Discovery and Pharmacology of a Novel Somatostatin Subtype 5 (SSTR5) Antagonist: Synergy with DPP-4 Inhibition

Article abstract of DOI:10.1021/acsmedchemlett.8b00305

We report new SSTR5 antagonists with enhanced potency, subtype selectivity, and minimal off-target activities as compared to previously reported compounds. Starting from the reported SSTR5 antagonist 1, we systematically surveyed changes in the central core and head piece while maintaining the diphenyl tail group constant. From this study the azaspirodecanone 10 emerged as a new highly potent and selective SSTR5 antagonist. Compound 10 lowered glucose excursion by 94% in an oral glucose tolerance test (OGTT) in mice following a 3 mg/kg oral dose. The compound increased both total and active circulating incretin hormone GLP-1 levels in mice at a dose of 10 mg/kg. A synergistic effect was also demonstrated when compound 10 was coadministered with a DPP-4 inhibitor, substantially increasing circulating active GLP-1[7-36] amide and insulin in response to a glucose challenge.

Full text of DOI:10.1021/acsmedchemlett.8b00305

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Letter
Discovery and pharmacology of a novel somatostatin
subtype 5 (SSTR5) antagonist: Synergy with DPP-4 inhibition
Weiguo Liu, Pengcheng P Shao, Gui-Bai Liang, John Bawiec, Jiafang He, Susan D Aster, Margaret Wu,
Chicchi Garry, John Wang, Kwei-Lan Tsao, Jin Shang, Gino Salituro, Yun-Ping Zhou, Cai Li, Taro E.
Akiyama, Daniel E. Metzger, Beth Ann Murphy, Andrew D. Howard, Ann E. Weber, and Joseph L Duffy
ACS Med. Chem. Lett., Just Accepted Manuscript • DOI: 10.1021/acsmedchemlett.8b00305 • Publication Date (Web): 12 Sep 2018
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Discovery and pharmacology of a novel somatostatin subtype 5
(SSTR5) antagonist: Synergy with DPP-4 inhibition
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Weiguo Liu*, Pengcheng P. Shao, GuiꢀBai Liang, John Bawiec, Jiafang He, Susan D. Aster, Margaret
Wu, Garry Chicchi, John Wang, KweiꢀLan Tsao, Jin Shang, Gino Salituro, YunꢀPing Zhou, Cai Li, Taꢀ
ro E. Akiyama, Daniel E. Metzger, Beth Ann Murphy, Andrew D. Howard, Ann E. Weber, Joseph L.
Duffy
Merck & Co., Inc., Kenilworth, New Jersey 07033, United States
ABSTRACT: We report new SSTR5 antagonists with enhanced potency, subtype selectivity, and minimal offꢀtarget activities as
compared to previously reported compounds. Starting from the reported SSTR5 antagonist 1, we systematically surveyed changes
in the central core and head piece while maintaining the diphenyl tail group constant. From this study the azaspirodecanone 10
emerged as a new highly potent and selective SSTR5 antagonist. Compound 10 lowered glucose excursion by 94% in an oral gluꢀ
cose tolerance test (OGTT) in mice following a 3 mg/kg oral
dose. The compound increased both total and active circulating
incretin hormone GLPꢀ1 levels in mice at a dose of 10 mg/kg.
A synergistic effect was also demonstrated when compound 10
was coadministered with a DPPꢀ4 inhibitor, substantially inꢀ
creasing circulating active GLPꢀ1[7ꢀ36] amide and insulin in
response to a glucose challenge.
