Discovery and Optimization of a Novel Triazole Series of GPR142 Agonists for the Treatment of Type 2 Diabetes

Article abstract of DOI:10.1021/acsmedchemlett.6b00314

GPR142 has been identified as a potential glucose-stimulated insulin secretion (GSIS) target for the treatment of type 2 diabetes mellitus (T2DM). A class of triazole GPR142 agonists was discovered through a high throughput screen. The lead compound 4 suffered from poor metabolic stability and poor solubility. Lead optimization strategies to improve potency, efficacy, metabolic stability, and solubility are described. This optimization led to compound 20e, which showed significant reduction of glucose excursion in wild-type but not in GPR142 deficient mice in an oral glucose tolerance test (oGTT) study. These studies provide strong evidence that reduction of glucose excursion through treatment with 20e is GPR142-mediated, and GPR142 agonists could be used as a potential treatment for type 2 diabetes.

Full text of DOI:10.1021/acsmedchemlett.6b00314

Letter
pubs.acs.org/acsmedchemlett
Discovery and Optimization of a Novel Triazole Series of GPR142
Agonists for the Treatment of Type 2 Diabetes
Liangqin Guo,*,† Dann L. Parker,† Yi Zang,† Ramzi F. Sweis,† Weiguo Liu,† Edward C. Sherer,†
Nicole Buist,‡ Jenna Terebetski,‡ Terri Kelly,∥ Randal Bugianesi,∥ Birgit T. Priest,∥ Karen H. Dingley,§
Xiaofang Li,§ Stan Mitelman,§ Gino Salituro,§ Maria E. Trujillo,∥ Michele Pachanski,∥ Melissa Kirkland,∥
Mary Ann Powles,∥ George J. Eiermann,∥ Yue Feng,§ Jin Shang,§ Andrew D. Howard,§
Feroze Ujjainwalla,† Christopher J. Sinz,† John S. Debenham,† Scott D. Edmondson,⊥,† Ravi P. Nargund,†
William K. Hagmann,⊥,† and Derun Li*,†
‡
§
†Departments of Medicinal Chemistry‡, Discovery Pharmaceutical Sciences, Pharmacokenetics Pharmacodynamics Drug
Metabolism, ∥Diabetes Research, and Cardiometabolic Disease, Merck & Co., Inc., MRL, 126 East Lincoln Avenue, PO Box 2000,
Rahway, New Jersey 07065, United States
S
* Supporting Information
ABSTRACT: GPR142 has been identified as a potential
glucose-stimulated insulin secretion (GSIS) target for the
treatment of type 2 diabetes mellitus (T2DM). A class of
triazole GPR142 agonists was discovered through a high
throughput screen. The lead compound 4 suffered from poor
metabolic stability and poor solubility. Lead optimization
strategies to improve potency, efficacy, metabolic stability, and
solubility are described. This optimization led to compound
20e, which showed significant reduction of glucose excursion
in wild-type but not in GPR142 deficient mice in an oral glucose tolerance test (oGTT) study. These studies provide strong
evidence that reduction of glucose excursion through treatment with 20e is GPR142-mediated, and GPR142 agonists could be
used as a potential treatment for type 2 diabetes.
KEYWORDS: GPR142 agonists, type 2 diabetes mellitus (T2DM), triazole, glucose-stimulated insulin secretion (GSIS), solubility
ype 2 diabetes mellitus (T2DM) is a disease derived from
Tmultiple causative factors and characterized by elevated
levels of plasma glucose (hyperglycemia) in the fasting state or
after administration of glucose during an oral glucose tolerance
test (oGTT).1 Type 2 diabetic patients have increased risk of
coronary heart disease, peripheral vascular disease, hyper-
tension, nephropathy, and retinopathy.2 Therefore, safe and
Figure 1. Examples of GPR142 agonists.
