Stimulation of glucose-dependent insulin secretion by a potent, selective sst3 antagonist

Article abstract of DOI:10.1021/ml200272z

This letter provides the first pharmacological proof of principle that the sst₃ receptor mediates glucose-stimulated insulin secretion (GSIS) from pancreatic β-cells. To enable these studies, we identified the selective sst₃ antagonist (1R,3R)-3-(5-phenyl-1H-imidazol-2-yl)-1- (tetrahydro-2H-pyran-4-yl)-2,3,4,9-tetrahydro-1H-β-carboline (5a), with improved ion channel selectivity and mouse pharmacokinetic properties as compared to previously described tetrahydro-β-carboline imidazole sst3 antagonists. We demonstrated that compound 5a enhances GSIS in pancreatic β-cells and blocks glucose excursion induced by dextrose challenge in ipGTT and OGTT models in mice. Finally, we provided strong evidence that these effects are mechanism-based in an ipGTT study, showing reduction of glucose excursion in wild-type but not sst₃ knockout mice. Thus, we have shown that antagonism of sst₃ represents a new mechanism with potential in treating type 2 diabetes mellitus.

Full text of DOI:10.1021/ml200272z

Letter
pubs.acs.org/acsmedchemlett
Stimulation of Glucose-Dependent Insulin Secretion by a Potent,
Selective sst3 Antagonist
Alexander Pasternak,* Zhe Feng, Reynalda de Jesus, Zhixiong Ye, Shuwen He, Peter Dobbelaar,
Scott A. Bradley, Gary G. Chicchi, Kwei-Lan Tsao, Dorina Trusca, George J. Eiermann, Cai Li, Yue Feng,
Margaret Wu, Qing Shao, Bei B. Zhang, Ravi Nargund, Sander G. Mills, Andrew D. Howard, Lihu Yang,
and Yun-Ping Zhou
Merck Research Laboratories, Rahway, New Jersey 07065, United States
S
* Supporting Information
ABSTRACT: This letter provides the first pharmacological proof of principle that the sst3 receptor mediates
glucose-stimulated insulin secretion (GSIS) from pancreatic β-cells. To enable these studies, we identified the
selective sst3 antagonist (1R,3R)-3-(5-phenyl-1H-imidazol-2-yl)-1-(tetrahydro-2H-pyran-4-yl)-2,3,4,9-tetrahy-
dro-1H-β-carboline (5a), with improved ion channel selectivity and mouse pharmacokinetic properties as
compared to previously described tetrahydro-β-carboline imidazole sst3 antagonists. We demonstrated that
compound 5a enhances GSIS in pancreatic β-cells and blocks glucose excursion induced by dextrose
challenge in ipGTT and OGTT models in mice. Finally, we provided strong evidence that these effects are
mechanism-based in an ipGTT study, showing reduction of glucose excursion in wild-type but not sst3
knockout mice. Thus, we have shown that antagonism of sst3 represents a new mechanism with potential in
treating type 2 diabetes mellitus.
KEYWORDS: somatostatin, type 2 diabetes, sst3, glucose-stimulated insulin secretion
ype 2 diabetes mellitus (T2DM) accounts for 90−95% of
treat T2DM;4,5 DPP-4 inhibitors such as sitagliptin represent
one recently introduced class of such agents. As part of our
continuing efforts to identify novel GSIS targets, Zhou and co-
workers recently determined that the somatostatin receptor
subtype 3 (sst3) is highly expressed in β-cells of human and
rodent islets, and knocking down expression of sst3 using
siRNA technology enhances GSIS in INS-1 cells (a rat
insulinoma cell line).6 Somatostatin (somatotropin release-
inhibiting factor, SRIF) is a cyclic tetradecapeptide existing in
two biologically active forms, SRIF-14 and N-terminal extended
SRIF-28, that acts as a neurotransmitter and hormone with
broad inhibitory effects on both endocrine (growth hormone,
insulin, glucagon, gastrin, cholecystokinin, etc.) and exocrine
(gastric acid, pancreatic enzymes, etc.) secretion. These effects
are mediated through interactions with five G-protein-coupled
somatostatin receptor subtypes (sst1, sst2, sst3, sst4, and sst5).7
Of the five somatostatin receptor subtypes, the specific
physiological functions of the individual receptor subtypes are
best understood for sst2 and sst5.8 In contrast to sst2 and sst5,
relatively little is known about the function of sst3. Expression
of sst3 has been described in brain, pituitary, stomach, pancreas,
thymus, thyroid, prostate, vascular endothelial cells, and various
human tumors. The sst3 receptor has been linked to apoptotic
signaling and proliferation and has been proposed as a possible
target for cancer therapy.9−11 To our knowledge, a role for the
sst3 receptor in regulating GSIS of pancreatic β-cells had not
T
clinical diabetes and represents a major and growing
health threat throughout the world. The overall estimated
worldwide prevalence of diabetes in 2000 was 2.8% (171
million people), with that number projected to increase to 4.4%