KEYWORDS: Somatostatin, SSTR5 antagonists, Type 2 diabetes mellitus (T2DM), Glucose-dependent insulin secretion (GDIS)
Somatostatin receptor subtype 5 (SSTR5) is one of five Gꢀ
protein coupled receptors that sense the peptide hormone soꢀ
matostatin (SST), also called somatotropin releaseꢀinhibiting
factor. SSTR1ꢀ5 are widely distributed throughout the body.1
Their endogenous ligands exist in two isoforms with 14 and
28 amino acids (SSTꢀ14 and SSTꢀ28), respectively.2 While
SSTꢀ14 is mainly secreted from pancreatic δ cells, neurons,
and the stomach, SSTꢀ28 mostly exists in the enteroendocrine
δ cells in the small intestine, colon, and pancreas.3 The SSTꢀ
mediated biological effects involve a broad range of functional
regulation and hormonal secretion control, including inhibiting
the secretion of both insulin and the insulinotropic glucagonꢀ
like peptide 1 (GLPꢀ1), which have been the subject of nuꢀ
merous studies and publications.4
perfused pancreas of SSTR5 KO mice as compared with wild
type (WT) mice.7 Pancreatic islets isolated from SSTR5 KO
mice displayed increased total insulin content as compared
with islets obtained from WT mice. As a result, the KO mice
exhibited decreased blood glucose and plasma insulin levels
and increased leptin and glucagon concentrations compared
with WT mice. In addition, the SSTR5 KO mice displayed
decreased susceptibility to high fat diet (HFD)–induced insulin
resistance.8
SSTR5 selective small molecule antagonists have been reportꢀ
ed to lower glucose and insulin excursion during an oral gluꢀ
cose tolerance test (OGTT) in both mice and rats.9,10,11,12 Based
on these cellular and preclinical pharmacology studies, SSTR5
is an attractive investigational target for treatment of type 2
diabetes mellitus (T2DM). Although a range of therapeutic
agents are available for the treatment of T2DM, such as sulꢀ
fonylureas, metformin, PPARγꢀselective agonists, DPPꢀ4 inꢀ
hibitors, and recently SGLT2 inhibitors, a high proportion of
diabetic patients still fail to achieve or maintain glycemic tarꢀ
gets due to limitations and/or liabilities associated with these
agents.13 An SSTR5 antagonist offers the possible dual effects
of increasing GLPꢀ1 release from the GI tract and promoting
insulin secretion from the pancreatic islets in response to
changes in blood glucose levels. Therefore, an SSTR5 antagoꢀ
nist could serve as monotherapy for the treatment of T2DM,
Selective antagonism of endogenous SST effects on SSTR5
should be beneficial for maintaining glucose homeostasis. The
target SSTR5 is prominently expressed in pancreatic islet β
cells as well as some δ and α cells.5 It is also highly expressed
in enteroendocrine cells of the gastrointestinal (GI) tract. SST
inhibits GLPꢀ1 secretion via primarily SSTR5,4 while its inꢀ
hibitory effect on insulin secretion is mediated by multiple
SST receptors, including SSTR5.6
Evidence for the role of SSTR5 in glucose homeostasis comes
from SSTR5 knockout (KO) mice. Increased glucoseꢀ
dependent insulin secretion (GDIS) was demonstrated in the
1
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and may also be synergistic in combination with antidiabetic
GLPꢀ1 protective agents such as DPPꢀ4 inhibitors. To this end,
we have investigated the small molecule SSTR5 selective
antagonists as therapeutic agents for treatment of T2DM and
their potential for synergistic effects with a DPPꢀ4 inhibitor.
This study involved optimization of a previously reported
SSTR5 selective antagonist, and full preclinical pharmacology
characterization of the optimized compound.
Page 2 of 7
selective SSTR5 antagonists,14 which was followed by addiꢀ
tional reports detailing the structureꢀactivity relationship
(SAR) around the aminopiperidine based core structures.15,16
These SSTR5 selective antagonists, such as 1 (Table 1), genꢀ
erally consist of three components; a heterocyclic head group,
an aminopiperidine core group, and a substituted aromatic tail
group. Recently, additional reports have appeared showing
variation is tolerated in all three regions of this lead series,
notably with the discovery of a spirocyclic core subunit.10,11, 12
These accounts prompted us to detail our optimization of this
lead series, and report our finding of preclinical pharmacologꢀ
ic synergy in promoting circulation of active GLPꢀ1 by oral
coadministration of an SSTR5 antagonist with a DPPꢀ4 inhibiꢀ
tor.
