Design of Potent and Orally Active GPR119 Agonists for the Treatment of Type II Diabetes

Article abstract of DOI:10.1021/acsmedchemlett.5b00207

We report herein the design and synthesis of a series of potent and selective GPR119 agonists. Our objective was to develop a GPR119 agonist with properties that were suitable for fixed-dose combination with a DPP4 inhibitor. Starting from a phenoxy analo

Full text of DOI:10.1021/acsmedchemlett.5b00207

Letter
pubs.acs.org/acsmedchemlett
Design of Potent and Orally Active GPR119 Agonists for the
Treatment of Type II Diabetes
Ping Liu,*,† Zhiyong Hu,† Byron G. DuBois,† Christopher R. Moyes,† David N. Hunter,† Cheng Zhu,†
Nam Fung Kar,† Yuping Zhu,† Joie Garfunkle,† Ling Kang,‡ Gary Chicchi,§ Anka Ehrhardt,§
Andrea Woods,§ Toru Seo,§ Morgan Woods,§ Margaret van Heek,§ Karen H. Dingley,∥ Jianmei Pang,∥
Gino M. Salituro,∥ Joyce Powell,∥ Jenna L. Terebetski,⊥ Viktor Hornak,# L. C. Campeau,∇
Joe Lamberson,∇ Fez Ujjainwalla,† Michael Miller,† Andrew Stamford,† Harold B. Wood,†
Timothy Kowalski,‡ Ravi P. Nargund,† and Scott D. Edmondson†
‡
§
∥
†Departments of Medicinal Chemistry, Diabetes Biology, Pharmacology, Pharmacokinetics, Pharmacodynamics and Drug
Metabolism, Basic Pharmaceutical Sciences, Chemical Modeling and Informatics, and ∇Process Research, Merck Research
⊥
#
Laboratories, Rahway, New Jersey 07065, United States
S
* Supporting Information
ABSTRACT: We report herein the design and synthesis of a series of potent and
selective GPR119 agonists. Our objective was to develop a GPR119 agonist with
properties that were suitable for fixed-dose combination with a DPP4 inhibitor.
Starting from a phenoxy analogue (1), medicinal chemistry efforts directed toward
reducing half-life and increasing solubility led to the synthesis of a series of benzyloxy
analogues. Compound 28 was chosen for further profiling because of its favorable
physicochemical properties and excellent GPR119 potency across species. This
compound exhibited a clean off-target profile in counterscreens and good in vivo
efficacy in mouse oGTT.
KEYWORDS: Type II diabetes, GPR119 agonists, chiral cis-cyclopropanes, benzyloxy analogues, oGTT
iabetes mellitus is a serious and chronic medical
condition that is rapidly growing throughout the world.
insulin secretion only when glucose levels are elevated, makes
GPR119 a very attractive target for the development of new
medications for T2D. Indeed, the industry has advanced
multiple GPR119 agonists, for example, GSK-1292263, PSN-
821, and MBX-2982, into the Phase II clinical trials.8 However,
despite tremendous efforts by academia and industry, the
theoretical benefits that GPR119 agonists can offer have thus
far been a challenge to demonstrate clinically.10,11
We were interested in developing a fixed-dose combination
(FDC) of a GPR119 agonist and a DPP4 inhibitor in the hope
that such a combination would provide greater effects than
either agent alone.12 Previously we reported the design and
synthesis of a series of GPR119 agonists with a cis-cyclopropane
as the core structure.13,14 Herein we report our continued
efforts in this area.
D
Generally, diagnosis is determined by measurement of fasting
plasma glucose and recently an international recommendation
has been made for the use of hemoglobin A1C (HbA1C) as a
time-integrated marker of glucose levels.1 Approximately, 90−
95% of diabetics have type 2 diabetes (T2D), and the
pathogenesis of this disease involves hepatic glucose over-
production, insulin resistance, and dysfunction of insulin
producing β-cells.2 T2D is initially managed by regular exercise
and dietary modifications; then, as it progresses, the disease is
managed by oral medications or injectables such as insulin and
GLP-1 agonists. Standard medications focus on glycemic
control, either through monotherapies or combination
therapies.3 In spite of the large number of available medications,
there is still an unmet medical need for orally effective new
treatments for diabetes that will offer better safety profiles and
reduced adverse effects.