effective treatments of T2DM are highly desirable. Recently
effects during an oral glucose tolerance test in mice and
monkeys.10 More recently, Wilson et al. reported GPR142
agonist 3 (h-GPR142, FLIPR, EC50 = 63 nM), which was active
in oGTT study in wide type mice, but not in GPR142 deficient
mice.11
there has been a focus on the development of novel agents that
promote glucose-stimulated insulin secretion (GSIS) from
pancreatic β-cells, such as DPP-4 inhibitors,3 which could
minimize the potential risk of hypoglycemia and other adverse
effects associated with many current therapies.4
Herein, we report our hit-to-lead efforts in discovering novel,
potent and orally bioavailable triazole GPR142 agonists and
their pharmacological effects in mice. Triazole 4 was identified
as a GPR142 agonist hit from a high throughput screen (HTS)
(Figure 2).12 It exhibited modest human GPR142 agonist
activity in a FLIPR assay (h-GPR142, FLIPR, EC50 = 115 nM)
and an inositol phosphate (IP) accumulation assay (h-GPR142,
GPR 142 is a Gq-coupled, family A seven transmembrane G-
protein-coupled receptor (GPCR) that is highly expressed in
pancreatic β-cells and has been identified as a potential GSIS
target for the treatment of T2DM.5,6 Considerable interest is
thus centered on the generation of potent and selective small
molecule ligands as possible therapeutic agents for T2DM
patients.7−11 For example, Yu et al. have reported the discovery
of potent aminopyrazole−phenylalanine based GPR142 agonist
1 (Figure 1), which showed GPR142 dependent stimulation of
insulin secretion in isolated mouse islets.9 Toda et al. reported
GPR142 agonist 2, which showed potent glucose lowering
Received: August 10, 2016
Accepted: October 6, 2016
© XXXX American Chemical Society
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Letter
a
Scheme 1. Synthesis of Triazole Analogues 10a−10c
Figure 2. Structure and profile of HTS hit 4.
IP, EC50 = 252 nM).13 Additionally, compound 4 had potent
mouse GPR142 activity (m-GPR142, FLIPR, EC50 = 37 nM;
m-GPR142, IP, EC50 = 23 nM). Unfortunately, 4 only showed
16% reduction of glucose excursion at a 10 mg/kg oral dose in
a mouse oral glucose tolerance test (oGTT).14 Given that 4 has
relatively low mouse microsomal stability (32% remaining after
incubation for 30 min in mouse microsomes), and low
solubility in phosphate buffer solution (PBS) at pH = 2 and
7, a better tool compound for in vivo proof-of-concept studies
was sought.
a
Reagents and conditions: (a) MsCl, Et3N, DCM; (b) NaN3, 15-
crown-5, DMF, 90 °C; (c) CuSO4, sodium ascorbate, t-BuOH/H2O;
(d) HCl, DCM/MeOH; (e) 1-bromonaphthalene, NaOtBu, BrettPhos
Pd G1, dioxane, 60 °C; (f) 1-isocyanatonaphthalene, Et3N, DCE; (g)
1-naphthoyl chloride, TEA, DCE.
FLIPR assay, suggesting that a rigid amide moiety was required
for GPR142 potency.
We then set out to replace the flat naphthyl group (Table 1,
10d−10g) to improve the physicochemical properties of the
current lead. The synthesis of 10d−10g was initiated with ethyl
2-bromoacetate 11 (Scheme 2). Azide displacement of the
We first investigated whether the amide could be replaced by
an amine, a reverse amide, or a urea linker (analogues 10a−10c,
Table 1). The synthesis of 10a−10c started with alcohol 5
a
Scheme 2. Synthesis of Triazole Amide Analogues 10d−10g
a
Table 1. SAR on the Amide and Naphthyl Replacements
a
Reagents and conditions: (a) NaN3, 15-crown-5, DMF, 90 °C; (B)
CuSO4, sodium ascorbate, t-BuOH/H2O; (c) LiOH, THF/MeOH/
H2O; (d) amine, HATU, DIEA, DMF.
bromide followed by the CuAAC reaction afforded triazole 13.
Ester hydrolysis of 13 gave acid 14. Amide coupling of amines
with 14 gave the final analogues 10d−10g. A very tight
structure−activity relationship (SAR) was observed. The
aliphatic tetrahydronaphthalene analogue 10d lost GPR142
activity. While 2,3-difluorophenyl analogue 10e was consid-
erably less potent than 4, the more lipophilic analogues, 2,3-
dimethylphenyl 10f and 2,3-dichlorophenyl 10g, maintained
GPR142 activity in both FLIPR and IP assays.
After we discovered that 2,3-dichlorophenyl could serve as a
replacement for the naphthyl group, we explored the SAR on
the middle phenyl ring, and the left-hand side imidazole ring
(Table 2). The general synthesis of 20a−20f is shown in
Scheme 3. Displacement of the 4-fluoro substituent of aryl
aldehyde 16 with imidazole 15 afforded aldehyde 17.