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Table 1. Lead Series of SSTR5 Antagonists
Structure
SSTR5a
SSTR5
hERGc
IC50
(ꢀM)
OGTTd
(%)
In our studies, 1 is a potent SSTR5 antagonist with good effiꢀ
cacy in our acute mouse oral glucose tolerance test (OGTT)
with 87% lowering of plasma glucose following a 10 mg/kg
binding
cAMP
h/mb
h/mb
Dose
oral dose with good residual whole blood exposure (C2.5h
=
IC50 (nM)
1.3/1.0
IC50 (nM)
3.1/2.7
(mg/kg)
0.11 ꢀM). We modified the class of SSTR5 antagonists repreꢀ
sented by 1 in an attempt to identify new lead structures with
diminished potency against cardiac ionꢀchannels such as
hERG, while maintaining SSTR5 antagonist potency and
SSTR subtype selectivity. Compounds were tested in an
SSTR5 filtration binding assay, which measures the competiꢀ
tive displacement of radiolabeled SSTꢀ28 from cell memꢀ
branes expressing the human or mouse SSTR5 receptor. Poꢀ
tent compounds were also tested in a functional assay in Chiꢀ
nese hamster ovary (CHOꢀK1) cells expressing the human or
mouse SSTR5 receptor. This whole cell assay measures the
compound’s ability to inhibit the SSTꢀ28 mediated reduction
of cAMP accumulation induced by forskolin. Potent comꢀ
pounds were also counter screened against the related memꢀ
brane binding assays for SSTR1ꢀ4.
87%
10
1
2
1.69
15
56%
30
2.5/16
4.5/6.1
3
4
7.6/2.7
247/98
0.26
0.21
13/N.D.
26/N.D.
60%
30
5
6
7
0.7/0.8
2.9/0.6
21/13
8.6/28
0.22
0.21
N.D.
For this optimization, we maintained the reported biaryl tail
piece (R) in 1, and synthesized clusters of individual analogs
to survey changes in the central core and head piece. The deꢀ
sign principle centered on replacing the 4ꢀaminopiperidine
core in 1 with alternative scaffolds while conserving the overꢀ
all architecture for activity. Representative lead compounds
from each of these clusters are listed in Table 1, and additional
SAR tables within each series and physicochemical data for 1-
10 are provided in the supporting information. A small set of
analogs with fused bicyclic core structures represented by 2
were prepared. The fused cyclopentylpyrole ring system
yielded potent SSTR5 antagonists. After a secondary SAR
screen of different head pieces (supplementary material Table
S1), compound 2 was found to be optimal and was selected for
further profiling (cisꢀracemic, more potent Cꢀ4 diastereomer
characterized as described in the supplementary material). The
compound showed reasonable oral bioavailability in a mouse
PK experiment (F = 48%, t1/2 = 1.7 h), and modest efficacy in
the OGTT assay with 56% lowering of plasma glucose excurꢀ
sion following a 30 mg/kg oral dose with high residual whole
blood exposure (C2.5h = 0.76 ꢀM). The compound was devoid
of significant offꢀtarget activity except for modest potencies
on hERG (MKꢀ499 binding IC50 = 15 ꢀM) and weak SSTR1
binding activity (IC50 = 6 ꢀM).
67.8/7.1
73/N.D.
8
9
1.6/2.5
83/32
67/N.D.
110/7.4
0.95
25
54%
30
94%
3
10
1.2/2.1
1.1/0.9
45
a
All IC50 values calculated are the mean of at least duplicate exꢀ
periments within a maximal threefold range. N.D. = not deterꢀ
mined.
b Potency against human (h) and mouse (m) SSTR5.
c
hERG inhibition measured by competitive binding with MKꢀ
499, a known hERG blocker.
d Decrease in oral glucose AUC vs vehicle in male C57BL/6 mice
fed with HFD (D12492) for 21 days, n=3, t=0ꢀ120 min, comꢀ
pound dosed 1h before glucose.