GPR119 is a G protein-coupled receptor whose expression in
humans, mice, and rats is highly restricted to pancreatic islets
and specific intestinal regions.4−6 GPR119 agonists are
proposed to regulate glucose homeostasis through stimulating
glucose-dependent insulin release both directly by enhancing
pancreatic-cell function and indirectly by the release of incretin
hormones from the small intestine.7−9 Theoretically, the
selectivity of expression, coupled with an ability to potentiate
Compound 1, our previous preclinical candidate, had
excellent potency, selectivity, and in vivo efficacy,14 but this
compound had a long half-life (t1/2) in rat (Figure 1), and the
clinically observed human half-life after single dose admin-
istration was significantly longer than desired,15 which rendered
1 unsuitable for FDC with sitagliptin (qd). Furthermore, this
Received: May 20, 2015
Accepted: July 10, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acsmedchemlett.5b00207
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ACS Medicinal Chemistry Letters
Letter
Figure 1. Previous preclinical candidate. (a)EC50 data: mean SD (%
control at max dose). (b)Calculated from Cl 2.9 mL/min/kg, Vd 3.4 L/
kg, and fu 0.2%. (c)HPLC LogD at pH 7.
compound exhibited poor solubility in biorelevant media,
including fasted-state simulated intestinal fluid (FaSSIF).16−18
The low solubility resulted in a high calculated dose number, an
increase in absorption risk and anticipated need for enhanced
formulation complexity.19−22 Since formulation complexity
would increase FDC development challenges, it was desirable
to identify compounds with improved physicochemical proper-
ties.23 Therefore, the lead optimization objective was to reduce
the projected human half-life and increase solubility, while
simultaneously maintaining other favorable properties.
Figure 2. Comparison of benzyloxy and phenoxy analogues. (a)EC50
data: mean SD (% control at max dose). (b)From Cl 9.0 mL/min/
kg, Vd 1.3 L/kg, and fu 1.6%. (c)HPLC LogD at pH 7. (d)fu of the
corresponding methylsulfone analogue (2%) used; Cl 13.5 mL/min/
kg, Vd 4.8 L/kg. (e)From Cl 13.5 mL/min/kg, Vd 4.8 L/kg, and fu
5.8%.
functional groups at both ends, including the favorable
piperidine right-hand side “capping” groups previously reported
for GPR119 agonists.12 As illustrated in Scheme 1, the synthesis
The plasma half-life is determined by two pharmacokinetic
parameters, intrinsic clearance (Clint), and unbound volume of
distribution (Vdu).24 Half-life can be shortened either by
increasing Clint or by decreasing Vdu of a compound. In most
cases, increasing Clint also leads to an increased dose projection
and potentially higher levels of metabolites, thus decreasing Vdu
is a preferable strategy to reduce half-life. Vdu can be modified
by adjusting the lipophilicity or introducing basic and acidic
functional groups.25 For compounds in the same class, reducing
lipophilicity usually leads to decreased Vdu. From phenoxy
analogue 1 to benzyloxy analogue 2, a significant drop in
lipophilicity was predicted (cLogP 3.8 vs 2.2), and measured
LogD dropped by 1.2. Indeed, lower unbound volume (81 vs
1725 L/kg) and shorter rat t1/2 (1.8 vs 14.7 h) were observed in
compound 2, where GPR119 potency was almost maintained
(human EC50 = 8.7 vs 3.3 nM). Similarly, from phenoxy
analogue 3 to benzyloxy analogue 4, unbound volume was
decreased from 242 to 62 L/kg, and t1/2 was reduced from 6.5
to 1.5 h (Figure 2). Although Clint changed in both cases, it was
the magnitude of Vdu reduction that caused the ratio of Vdu to
Clint to drop by 8-fold from 1 to 2 and 4-fold from 3 to 4, which
a
Scheme 1. Synthesis of Chiral Synthon (R,R)-9
a
Reagents and conditions: (a) CBr4, PPh3; (b) nBuLi, THF, then
paraformaldehyde; (c) H2, quinoline, Lindlar catalyst, EtOAc; (d)
Charette cyclopropanation, Et2Zn/CH2I2, dichloromethane, −20−0
°C.
of the central cyclopropyl piperidine piece, the chiral synthon 9,
started with the commercially available piperidine aldehyde 5.