Alkynylation of aldehyde 17 with the Bestmann−Ohira reagent
afforded alkyne 18, which was reacted with azide 19 to give
triazole products 20a−20f. A similar route was used to prepare
analogue 20g.
As shown in Table 2, 10g demonstrated moderately low
microsome stabilities across various species and poor solubility.
Replacing OMe with F resulted in modestly improved potency
and liver microsome stability (20a). However, 2-fluoro
substitution 20b on the middle phenyl ring reduced potency.
It is noteworthy that the unsubstituted analogues 20c and 20d
maintained good GPR142 potency and showed balanced
human and mouse GPR142 potency in both FLIPR and IP
assays.
a
nd = not determined; assay protocols: see ref 15.
(Scheme 1). Mesylation of 5 followed by azide displacement
gave azide 6. A copper(I)-catalyzed azide−alkyne cycloaddition
(CuAAC) reaction of azide 6 with known alkyne 712 furnished
triazole 8 in good yield. Deprotection of the Boc group of 8
afforded amine 9, which was subsequently converted to 10a−
10c.
FLIPR assays were used to first assess GPR142 potency given
their higher throughput. Potent compounds of interest from
the FLIPR assay were then tested in GPR142 Inositol
phosphate (IP) assays as secondary assays.13 Amine 10a,
reverse amide 10b, and urea 10c lost GPR142 potency in the
B
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increased to 47° with 2-methyl imidazole analogue 20e.18 To
our satisfaction, 20e improved solubility in PBS dramatically at
pH = 2 and modestly at pH = 7, while maintaining good
GPR142 potency. It is worth noting that these dihedral angles
are rather similar and that the influence on solubility may be
small. The substitutions on the molecules modulate the
physicochemical properties and influence the solubility and
metabolic stability, which may explain the poor solubility of
10g, even with a dihedral angle of 44°.18 Since the pH = 7
solubility of 20e was still low, the aza analogue 20f was
designed and synthesized in hope of improving solubility by
reducing cLogP. Although the improvement in solubility was
not significant with this modification, the GPR142 activity was
well tolerated, and human liver microsome stability was further
improved. To further disrupt the planarity, analogue 20g with
an additional methylene linker was prepared. However, this
modification resulted in significant loss of GPR142 activity.
Inspired by the methyl effect in 20e, we were also interested
in whether a methyl group could be incorporated into the right-
hand side of the molecule (Table 3). Indeed the solubilities of
a
Table 2. SAR on the Left Side Imidazole Phenyl Moieties
Table 3. Methylated Analogues of 20e
a
nd = not determined; h/r/m LM % remaining = percentage of
compound remaining intact after incubation in human/rat/mouse liver
microsomes at 1 μM for 30 min at 37 °C.
Scheme 3. General Synthesis of Triazole Analogues 20a−
a
20f
methylated analogues 21a and 21b were significantly improved,
potentially by disrupting the crystal packing of the right-hand of
the molecules.18 Unfortunately, those modifications were not
tolerated for GRP142 activity.
Given their improved GPR142 potency and metabolic
stability, compounds 20a, 20e, and 20f were further profiled
(Table 4). These compounds exhibited acceptable selectivity
profiles in CYPs 3A4 and 2D6 and in cardiac ion channels, and
good permeability (Papp) in LLC-PK1 cells. These compounds
were also evaluated in rat pharmacokinetic studies (rat PK). All
three analogues showed low to modest plasma clearance (Clp)
and good oral bioavailabilities (F%). When corrected for
plasma protein binding, however, compounds 20e and 20f
a
Reagents and conditions: (a) K2CO3, DMF, heat; (b) K2CO3,
MeOH; (c) CuSO4, sodium ascorbate, t-BuOH/H2O.
Although the potency and metabolic stability were improved,
20c and 20d still suffered from poor solubility in phosphate
buffered saline (PBS). It is well-known that poor solubility of
drug candidates presents challenges during drug develop-
ment.15 Improving aqueous solubility was therefore viewed as
essential to identify a promising tool compound or potential
drug from this series.