The carbonꢀlinked head group series represented by 3 was also
explored. A variety of 2ꢀaryl substituents provided similar
potency among the 2,5ꢀdisubstituted imidazole derivatives
such as 3, however a significant loss of potency was observed
Literature reports of small molecule SSTR5 selective antagoꢀ
nists are relatively few. Martin reported the first nonpeptidic
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for the corresponding 3ꢀoxadiazole derivative (Table S1).
BuchwaldꢀHartwig CꢀN coupling with 4ꢀbromobenzoic meꢀ
thyl ester 12 followed by deprotection of the Boc group afꢀ
forded 13. This intermediate was then alkylated with 14 folꢀ
lowed by hydrolysis of the ester to give 10. The compounds
discussed in this communication were synthesized by similar
sequences with starting materials that are either commercially
available or can be made with simple and wellꢀestablished
steps.
1
2
3
4
5
6
7
8
Compound 3 is a potent inhibitor of hERG (MKꢀ499 binding
IC50 = 0.29 ꢀM) and also maintained potent SSTR3 antagonist
activity (IC50 = 119 nM). This ancillary activity was persistent
across the entire carbonꢀlinked imidazole core series.
The sulfonamide series represented by 4 and 5 was derived
from extending the 4ꢀaminopiperidine core in 1 to spiroꢀ or biꢀ
piperidines and replacing the head piece with a sulfonamide.
This series of sulfonamides is comprised of highly potent and
highly selective SSTR5 antagonists with moderate bioavailaꢀ
bility but with excellent in vivo efficacy in OGTT assays.
Compound 5 (mouse PK, F = 13%) lowered glucose excursion
in OGTT by 60% following an oral dose of 30 mg/kg despite
moderate residual whole blood exposure (C2.5h = 0.092 ꢀM).
However, similar to the arylimidazole series characterized by
3, this class of analogs was consistently potent in inhibiting
hERG. Sustained SAR investigation efforts failed to mitigate
this offꢀtarget activity.
Compound 10 is an advanced tool for the investigation of
SSTR5 pharmacology.17 It is a very potent and highly selecꢀ
tive SSTR5 antagonist with hSSTR5 binding (IC50 = 1.2 nM)
and cAMP antagonist (IC50 = 1.1 nM). It is inactive in the
binding assay against hSSTR1ꢀ4 (IC50 > 10 ꢀM), and this repꢀ
resents improved subtype selectivity as compared to 1
(hSSTR1 IC50 < 300 nM). At higher concentrations, 10 exhibꢀ
ited partial agonist activity in the hSSTR5 cAMP assay,
achieving 44% maximal activation at 8.3 ꢀM with an inflecꢀ
tion point of 2.7 ꢀM. The antagonist 10 is highly selective
over hERG (MKꢀ499 binding IC50 = 45 ꢀM) and other cardioꢀ
vascular ion channels (IKs, Cav1.2, Nav1.5 IC50 > 15 ꢀM).
Analysis of 10 in over 160 ancillary target assays (Eurofins
Panlabs screen) revealed only moderate binding activity
against the prostanoid DP receptor (IC50 = 3 ꢀM).
9
10
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The ether linked series, such as 6 and 7, was designed by reꢀ
placing the connecting NH in 1 with an O or CH2O group.
Similar to the sulfonamide series, all of the etherꢀlinked comꢀ
pounds afforded persistent inhibition of hERG. Although
these compounds were highly selective SSTR5 antagonists,
their potencies were generally moderate without significant
changes in ion channel activities.
