
ND
4
17a
17b
Me
Me
53,600
1.7
27.4
156.1
13.5
11.2
625.0
16,300
>100,000
ND
17c
17d
17e
25a
25b
25c
Me
Me
Me
Et
F
CF3
7,300
>100,000
ND
Et
Et
a
Two internal standard compounds were included in all
the assay runs to track the robustness of the assays (n = 3)
and data were within 3ꢀfold of the reported values.
Standard deviation was within 10%.
Literature
compounds 3 and 4 were also tested for comparison.
The most potent analogue 17c in this new
series of DPPꢀ4 inhibitors was further
characterized. It showed no significant CYP450
inhibition (>50 ꢀM for CYP3A4, 2C8, 2C9 and
2D6) or timeꢀdependent CYP3A4 inhibition.
The compound displayed weak activity in the
MKꢀ499 displacement binding assay for hERG
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lowering in this model was similar to that
achieved with alogliptin at oral dose of 3 mg/kg.
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Figure 4 Ex vivo pharmacodynamic data of
Figure 3 OGTT data of compound 17c
compound 17c
In
the
corresponding
ex
vivo
As revealed in Figure 5, compound 17c
(yellow) binds in the DPPꢀ4 binding site in a
very similar way to that observed for alogliptin
(3, blue). The amino group binds to the
conserved glutamic acids (E205 and E206), and
the CN group is within hydrogen bonding
distance of Arg125. The tricyclic core is
stacked against Y547, forming a more extensive
interaction than that observed with alogliptin.
Elements of the tricyclic core also enage in
hydrogen bonds to the backbone NH of Tyr631,
to the backbone NH of Trp629, to the sideꢀchain
of Lys544 (through a water molecule), and to
two other ordered water molecules.
pharmacodynamic
differentiating
assay,
compound 17c was dosed orally at 1, 3 and 10
mg/kg to C57BL/6N mice, and a time course of
plasma DPPꢀ4 inhibition was measured at 2h, 6h
and 24h. As shown in Figure 4, at doses of 3
and 10 mg/kg, plasma DPPꢀ4 activity was
inhibited by > 80% (uncorrected for assay
dilution) at 2 h and maintained at 6 h. The
effect had returned to near baseline at 24 h. The
relative high ratio of inhibition at 6 h to that at 2
h (≥ 0.8) for all the three doses suggested longꢀ
acting potential for 17c (ratios > 0.7 are
typically a good predictor of extended duration
of action), which is consistent with what the low
in vitro clearance would indicate.
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and critical medicinal chemistry followꢀup of
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the observed biology.
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ABBREVIATIONS
T2DM, type 2 diabetes mellitus; DPPꢀ4,
dipeptidyl peptidase 4; DPPꢀ8, dipeptidyl
peptidase 8; DPPꢀ9, dipeptidyl peptidase 9;
FAP, seprase or fibroblast activation protein;
Figure 5 Superposition of compound 17c
(yellow) and alogliptin (3, blue) in the DPPꢀ4
active site using their coꢀcrystal structures of
DPPꢀ4 (PDB codes 5I7U and 3G0B). The
image was generated using PyMol.
GIP,
glucoseꢀdependent
insulinotropic
polypeptide; GLPꢀ1, glucagan like peptideꢀ1;
QPP, quiescent cell proline dipeptidase; OGTT,
oral glucose tolerance test; QW, onceꢀweekly;
SAR, structureꢀactivity relationship; PMB, paraꢀ
methoxybenzyl; TFA, trifluoroacetic acid.
In summary, we have identified a series of
potent and selective DPPꢀ4 inhibitors with a
novel tricyclic core. Among them, compound
17c demonstrated robust glucose reduction
efficacy after oral administration in mice, as
well as potential for a long duration of action.
The successful identification of this novel class
of DPPꢀ4 inhibitors was made possible by
serendipity as well as careful analytical work
ACKNOWLEDGEMENT
The authors would like to thank Dr. TseꢀMing
Chan for NMR analytical support and helpful
discussion. We also thank Mr. Wilfredo Pinto
for HRMS analysis.
SUPPORTING
INFORMATION
AVAILABLE Experimental details for
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Hicks, J.; Lyons, K.; He, H.; Salituro, G.; Tong, S.;
synthetic
procedures
and
compound
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5
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Patel, S.; Doss, G.; Petrov, A.; Wu, J.; Xu, S.; Sewell,
C.; Zhang X.; Zhang, B.; Thornberry, N. A.; Weber,
A. E. Omarigliptin (MKꢀ3102): a novel longꢀacting
DPPꢀ4 inhibitor for onceꢀweekly treakment of typeꢀ2
diabetes. J. Med. Chem. 2014, 57, 3205ꢀ3212.
characterization for compounds 6-25 as well as
biological assay conditions. This material is
available free of charge via the internet at
http://pubs.acs.org.
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