Corey−Fuchs type reaction was used to convert aldehyde 5 to
propargyl alcohol 7 by a two-step sequence via dibromo-olefin
intermediate 6.28 Reduction of the alkyne in 7 with Lindlar’s
catalyst gave cis-alkene 8, which was subject to Charette’s
enantioselective cyclopropanation reaction.29 Thus, using the
dioxaborolane ligand derived from (S,S)-N,N,N′,N′-tetrame-
thyltartaric acid diamide as a chiral auxiliary, the desired chiral
synthon (R,R)-9 was obtained as a white solid (>98% de and
>98% ee) after recrystallization from heptane.30
was approximately reflected in the reduction in t1/2
,
respectively. In addition, from phenoxy analogues to benzyloxy
analogues (1, 3 vs 2, 4), the decreased cLogP and LogD value
correlated with an increase in solubility. For example,
compound 4 demonstrated improved FaSSIF solubility over
3 (127 vs 61 μM). Finally, to our delight, compound 4 also
displayed higher GPR119 potency (0.8 vs 1.7 nM).
In recent years the concept of lipophilic ligand efficiency
(LLE), which combines both potency and lipophilicity, has
been shown to be very useful in measuring the progress of the
lead optimization process.26 In this regard, the LLE was
significantly increased from phenoxy analogues 1 and 3 to
benzyloxy analogues 2 and 4: LLE was 4.7 vs 5.9 for
compounds 1 and 2, and 3.8 vs 5.0 for compounds 3 and 4.27
Encouraged by these initial results, further structure−activity
relationship (SAR) efforts were directed toward finding a
compound with an even more favorable physicochemical
profile. Our optimization efforts kept the central cyclopropyl
piperidine core intact and focused on surveying a variety of
With key intermediate 9 in hand, the benzyloxy analogues
can be efficiently assembled (Scheme 2).30 In the presence of a
base such as NaH or NaHMDS, SN2 type reaction between 9
and an appropriate benzyl halide gave benzyl ether 10, which
upon deprotection of the Boc group provided piperidine
intermediate 11. The synthesis was divergent at this point
depending on the type of the piperidine capping groups. If the
capping group is a pyrimidine, an SNAr reaction was performed
(2, 18, 19, 23−31, 33, and 34). To introduce the 1-
methylcyclopropyloxycarbonyl capping group in 22, intermedi-
ate 11 was reacted with the preformed succinimide 12.31 In the
case of the oxadiazole capping group (4, 20, and 21),
B
DOI: 10.1021/acsmedchemlett.5b00207
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ACS Medicinal Chemistry Letters
Letter
a
data is summarized in Table 1. In general, these benzyloxy
analogues possessed good to excellent potency and a full
agonist response if the appropriate piperidine capping groups
were chosen on the right, such as 5-substitued pyrimidine,
isopropyl oxadiazole, and 1-methylcyclopropyloxycarbonyl, and
favorable substituents were incorporated on the left, such as
methylsulfone and tetrazole.12−14 Several trends were observed.
While hydroxyethylsulfone somewhat increased potency (18 vs
2), ethylsulfone somewhat decreased potency (31 vs 28).
Replacing 2-pyridyl with 2-fluorophenyl group resulted in
significant improvements in FaSSIF solubility (27 vs 19), which
could not be predicted by the cLogP and measured LogD
values. The 5-position of the pyrimidine capping group was
compatible with many functional groups of which methoxy and
methoxymethyl (MOM) were effective at improving solubility
(23, 25, and 28). Finally, all the benzyloxy analogues in Table 1
exhibited relatively short t1/2s in rat compared to the phenoxy
analogues and had predicted human half-lives in the range of 2
to 38 h.35
Compound 28, with FaSSIF solubility of 161 μM, cLogP of
2.4, and LLE of 6.3, was identified as a potent GPR119 agonist
with suitable physicochemical properties for a fixed-dose-
combination and therefore was further profiled. An off-target
screen of this compound was performed against a panel of 168
receptors, ion channels, and enzymes, and no off-target
activities were found with IC50s < 10 μM. In a cardiac ion
channel functional blockade activity panel,36 28 exhibited mild
inhibition of hERG with a calculated IC50 of 13 μM.37 There
were no effects on IKs or INa up to the highest tested
concentration of 30 μM. Compound 28 was also selective over
CYP 3A4 (IC50 = 40 μM) and hPXR (EC50 > 30 μM, 39%
Act).38
Scheme 2. Synthesis of Benzyloxy Analogues
a
Reagents and conditions: (a) Base, THF; (b) TFA, dichloromethane;
(c) Het-X, Cs2CO3, DMF; (d) Et3N, dichloromethane; (e) Br-CN,
K2CO3, CHCl3, reflux; (f) iPr−C(NH)NHOH, ZnCl2, THF, reflux.