The pharmacokinetic properties of 10 indicated that it is a
suitable tool for in vivo preclinical testing. The oral bioavailaꢀ
bility of 10 in rat, dog, and rhesus ranges from 40%ꢀ72% with
unbound free fractions of 2.2%ꢀ5.7% across species (Table 2).
The compound shows no appreciable inhibition of human
P450 enzymes (CYP3A4, 2D6, 2C9 IC50 > 50 ꢀM) and no
appreciable PXR activation. The solubility of 10 was modest
in neutral aqueous solution (0.3 mg/mL), but it was more solꢀ
uble in a 10% Tween formulation (5.3 mg/mL). This formulaꢀ
tion was used for pharmacokinetic studies.
Finally, replacing the 4ꢀaminopiperidine in 1 with spiroheteroꢀ
cycle variants afforded series represented by 8 and 9, which
showed promise in improving both potency and offꢀtarget
selectivity. Compound 8, tested as a racemic mixture, is one of
the most potent binders to the SSTR5 receptor while 9 affordꢀ
ed high selectivity over ion channel activities, with MKꢀ499
IC50 = 25 ꢀM. Compound 9 displayed good oral bioavailabilꢀ
ity and reasonable in vivo efficacy of 54% glucose lowering in
OGTT assay at a 30 mg/kg oral dose with good whole blood
exposure (C2.5h = 0.46 ꢀM), and despite its moderate mSSTR5
binding potency (IC50 = 32 nM) and mSSTR5 functional poꢀ
tency (IC50 = 7.4 nM). Examination of the emerging SAR inꢀ
dicated that significant SSTR5 potency was gained by the
spiroheterocycle core group as in 8, whereas significant selecꢀ
tivity over hERG was gained by the carboxylꢀcontaining head
group as in 2. Combining these features (including supporting
information compounds S25 – S30) led to the optimal 10,
which provided the desired profile of potency and selectivity.
This compound was chosen for more extensive pharmacologiꢀ
cal profiling.
Table 2. Pharmacokinetic Properties of compound 10
Species
Dosea
Fub
Clc
Vd
t
F
½
(iv/po)
(%)
(K/kg)
(h)
1.9
(%)
Rat
1 / 2
5.7
4.4
5.4
15.2
2.2
2.38
2.82
1.39
41
72
40
16.
5
Dog
0.25 / 1
0.25 / 1
Rhesus
aDosed in mg/kg
11.8
2.0
bMeasured at 0.1 ꢀM concentration with [3Hꢀ10]; Fu (%) for huꢀ
man and mouse are 2.2 and 4.6 respectively.
cMeasured in mL/kg/min.
Scheme 1. Synthesis of spiropiperidine analog 10
The pharmacology of 10 was investigated to more fully profile
the opportunity provided by selective antagonism of SSTR5.
Ex vivo, 10 was incubated with isolated human pancreatic
islets from nonꢀdiabetic donors using a method we have previꢀ
ously reported (Figure 1).18 The compound potentiated insulin
secretion in a glucoseꢀdependent manner. In the presence of
high glucose concentration (16 mM, labeled G16), insulin
secretion in human islets was significantly enhanced by 10 at
both 5 ꢀM and 0.5 ꢀM compound concentration, presumably
by blocking the inhibitory effect of endogenous SSTꢀ14 and
SSTꢀ28 secreted from these islets on insulin secretion. Howꢀ
ever, insulin secretion at low glucose concentration (2 mM,
labelled as G2) was not affected by 10, consistent with the
GDIS mechanism. The effect of 10 was similar to 50 nM of
o
Reagents and conditions: (a) K3PO4, Pd2(dba)3, dioxane, 100 C,
88%; (b) HCl, dioxane, EtOAc, RT, 95%; (c) Cs2CO3, DMF, RT,
o
86%; (d) LiOH, MeOH, 50 C, 79%. For synthesis of intermediꢀ
ate 14, see supporting information.
