Discovery of MK-8282 as a Potent G-Protein-Coupled Receptor 119 Agonist for the Treatment of Type 2 Diabetes

Article abstract of DOI:10.1021/acsmedchemlett.8b00073

The ever-growing prevalence of type 2 diabetes in the world has necessitated an urgent need for multiple orally effective agents that can regulate glucose homeostasis with a concurrent reduction in body weight. G-Protein coupled receptor 119 (GPR119) is a GPCR target at which agonists have demonstrated glucose-dependent insulin secretion and shows beneficial effects on glycemic control. Herein, we describe our efforts leading to the identification of a potent, oral GPR-119 agonist, MK-8282, which shows improved glucose tolerance in multiple animal models and has excellent off-target profile. The key design elements in the compounds involved a combination of a fluoro-pyrimidine and a conformationally constrained bridged piperidine to impart good potency and efficacy.

Full text of DOI:10.1021/acsmedchemlett.8b00073

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Discovery of MK-8282 as a potent G-Protein-Coupled
Receptor 119 agonist for the treatment of Type 2 Diabetes
Santhosh Francis Neelamkavil, Andrew W. Stamford, Timothy Kowalski, Dipshikha Biswas, Craig
Boyle, Samuel Chackalamannil, Yan Xia, Charles Jayne, Bernard Neustadt, Jinsong Hao, Hong
Liu, Xing Dai, Hana Baker, Brian Hawes, Kim O'Neill, Huadong Tang, and William J. Greenlee
ACS Med. Chem. Lett., Just Accepted Manuscript • DOI: 10.1021/acsmedchemlett.8b00073 • Publication Date (Web): 10 Apr 2018
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Discovery of MK-8282 as a Potent G-Protein-Coupled Receptor 119
Agonist for the Treatment of Type 2 Diabetes
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Santhosh F. Neelamkavil,* Andrew W. Stamford, Timothy Kowalski, Dipshikha Biswas, Craig Boyle,
Samuel Chackalamannil, Yan Xia, Charles Jayne, Bernard Neustadt, Jinsong Hao, Hong Liu, Xing Dai,
Hana Baker, Brian Hawes, Kim O’Neill, Huadong Tang and William J. Greenlee
MRL, Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033 USA
KEYWORDS: GPR119, Type 2 Diabetes, oGTT, sitagliptin.
ABSTRACT: The ever-growing prevalence of Type-2 diabetes in the world has necessitated an urgent need for multiple orally ef-
fective agents that can regulate glucose homeostasis with a concurrent reduction in body weight. G-Protein coupled receptor 119
(GPR119) is a GPCR target at which agonists have demon-
strated glucose-dependent insulin secretion and shows bene-
ficial effects on glycemic control. Herein, we describe our
efforts leading to the identification of a potent, oral GPR-119
agonist, MK-8282, which shows improved glucose tolerance
in multiple animal models and has excellent off-target profile.
The key design elements in the compounds involved a combi-
nation of a fluoro-pryimidine and a conformationally con-
strained bridged piperidine to impart good potency and efficacy.
Diabetes Mellitus (DM) is a chronic metabolic disorder and in
2016 was reported as the 7th leading cause of death in the
United States.1 An estimated 422 million individuals were
living with diabetes in 2014, a number which is expected to
significantly increase by 2030.2 Type 2 diabetes comprises
90% of people with diabetes around the world and is charac-
terized by hepatic glucose overproduction, insulin resistance
and insulin-producing pancreatic β-cell dysfunction. Multiple
treatments aimed toward glycemic control are now available
either as immunotherapies or combinations with hypoglyce-
mia and weight-gain risks being the major limitations.3 In this
regard, several deorphanized G protein receptors (GPCRs)
including GPR119, have attracted attention as potential tar-
gets for Type 2 Diabetes (T2D) to provide glucose-dependent
insulin secretion.4
Arena compounds.9 Herein, we will report our optimization
efforts that led to the identification of the preclinical candi-
date MK-8282.