intermediate 11 was converted to cyano substituted piperidine
13 by treatment with cyanogen bromide; then the cyano group
was converted to the isopropyl oxadiazole by zinc chloride
mediated reaction with N-hydroxyisopropylimidamide, fol-
lowed by acid mediated cyclization.32
The synthetic sequence for acetamide analogue 32 is shown
in Scheme 3. After three straightforward manipulations, Boc
a
Scheme 3. Synthesis of Acetamide Analogue 32
The promising in vitro profile of 28 was followed by
characterization of this compound in vivo. In a mouse oGTT39
and PK/PD dose−response study, compound 28 showed a
dose-dependent lowering of blood glucose excursion, as
represented by the excursion AUC from 0−120 min (Figure
3). Based upon this data, the MEDmax (minimal efficacious dose
for maximal efficacy) was 3 mpk. The blood concentrations of
28 at 90 min post-dosing increased approximately linearly at
0.3, 1, 3, and 10 mpk (18 5, 86 8, 302 57, and 622 160
nM, respectively).
The pharmacokinetic profile of 28 was evaluated in rat, dog,
and monkey (Table 2). Overall, this compound possessed good
PK properties in dogs (t1/2 17 h, F 60%), but lower oral
bioavailability in rats and monkeys, likely due to more extensive
metabolism in these species relative to dogs (Clint was 1104,
319, 60, and 42 mL/min/kg in rat, monkey, dog, and human
liver microsomes, respectively).41 Compared to lead compound
1, 28 had a much lower Vdu (1725 vs 54 L/kg) in rat, which
contributed heavily to t1/2 reduction (rat t1/2 14.7 vs 1.0 h).
Based upon a plasma trough target of 549 nM (from the
MEDmax in mouse and a blood/plasma ratio of 0.55), the
projected human half-life of 28 was ∼15 h and estimated
human QD dose was ∼300 mg.42
The pharmaceutical properties of 28 were also assessed. The
crystalline free base of this compound was obtained from
recrystallization with water, and it was characterized as its solid
state form. The solubility of this form was evaluated in IV and
PO vehicles that were acceptable for safety studies. After
equilibration in vehicles and biorelevant media, compound 28
demonstrated solubility of 129 mg/mL in PEG200, 325 mg/
mL in PEG400, 56 μg/mL in FaSSIF, and 0.87 mg/mL in
a
Reagents and conditions: (a) 4 N HCl in dioxane; (b) 2-chloro-5-
methoxymethylpyrimidine, Cs2CO3, DMSO, 60 °C, 76%; (c) NaH, 4-
bromo-1-(bromomethyl)-2-fluorobenzene, DMF, 96%.; (d)
BrZnCH2COOtBu, Pd2(dba)3, X-Phos, THF, 60 °C, 98%; (e) TFA,
dichloromethane, 100%; (f) morpholine, HOBT, EDC, diisopropyle-
thylamine, dichloromethane, 69%.
deprotection, pyrimidine installation, and benzyl ether
formation, aryl bromide 16 was transformed to aryl acetate
17 through an efficient Negishi type coupling.33 Finally, tert-
butyl ester hydrolysis and amide formation completed the
synthesis of 32.