The synthesis of compound 10 is outlined in Scheme 1. Startꢀ
ing with Boc protected spiropiperidine intermediate 11,
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the GDIS peptide GLPꢀ1, as well as linoleate, a small moleꢀ
300
250
200
150
100
50
Vehicle
Glipizide, 10 mg/kg
10, 3 mg/kg
cule GPR40 agonist used as a positive control.19 The secretion
of SSTꢀ14 and glucagon in these islets was similarly moniꢀ
tored in this experiment, and was unaffected by 10 (data not
shown).
Trt
1
2
3
4
10, 30 mg/kg
5
6
7
8
0
-60
0
60
120 180 240
Time (min)
9
Figure 2. Blood glucose in 4ꢀhr fasted lean mice following adꢀ
ministration of 10 or glipizide.
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Inhibition of the DPPꢀ4 enzyme, which is responsible for the
rapid degradation of active GLPꢀ1[7ꢀ36] amide to inactive
GLPꢀ1[9ꢀ36] amide in vivo, is a proven therapy for the treatꢀ
ment of T2DM. Given that a selective SSTR5 antagonist poꢀ
tentiates glucoseꢀinduced secretion of GLPꢀ1, we anticipated
that coadministration of a DPPꢀ4 inhibitor and an SSTR5 anꢀ
tagonist should have synergistic effects on circulating active
GLPꢀ1[7ꢀ36] and therefore GDIS. As shown in the OGTT
assay results in Figure 3, administration of the SSTR5 antagoꢀ
nist 10 to lean C57/B6N mice afforded a substantial increase
in circulating total GLPꢀ1 and plasma insulin levels, and a
measurable increase in circulating active GLPꢀ1 (blood measꢀ
urements taken 5 minutes post glucose challenge). The combiꢀ
nation of 10 with the DPPꢀ4 inhibitor desꢀfluoro sitagliptin21
resulted in significantly increased circulating active GLPꢀ1
and further increased plasma insulin levels, compared with
either 10 or the DPPꢀ4 inhibitor alone. Similar synergistic
efficacy between SSTR5 antagonists and DPPꢀ4 inhibitors
were recently independently reported by researchers using
healthy mice, DIO mice, ZDF rats, and several GDIS receptor
KO mouse strains.12,22
Figure 1. Compound 10 increased glucoseꢀdependent insulin
secretion in isolated human islets with 2 mM and 16 mM of gluꢀ
cose (G2, G16). *P<0.05 vs DMSO.
Compound 10 also lowered glucose excursions in vivo in a
doseꢀdependent manner during OGTT in HFD mice (Table 3).
Oral administration of 0.03 to 3 mg/kg of 10 doseꢀdependently
reduced the net glucose area under the curve (AUC) in OGTT
mouse ranged from 23% to 84% as compared to vehicle.
Plasma exposures of the compound were measured 3 hours
post dose. From nine related OGTT experiments in HFD mice,
we calculate the minimal exposure for maximal efficacy
(EC90) = 484 nM. Furthermore, the exposure required for sigꢀ
nificant efficacy (> 50% reduction) may be calculated (EC50
>
54 nM). Taking into consideration the measured free fraction
in mouse plasma (Fu% = 4.6), the unbound concentration of 10
affording EC50 is 2.5 nM. This is roughly consistent with the
mouse SSTR5 IC50 (0.9 nM) in the cellꢀbased cAMP assay.
The OGTT efficacy of 10 was entirely ablated in SSTR5 KO
mice (supporting information), validating SSTR5 as the bioꢀ
logical target.
Table 3. Compound 10 dose titration in HFD mice OGTT
Oral dose
Blood glu AUC Plasma exposure (nM @ 3h)
(mg/kg)
(change %)a
ꢀ84%**
ꢀ74%*
whole blood
unbound
16.1
3
351
131
34
1
6.0
1.6
0.3
ꢀ59%*
0.1
ꢀ58%*
11
0.5
0.2
(MED)b
0.03
ꢀ23%
4
aReduction in blood glucose AUC as compared to vehicle, n = 8.