Figure 1: Changing methyl (1) to fluoro (2) pyrimidine improves
oGTT efficacy
Our interest in GPR119 agonists with bridged piperidines have
previously been reported (Fig. 1).7 Although these com-
pounds had good in vitro activity in a cAMP assay, they did
not show robust efficacy in our acute oGTT (oral glucose tol-
erance test) screen.11 These compounds were highly lipophilic
with poor solubility and were also characterized by poor
plasma exposures (low AUC) in rat and rhesus. We hypothe-
sized that if we could reduce the lipophilicity of compound 1,
by changing the methyl group in the pyrimidine core to fluo-
rine, it would provide better physiochemical properties and
may also improve the in vivo activity. As can be seen from
Figure 1, compound 2 had a ClogP value of 3.7 compared to
Compound 1 which had a ClogP of 4.31 (ClogP values were
measured using ChemDraw). Though the plasma exposures in
rat (AUC) of compound 2 did not significantly improve with
GPR119 is a class A (rhodopsin-like) GPCR which is primarily
expressed in the pancreas, fetal liver and GI tract in humans.5
Multiple synthetic agonists of GPR119 have been reported by
us and others that show efficacy in rodent models of diabetes
and obesity.6-8 However, there have also been reports of
GPR119 agonists that entered clinic and have been discontin-
ued at phase 1 and 2 stages. Compounds from Arena, Prosidi-
on (now Astellas) and GSK have all entered clinical trials and
have been discontinued except Metabolex.9-10
Since the initial reports from Jones et al of an optimized
GPR119 agonist, multiple pharmaceutical companies includ-
ing us have prepared GPR119 agonists inspired by the original
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this change, we were very excited to see the dramatic im-
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provement in glucose lowering, in the oGTT screening assay
with the unbound exposures at the time of measurement (the
oGTT values in Figure 1, Tables 1 and 2 were derived from a
screen which measured glucose at a single 20 minute time
point post glucose administration).11 Encouraged by this fact,
we did a quick SAR by changing the sulfonamide to carbamate
in Compound 2 and looking at multiple carbamate variations
as in Table 1. Unfortunately most of these carbamates also
exhibited poor rat plasma exposures. However we were
pleased to identify compound 4 which showed good potency
and activity in oGTT at 3 mpk. Unlike other carbamates this
compound showed measurable unbound plasma levels in rat
PK studies albeit with very low concentrations.
9
Figure 2. Modification of the bridge improves solubility
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Generally, tying up the piperidine by introducing a conforma-
tional lock could work favorably, if it is on the bioactive con-
formation. We wondered if the bridge in Compound 7 is at
the ideal position, based on the weaker activity and decided
to move it away from the carbamate nitrogen. We reasoned
that this would also enable the carbamate some flexibility in
its orientation. We thus moved the bridge one carbon away
from the functionalized nitrogen and ended up with the type
of compounds highlighted in Table 2. We have recently re-
ported on this type of oxazabicyclo[3.3.1]nonanes with a
methylpyrimidine ring system.13 However, the fluoropyrimi-
dine core consistently showed superior oGTT activity in our
hands and so this novel bridge was combined with the fluoro
core and we made compounds shown in Table 2. In this case,
we also found that we could generate both syn and anti-
ethers with the bridged ring system and syn was more pre-
ferred (Pfizer has also identified similar bridged ring sys-
tems).14
Table 1: Comparison of carbmate SAR
Compounds in Table 2, highlight the aryl group SAR on the
left hand side while keeping the new bridged piperidine ring
and the preferred cyclopropyl-methyl group intact on the
right side of the molecule. As can be seen, for the first time,
we were able to generate a good balance of potent in vitro
numbers and low ClogP values into the compounds and this
resulted in multiple compounds with good activity, in vitro
and in vivo.15 Specifically, compounds 8, 10, 12 and 14,
showed excellent efficacy in our oGTT screening assay at 3
mpk with good overall pharmacokinetic properties. Bis-
ethers, generally, did not show consistent in vivo efficacy,
however, compound 13 was an exception. This core did not
tolerate major additions to the aryl group and most of the
effort involved fine tuning SAR with smaller groups.
We reasoned that if we could make this bridge less lipophilic
and convert the ethylene bridge on the piperidine on the
right hand side to an oxa-bicyclo ring system, it could result in
improved physiochemical properties that could translate into
improved exposures (Figure 2). We hypothesized that as most
of the functionalities in the core were maintained, the activity
would not be affected. However, nearly all these compounds
were much weaker in the in vitro assays, though it was grati-
fying to see that, as predicted, these compounds had excel-
lent solubility and higher unbound fractions. The best from
this class, compound 7, is shown in Figure 2.12 As can be seen
the bridge modification reduces the lipophilicity ClogP by 1.3
units which translated into improved properties. Note also
that unlike the ethylene bridged rings which had the anti-
orientation with pyrimidine ethers we could only make the
syn-version here as all our efforts to make the anti-
compounds with this oxygen bridge failed. We believe the
morpholine ring system (compound 7) provides a steric con-
straint for reduction of the ketone from the same side and
hence only the syn alcohol is obtained.