The Yalkowsky solubility equation (Log[solubility (M)] =
0.5 − (Log P) − 0.01{[melting point (°C)] − 25})
demonstrates that LogP and melting point are two key
parameters that determine solubility.16 In addition, as
summarized by Ishikawa, one effective strategy to reduce
melting point is disrupting molecular planarity to decrease
crystal packing.17 We hypothesized that the degree of planarity
of the linear triaryl would influence crystal packing. Conforma-
tional analysis using density functional theory of compound
20d indicated that the dihedral angle between the phenyl and
terminal imidazole was 38°, while the preferred angle was
Table 4. Profile of 20a, 20e, and 20f
20a
20e
9.4
20f
a
CYP IC50 (μM)
2D6
>50
>50
>30
18
43
3A4
15
21
a
ion channels IC50 (μM)
Nav1.5
hERG
Cav1.2
10−6 cm/s
Clp
>30
3.4
2.2
4.5
>30
25
21
28
>30
35
b
Papp
c
rat PK (1 mpk IV, 2mpk
8.7
>8700
0.6
13
13
PO)
Clu
1000
197
t1/2 (h)
F (%)
fu%
0.9
56
1.3
0.9
100
6.6
52
<0.1
a
b
See ref 13 for assay protocols. See ref 19 for assay protocols.
c
Compounds were dosed in male Sprague−Dawley rats as a solution
in DMSO/PEG-200/H2O (1:4:5); Clp, Clu in mL/min/kg.
C
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exhibited lower unbound clearance (Clu = Clp/fu; fu = unbound
or free fraction of compound in plasma) in rats compared to
20a.
Compound 20e was selected for evaluation of its ability to
potentiate glucose-stimulated insulin secretion (GSIS) ex vivo
in freshly isolated mouse islets (Figure 3).20 While treatment at
glucose lowing effect by 20e was GPR142 mediated, 20e was
tested in GPR142 KO mice in the same oGTT paradigm, and
the compound did not reduce glucose excursion in these KO
mice (Figure 5). This suggests that the glucose lowering effect
of 20e is mediated through its GPR142 agonist activity.
Figure 5. Glucose AUC0−120 min following glucose challenge post 20e
treatment in both wild type and GPR142 KO mice; N = 7. +p < 0.01 vs
KO treatments; **p < 0.001 vs WT veh + dex.
Figure 3. Compound 20e and GLP-1 showed glucose-dependent
insulin secretion in isolated mouse islets. *p < 0.05; *** p < 0.0001
versus vehicle (1-way ANOVA test).
low glucose concentration (2 mM) did not show any effect on
insulin secretion, at high glucose concentration (16 mM),
treatment with 20e showed a modest effect on increasing
insulin secretion. In the same experiment, GLP-1 showed a
significant effect on enhancing insulin secretion in a glucose-
dependent manner as anticipated.
In summary, a novel class of triazole GPR142 agonists was
discovered from HTS. Optimization of an initial HTS hit
focused on improving not only GPR142 potency, but also
metabolic stability and solubility. Compound 20e demonstrated
robust reduction of glucose excursion in wild-type but not in
GPR142 KO mice. This mechanism-based glucose reduction
provided strong evidence that GPR142 agonists could be
potentially used in type 2 diabetes treatment. Further
development of this class of compounds will be reported in
due course.
Compound 20e was further evaluated in vivo in lean mice in
an oral glucose tolerance test (oGTT).20 In Figure 4, the black
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acsmedchem-
lett.6b00314.
Syntheses and characterization data for compound 20e,
assay protocols, and computational modeling (PDF)
AUTHOR INFORMATION
■
Corresponding Authors
*Tel: 908-740-3355. E-mail: liangqin_guo@merck.com.
*Tel: 908-740-7326. E-mail: derun_li@merck.com.
Figure 4. Compound 20e showed a dose-dependent reduction of
glucose excursion in mouse oGTT; N = 7. **p < 0.001 versus vehicle
group via ANOVA and Dunnett’s post-test; total plasma drug levels @
2.5 h postdosing, 30 mg/kg (11.5 μM), 3 mg/kg (0.274 μM), and 1
mg/kg (0.044 μM).
Author Contributions
⊥Project leads.
Notes
The authors declare no competing financial interest.
bar represents the glucose excursion after the mice were orally
challenged with 5 g/kg dextrose. Compound 20e showed a
dose-dependent reduction of glucose excursion at oral doses
from 1 to 30 mpk. At 30 mpk, 20e achieved 89% glucose
AUC0−120 min reduction (11.5 μM of total 20e and 149 nM of
free 20e @ 2.5 h postdose). To demonstrate that the observed
ACKNOWLEDGMENTS
■
The authors gratefully acknowledge Dr. Eric Meade, Dr.
Andrew Stamford, and Dr. Jeffrey Hale for reviewing and
providing comments on this manuscript; and Jason L. Hoar for
liver microsome stability studies.
D
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