*P<0.01 vs veh; **P<0.001 vs veh.
bMED = minimal dose for significant efficacy.
As a glucoseꢀresponsive mechanism, administration of an
SSTR5 antagonist is expected to afford minimal risk of hypoꢀ
glycemia. This risk was assessed in 4ꢀhr fasted lean
C57BL/6N mice (Figure 2). An efficacious oral dose of 10 (3
mg/kg) and a supraꢀefficacious dose (30 mg/kg) administered
to the mice did not decrease basal glucose levels significantly
over the subsequent 5 hours. Glipizide, a marketed sulfonyluꢀ
rea K+ꢀATP blocker, was utilized as a positive control in this
experiment.20 Glipizide dosed orally at 10 mg/kg caused sigꢀ
nificant decreases of basal blood glucose levels starting at 60
minutes after dosing.
Figure 3. Combination of 10 with DPPꢀ4 inhibitor desꢀFꢀ
sitagliptin (DP4) (10+10 mpk) in HFD mouse OGTT studies.
*P<0.05 vs veh; **P<0.01 vs. veh; #P<0.001 vs 10.
In summary, we have identified multiple new lead SSTR5
antagonists through systematic lead hopping efforts based on
the existing literature compound 1. Medicinal chemistry iteraꢀ
tion and SAR optimization led to the discovery of azaspiꢀ
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rodecanones, a novel series of highly selective and potent
1
2
3
4
5
6
7
8
SSTR5 antagonists with diverse structural features and miniꢀ
mal offꢀtarget activity profiles regarding hERG, PXR, and
CYP inhibition. We demonstrated that the exemplar SSTR5
antagonist 10 significantly lowers glucose excursions in a
doseꢀdependent manner in a rodent diabetic model without
risk of hypoglycemia. The compound increased pancreatic
insulin secretion as well as total and active GLPꢀ1 release, and
demonstrates synergistic effects in combination with DPPꢀ4
inhibitors. These results indicate that selective SSTR5 antagoꢀ
nists could serve as therapeutic agents for the treatment of
type 2 diabetes as either monotherapy or in combination with
existing antiꢀdiabetic drugs such as sitagliptin. Further optimiꢀ
zation of this lead compound to achieve desirable physical
chemical and pharmacokinetic properties are discussed in the
following manuscript in this issue.
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R. A.; Binggeli, A.; Kuennecke, B.; Christ, A. D. Novel, nonꢀpeptidic
somatostatin receptor subtype 5 antagonists improve glucose tolerꢀ
ance in rodents. Regul. Pept. 2010, 159, 19–27.
ASSOCIATED CONTENT
Supporting Information
(10) Yamasaki, T.; Hirose, H.; Yamashita, T.; Takakura, N.;
Morimoto, S.; Nakahata, T.; Kina, A.; Nakano, Y.; Tamura, Y. O.;
Sugama, J.; Odani, T.; Shimizu, Y.; Iwasaki, S.; Watanabe, M.;
Maekawa, T. Discovery of novel somatostatin receptor subtype 5
(SSTR5) antagonists: Pharmacological studies and design to improve
pharmacokinetic profiles and human Etherꢀaꢀgoꢀgoꢀrelated gene
(hERG) inhibition. Bioorg. Med. Chem. 2017, 25, 4153–4162.
(11) Hirose, H.; Yamasaki, T.; Ogino, M.; Mizojiri, R.; Tamuraꢀ
Okano, Y.; Yashiro, H.; Muraki, Y.; Nakano, Y.; Sugama, J.; Hata,
A.; Iwasaki, S.; Watanabe, M.; Maekawa, T.; Kasai, S. Discovery of
novel 5ꢀoxaꢀ2,6ꢀdiazoaspiro[3.4]octꢀ6ꢀene derivatives as potent, seꢀ
lective, and orally available somatostatin receptor subtype 5 (SSTR5)
antagonists for the treatment of type 2 diabetes mellitus. Bioorg. Med.