Table 2: Comparison of Aryl SAR with oxa-bicyclo ring and
pharmacokinetic profile
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O
O
NC
O
O
O
NC
O
N
N
N
N
N
N
N
N
N
O
1
2
Ar
O
O
N
O
N
O
X
O
H
H
F
F
H
Cl
F
H
F
H
Compound 15
hEC50 = 6 nM (89% max)
mEC50 = 43 nM (90% max)
MW / ClogP = 485 / 3.4
Compound 16
3
4
5
hEC50 = 10 nM (51%)
mEC50 = 60 nM (60%)
MW / ClogP= 488 / 2.89
Compound#
8
Ar
X
hEC50 (nM)
mEC50 (nM)
oGTT@ 3mpk
21%
NH
6
25
(%max= 78)
(%max= 76)
O
O
NC
O
6
7
8
9
F
NC
O
N
N
N
N
N
O
O
N
F
N
O
O
N
O
H
13
113
(%max= 108)
31%
27%
NH
NH
NH
Cl
F
H
H
9
F
F
H
(%max= 78)
Compound 17
Compound 18
hEC50 = 49 nM (62% max)
mEC50 = 312 nM (70% max)
MW / ClogP = 501 / 1.99
hEC50 = 10 nM (59%)
mEC50 = 60 nM (88%)
MW / ClogP= 502 / 3.4
F
F
F
15
44
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10
(%max= 94)
(%max= 73)
F
N
O
O
NC
NC
O
N
N
N
N
N
N
17
58
26%
27%
11
N
N
(%max= 63)
(%max= 84)
O
O
O
N
O
H
Cl
Cl
Cl
F
H
O
N
N
Compound 19
Compound 20
hEC50 = 212 nM (% max = 56)
mEC50 = 248 nM (% max = 100)
N
19
278
(%max= 83)
hEC50 = 188 nM (41%)
mEC50 = 516 nM (46%)
MW / ClogP = 518 / 1.64
NH
O
(%max= 73)
12
MW / ClogP = 509 / 2.8
F
Figure 3. Carbamate SAR in oxa-bicyclo ring system
20%
29%
75
26
13
(%max= 136)
(%max= 114)
F
Scheme 1
NC
58
NH
10
14
(%max= 99)
(%max= 92)
Cl
The 4-chloro-cyano aryl in 14 had best overall properties and
so to generate carbamate SAR on the right hand side we
picked this as our preferred group. Figure 3 shows a small
selection of the best compounds from this effort and as can
be seen multiple groups were tolerated but none showed
activity superior to 14. We also looked at several carbamate
isosteres (ureas, amides and sulfonamides), however, the
pyrimidyl group as in compound 20, which also had the fluoro
changed to a cyclopropyl, was the best of the lot. Based on
the overall profile we then decided to select compound 14 for
further follow-up.
The synthesis of compound 14 is shown in Scheme 1. The
commercially available fluoro-malonate was treated with
formamidine, to generate the dihydroxy fluoro-pyrimidine 21
which was then converted to the bis-chloropyrimidine 22. A
single chloride could be displaced by treatment with the cor-
responding aniline, in the presence of sodium hydride, in
good yield to give the key intermediate 23. The bridged piper-
idine alcohol 26 was made by previously reported proce-
dures.16-17 Displacement of aryl chloride 23 with the alcohol
26 then resulted in the syn and anti-versions of the pyrimidyl
ether which were separated through column chromatog-
raphy. The syn version which was the more active and pre-
ferred compound was then deprotected and coupled with
activated methyl-cyclopropyl carbonate to provide compound
14. This was a very convergent method to generate this com-
pound and multi-gram quantities of the same, was prepared
for follow-up studies.
aReagents: (a) NHCHNH2.HCl, MeOH, 100%; (b) POCl3, PhNEt2,
96%; (c) NaH, THF, 76%; (d) BnNH2, (HCHO)n, AcOH, iPrOH, 50%;
(e) NaBH4, MeOH, 60% (f) Pd/C, H2, MeOH, (Boc)2O, 83%; (g)
NaH, THF, 54%; (h) 4N HCl, Dioxane, Et3N, CH2Cl2, 90% over 2
steps.
Compound 14 showed >150 fold selectivity over other recep-
tors (Eurofin panlabs assay), transporters and ion channels.