The in vitro agonist activity for human and mouse receptors
was evaluated by two measures: the potency measure as
expressed in EC50 values in a cAMP assay and the magnitude of
agonist activity measure as expressed in % control at the
maximum dose compared to an internal agonist control.34 The
C
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ACS Medicinal Chemistry Letters
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Table 1. SAR Efforts and Identification of Compound 28
a
a
b
d
cmpd
hGPR119 EC50 (nM)
mGPR119 EC50 (nM)
FaSSIF (μM)
cLogP
HPLC LogD (pH 7)
rat t1/2 (h)
pred. human t1/2 (h)
2
8.7 3.4 (53%)
2.3 0.3 (68%)
1.5 0.1 (83%)
4.2 1.0 (87%)
1.7 0.1 (129%)
4.8 1.8 (121%)
4.5 2.9 (79%)
1.7 1.1 (75%)
3.3 1.9 (94%)
2.4 2.1 (85%)
2.5 1.9 (98%)
2.1 1.3 (88%)
3.1 1.2 (87%)
4.6 5.0 (95%)
7.1 1.4 (58%)
3.2 0.6 (104%)
1.1 0.3 (84%)
4.5 1.9 (80%)
3.6 0.1 (56%)
1.7 0.4 (121%)
2.5 2.1 (153%)
9.9 5.5 (76%)
4.8 0.1 (105%)
15 0.3 (108%)
1.4 1.2 (85%)
2.3 0.6 (96%)
5.2 2.1 (87%)
4.5 5.6 (131%)
5.5 2.7 (115%)
1.9 0.8 (97%)
8.9 9.5 (109%)
3.3 1.6 (70%)
12.5 0.8 (87%)
3.7 0.8 (99%)
3.8 1.0 (75%)
5.8 3.3 (67%)
nd
2.2
2.9
2.5
3.6
4.1
3.6
3.1
3.7
2.4
2.8
3.6
2.4
2.7
2.7
2.9
3.0
2.9
2.6
3.7
4.8
3.6
3.8
3.9
3.8
4.0
4.2
3.5
4.2
4.3
3.5
3.9
3.9
3.8
3.4
3.7
3.6
1.8
0.9
1.3
2.2
1.4
1.0
0.6
0.8
nd
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
83
5−7
8−9
9−14
5−9
6−7
4−6
5−7
8−9
12−13
13
7
144
103
127
151
101
155
92
c
1.2
1.5
c
140
161
143
137
129
172
133
115
1.0
1.0
1.4
26
26
c
1.0
21
2.1
0.4
21
2
c
3.0
38
0.5
4
a
Human and mouse GPR119 EC50 data expressed as mean SD (n ≥ 2 independent experiments). The percentage in parentheses, % control at
max dose: magnitude of cAMP stimulation expressed in % compared to an internal agonist control; the control was defined to have 100% cAMP
b
c
stimulation. Kinetic solubility in fasted-state simulated intestinal fluid (FaSSIF) at pH 6.5; in parentheses are cLogP values. Effective t1/2 calculated
d
from MRT × 0.693 (for compounds exhibiting biphasic PK). Predicted solely based on rat PK. Where there is only one number (compounds 27−
34), allometry was not used since rat Clint was much higher than human. Also, a predicted human half-life in the range of 8−48 h was considered
acceptable for further profiling and could potentially support once daily dosing.
a
Table 2. Plasma Pharmacokinetic Profile of Compound 28
species
Plasma Cl (mL/min/kg)
Vd (L/kg)
t1/2 (h)
F (%)
b
rat
41
6.0
16
2.2
6.5
2.0
1.0
17
27
60
5
c
dog
monkey
d
2.3
a
b
PPB for 28 (fu): r 4.1%, d 5.5%, rh 3.2, h 4.9%. Rat Wistar Han:
c
d
Clint = 1000 mL/min/kg; Vdu = 54 L/kg. Dog Beagle. Rhesus
monkey.
simulated gastric fluid (SGF). Finally, compound 28 falls nicely
within the druglike property space: MW 464, cLogP 2.4, HPLC
LogD 3.5, LLE 6.3, and PFI 5.5.43
In summary, we have designed and synthesized a series of
GPR119 agonists with properties that may be suitable for fixed-
dose combination. A major focus of the optimization effort was
to reduce the predicted t1/2 in humans and improve solubility of
the phenoxy lead. Half-life was reduced by modifying the
unbound volume of distribution (Vdu) through reducing
lipophilicity, and solubility was improved by incorporating
solubilizing groups such as MeO and MOM moieties. These
efforts led to the identification of compound 28 that possessed
excellent potency, selectivity, and improved physicochemical
Figure 3. oGTT and PK/PD dose response of compound 28 in lean
mice. (a)Positive control MBX-298240 was more efficacious than 28
probably because it had better mouse PK; the two compounds had
comparable mouse potency.
D
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ACS Medicinal Chemistry Letters
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ASSOCIATED CONTENT
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S
* Supporting Information
Synthetic procedures and characterization data of selected
compounds, conditions for the biological assays, and protocol
for pharmacokinetic and pharmacodynamic studies. The
Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acsmedchem-
lett.5b00207.
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AUTHOR INFORMATION
■
Corresponding Author
*Phone: 732-594-0321. Fax: 732-594-9556. E-mail: ping_liu2@
merck.com.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Dr. Jeffrey J. Hale for insightful suggestions.
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