Chem. 2017, 25, 4175–4193.
Supporting information is available free of charge on the ACS Publicaꢀ
tions website at http://pubs.acs.org.
Experimental procedures for the preparation of compounds 2ꢀ10. SAR
table of additional representative analogs. In vitro and in vivo assay protoꢀ
cols. SSTR5 WT/KO OGTT study results (PDF).
AUTHOR INFORMATION
Corresponding Author
*(U.S.) Phone: 908ꢀ740ꢀ3782. Eꢀmail: weiguo_liu@merck.com
Author Contributions
The manuscript was written through contributions of all authors. All
authors have given approval to the final version of the manuscript.
(
12) Farb, T. B.; Adeva, M.; Beauchamp, T. J.; Cabrera, O.;
Coates, D. A.; Meredith, T. D.; Droz, B. A.; Efanov, A.; Ficorilli, J.
V.; Gackenheimer, S. L.; MartinezꢀGrau, M. A.; Molero, V.; Ruano,
G.; Statnick, M. A.; Suter, T. M.; Bokvist, K. B.; Barrett, D. G. Reguꢀ
lation of endogenous (male) rodent GLPꢀ1 secretion and human islet
insulin secretion by antagonism of somatostatin receptor 5. Endocri-
nology 2017, 158, 3859ꢀ3873.
(13) Maruthur, N. M.; Tseng, E.; Hutfless, S.; Wilson, L. M; Suaꢀ
rezꢀCuervo, C.; Berger, Z.; Chu, Y.; Iyoha, E.; Segal, J. .B; Bolen, S.;
Diabetes medications as monotherapy or metforminꢀbased combinaꢀ
tion therapy for type 2 diabetes: A systematic review and metaꢀ
analysis. Ann. Intern. Med. 2016, 164, 740–751.
Funding
All authors were employees of Merck & Co., Inc., Kenilworth, NJ, USA
during the time this research was conducted. All research was funded by
Merck Research Laboratories, Merck & Co., Inc., Kenilworth, NJ, USA.
ABBREVIATIONS
SSTR5, somatostatin receptor subtype 5; SST, somatostatin; GLPꢀ1, gluꢀ
cagonꢀlike peptide 1; GI, gastrointestinal; KO, genetic knockout; GDIS,
glucoseꢀdependent insulin secretion; WT, genetic wildꢀtype; HFD, high
fat diet; OGTT, oral glucose tolerance test; T2DM, type 2 diabetes melliꢀ
tus; AUC, area under the curve; DPPꢀ4, dipeptidyl peptidase 4; SGLT2,
sodiumꢀglucose coꢀtransporter 2; PK, pharmacokinetic; mpk, milligram
per kilogram; SAR, structure activity relationshipl; CHO, Chinese hamster
ovary.
(14) Martin, R. E.; Green, L. G.; Guba, W.; Kratochwil, N.; Christ,
A. Discovery of the first nonpeptidic, smallꢀmolecule, highly selecꢀ
tive somatostatin receptor subtype 5 antagonists: A chemogenomics
approach. J. Med. Chem. 2007, 50, 6291–6294.
(
15) Martin, R. E.; Mohr, P.; Maerki, H. P.; Guba, W.; Kuratli, C.;
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Discovery and pharmacology of a novel somatostatin subtype 5
(SSTR5) antagonist: Synergy with DPP-4 inhibition
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Weiguo Liu*, Pengcheng P. Shao, Gui-Bai Liang, John Bawiec, Jiafang He, Susan D. Aster,
Margaret Wu, Garry Chicchi, John Wang, Kwei-Lan Tsao, Jin Shang, Gino Salituro, Yun-Ping
Zhou, Cai Li, Taro E. Akiyama, Daniel E. Metzger, Beth Ann Murphy, Andrew D. Howard, Ann
E. Weber, Joseph L. Duffy
Merck & Co., Inc., Kenilworth, New Jersey 07033, United States
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