The pharmacokinetic profile of compound 14 was then tested
in rat, monkey and dog. It was gratifying to see that it had
excellent oral bioavailability (>35%) and half-life in all three
species (Table 3).
Table 3: Comparison of compound 14 PK across species
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Species
IV/PO
(mpk)
CLp
Vdss
t½
(h)
po AUC
F
vivo and the impact of co-administration with DPP-IV inhibi-
tion on plasma GLP-1.19 For this purpose we monitored plas-
ma GLP-1(7-36) amide levels in response to a glucose admin-
istration in lean mice treated with sitagliptin, compound 14,
or a combination of both agents.
(mL/min/kg)
(L/kg)
(µMꢀh)
(%)
1
2
3
4
Rat
1/30
1/3
7.3
3.1
5.8
2.6
4.4
8.8
12
70
63
13
35
38
Monkey
Dog
1/10
0.77
131
43 (est)
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7
8
9
Compound 14 was then evaluated in an oGTT in lean C57Bl/6
mice. Unlike the acute screening assay, we monitored blood
glucose for 60 minutes after oral administration. The vehicle
or drug in this study was administered 30 minutes prior to the
challenge; data are presented as area under the curve (AUC)
and/or a graph. As can be seen in Figure 4, compound 14
reduced glucose excursion in a dose down experiment from 1
to 0.03 mpk. At doses above 1 upto 30 mpk the reduction in
glucose excursion were similar at ~50%. The Cmax for the
lowest dose which achieved significant excursion (0.3 mPk, t =
1h), was 60 nM (Figure 4).18
AUC0-60min
18000
Vehicle
MK-8282
16000
10
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13
14
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14000
*
12000
10000
Wildtype
Genotype
Gpr119-/-
AUC0-60min
Fig-
ure 6: oGTT in WT and GPR119-/- mice with 14
15000
Cmax (1h) = 60 nM
14000
Sitagliptin increased GLP-1 levels after a glucose challenge,
whereas administration of compound 14 alone did not impact
plasma GLP-1. However, when both sitagliptin and GPR119
agonist 14 were dosed together, we saw a significant increase
in GLP-1 levels prior to and 10 minutes after glucose admin-
istration (Figure 7).
*
13000
12000
11000
10000
9000
*
*
23% 46% 49%
21%
8000
7000
30
6000
Vehicle
Water Veh 0.03 0.1
0.3
1
Sitagliptin (3 mpk)
MK-8282 (1 mpk)
Combo
20
Figure 4: oGTT dose down of Compound 14
10
0
Next we took compound 14 into two known diabetic disease
models, namely, DIO and Leprdb/db mice. Here again we were
able to show improvement in an oGTT, with a reduction in
glucose excursion that was comparable to that observed in
lean mice albeit at higher doses (Figure 5).
0
10
Time (min)
Figure 7: Plasma GLP-1[7-36] amide levels in response to oral
glucose administration in lean mice.
The impact of co-administration of sitagliptin and compound
14 on plasma glucose after an oGTT was also evaluated in
Sprague-Dawley rats. As shown in Figure 8, both sitagliptin (1
mpk) and compound 14 (3 mpk) alone, reduced glucose ex-
cursion to similar levels, however, the combination of agents
produced an apparent additive effect on this excursion.
Figure 5: oGTT in DIO and db/db mice with compound 14
To ensure that the glucose dependent mechanism is indeed
mediated through GPR119 we also tested 14 in GPR119
knockout mice. As expected 14 did not improve glucose tol-
erance in the GPR119 KO mice and reduced the levels only in
wild type animals (Figure 6). As prior work demonstrated that
GPR119 agonists increase incretin release from enteroendo-
crine cells, we evaluated the effect of 14 on GLP-1 release in
4
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duced obese; AUC, area under the curve; GLP-1, glucagon like
1
2
peptide 1; GPCR, G protein coupled receptors; DM, diabetes
mellitus.
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REFERENCES
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6
(1) Health, United States 2016. A report U.S. Department of
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(2) Global report on Diabetes 2016. World Health Organiza-
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(4) Albrechtsen, N. J. W.; Kuhre, R. E.; Deacon, C. F.; Holst, J. J.
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(5) Shah, U.; Kowalski, T. J. GPR119 agonists for the potential
treatment of type 2 diabetes and related metabolic disor-
ders. Vitamins and Hormones. 2010, 84, 414-458.
(6) Jones, R. M.; Leonard, J. N.; Buzard, D. J.; Lehmann, J.
GPR119 agonists for the treatment of type 2 diabetes. Ex-
pert Opinion on Therapeutic Patents. 2009, 1339-1359.
(7) Xia, Y.; Chackalamannil, S.; Greenlee, W. J.; Jayne, C.; Neu-
stadt, B.; Stamford, A.; Vaccaro, H.; Xu, X. L.; Baker, H.;
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(8) Zhu, C.; Wang, L.; Zhu, Y.; Guo, Z. Z.; Liu, P.; Hu, Z.;
Szewczyk, J. W. et al. Discovery of phenyl acetamides as
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Lett. 2017, 27, 1124-1128.
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(11) In this oGTT screen, test compound or vehicle was orally
administered to overnight-fasted animals at 3 to 10 mg/kg.
Glucose was administered to the animals 30 min post-
dosing (3 g/kg po), and blood glucose levels were meas-
ured using a hand-held glucometer (Bayer Breeze 2) prior
to compound or vehicle dosing, prior to glucose admin-
istration, and 20 min after glucose administration. Efficacy
in this assay was expressed as % blood glucose lowering at
20 minute post glucose treatment. This was defined as
[(1-(20 min glucose of test compound treated mice/20 min
glucose of vehicle treated mice))x100]. Typically, highly ef-
ficacious compounds in this assay gave glucose lowering
values of 20% or greater.
Figure 8: GPR 119 agonism and DPP-IV inhibition display additivi-
ty on oGTT in lean rats.
In summary we have identified a novel, potent GPR119 ago-
nist by coupling a fluoro-pyrimidine to a constrained bridged
piperidine ring system. Fine-tuning the SAR by balancing lipo-
philicity with potency, we discovered compound 14, which
showed robust glucose lowering in lean as well as DIO and
diabetic mice. We also showed the lack of efficacy in GPR119
knockouts to prove that the glucose lowering mechanism is
mediated through this receptor. We were also able to
demonstrate cooperativity with DPP-IV inhibition in lowering
blood glucose levels. Based on the excellent potency, clean
ancillary target profile, good oral bioavailability and expo-
sures and promising in vivo data in disease models, we se-
lected compound 14 as our preclinical candidate MK-8282.
Further follow-up of GPR119 agonists and additional SAR will
be disclosed in the near future.
ASSOCIATED CONTENT
Supporting Information
1
Synthetic experimental details including H NMR and mass spec-
tral data for selected compounds and description of primary
biological assays. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*(U.S.) Phone: 908-740-4062. E-mail: San-
thosh.neelamkavil@merck.com
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
The authors would like to thank Dr. John Piwinski for his support
(12) Xia, Y.; Boyle, C. D.; Greenlee, W. J.; Chackalamannil, S.;
Jayne, C. L.; Stamford, A. W.; Dai, X.; Harris, J. M.; Neu-
stadt, B. R.; Neelamkavil, S. F.; et al. PCT Int.
Appl. 2009, WO 2009055331 A2.
(13) Dai, X.; Stamford, A.; Liu, H.; Neustadt, B.; Hao, J.; Kow-
alski, T.; Hawes, B.; Xu, X.; Baker, H.; O’Neill, K.; Woods,
M.; Tang, H.; Greenlee, W. Discovery of oxazabicy-
clo[3.3.1]nonane derivatives as potent and orally active
of this program.
ABBREVIATIONS
GPR119, G-protein coupled receptor 119; SAR, structure activity
relationships; oGTT, oral glucose tolerance test; DIO, diet in-
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GPR119 agonists. Bioorg. Med. Chem. Lett. 2015, 25, 5291-
5294
1
(14) McClure, K. F.; Darout, E.; Guimaraes, C. R. W.; DeNinno et
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formation based hypothesis for understanding agonist re-
sponse. J. Med. Chem. 2011, 54, 1948-1952.
(15) A table of ClogP values for compounds in Table 2 is pro-
vided in the supporting information.
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(16) Neelamkavil, S. F.; Neustadt, B. R.; Stamford, A.; Xia, Y.;
Harris, J. M.; Boyle, C. D.; Chackalamannil, S.; Biswas, D.;
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(17) Neelamkavil, S. F.; Stamford, A.; Chackalamannil, S.;
Greenlee, W. J. 2014, US 8912206.
(18) A table with plasma protein binding values in rat, mouse,
monkey, dog and human, is provided in the supporting in-
formation. In rat, these molecules were highly protein
bound with only 1% free levels observed.
(19) Chu ZL, Carroll C, Alfonso J, Gutierrez V, He H, Lucman A et
al. A role for intestinal endocrine cell-expressed g protein-
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