(366 million people) by 2030.1 Within the United States, a
2001 estimate of the prevalence of diagnosed diabetes cases was
even greater at 7.9% of the population (16.7 million people),
with an even larger number of sufferers believed to be
undiagnosed.1 Because of the trend of increasing rates of
obesity in the United States and developing world, the vast
majority of newly diagnosed cases of diabetes are anticipated to
fall within T2DM spectrum.2 Diabetes mellitus carries a
tremendous human suffering and economic burden as a
consequence of the associated chronic complications (blind-
ness, end-stage renal disease, limb amputations, heart disease,
stroke, etc.) and increased morbidity and mortality. Unfortu-
nately, despite numerous medication options for the treatment
of T2DM, most patients fail to achieve long-term glycemic
control, and new treatment options are urgently needed.3
A decline in glucose-stimulated insulin secretion (GSIS)
from pancreatic β-cells is one of the primary defects associated
with the development and progression of T2DM. Agents such
as sulfonyl ureas and related K-ATP channel blockers that
increase insulin secretion from β-cells are efficacious in
lowering glucose, but because their effects are continuous and
not dependent on plasma glucose levels, they carry the risk of
evoking hypoglycemia and accelerating the loss of islet
function. As such, identification of novel targets for stimulating
GSIS has been a major strategy in the quest for new agents to
Received: November 12, 2011
Accepted: February 13, 2012
Published: February 27, 2012
© 2012 American Chemical Society
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ACS Medicinal Chemistry Letters
Letter
been previously described prior to this report. This letter
describes the development of an sst3 antagonist with suitable
somatostatin receptor subtype and off target selectivity and
rodent pharmacokinetic properties, to provide in vivo proof of
principal that antagonism of sst3 represents a viable novel
strategy for stimulation of GSIS and, possibly, for treatment of
T2DM.
Relatively few small molecule nonpeptide sst3 antagonists
have been described in the literature.12 Several examples are
shown in Figure 1. Compound 1 was described by Novartis
scientists as a potent, selective silent competitive sst3 antagonist
(human sst3 binding affinity <10 nM, selectivity against human
sst1, sst2, sst5 all >150-fold; selectivity against sst4 21-fold;
cAMP functional antagonist potency pKB = 7.88).13,14
Tetrahydro-β-carboline imidazole compounds 2 and 3 were
described by Poitout, Thurieau, and co-workers at the Institut
Henri Beaufour as having high binding affinities for sst3 (0.64
and 1.7 nM, respectively), both with >1000-fold selectivity over
the other somatostatin receptor subtypes.15 In functional
assays, these compounds behaved as competitive antagonists
of sst3. Novartis scientists described closely related β-carboline
imidazole sst3 antagonists such as 4 (sst3 human pKd 8.69,
>400-fold selective against other receptor subtypes) in a
recently issued patent, which claims these compounds as
potential treatments for depression, anxiety, bipolar disorder,
and cancer.16 Unfortunately, in our hands, compounds 2−4 had
poor pharmacokinetic properties in mice with high clearance
rates (126, 95, and 31 mL/min/kg, respectively) and poor
plasma exposures following oral dosing. This limited the
usefulness of these compounds as tools for in vivo
pharmacological assessment of sst3 as a potential new GSIS
target. Moreover, while not reported for these compounds,
based on internal assays, compounds 2−4 had high affinities for
several cardiac ion channels including the hERG channel
(binding IC50 = 150, 77, and 176 nM, respectively) and/or the
L type Ca2+ channel (binding IC50 = 128, 308, and 1526 nM,
respectively). We chose to explore modifications of compounds
related to 2−4 in an effort to identify novel analogs with
improved pharmacokinetic and off-target profiles. On the basis
of the slight improvement in Ca2+ channel selectivity observed
upon incorporation of oxygen atoms into the n-butyl groups of
2 leading to 4, we decided to combine features of compounds 3
and 4 by making 1-heterocycle substituted β-carboline
analogues (5), a significant divergence from the original
structure of the series reported in Novartis and Institut Henri
Beaufour patents.
Figure 1. Previously described sst3 selective antagonists.
Scheme 1. Synthesis of β-Carboline Analogues 5
Analogues were readily prepared according to Scheme 1.
Boc-D-Trp was treated with bromoacetophenone in the
presence of cesium carbonate to provide ester 6. The addition
of toluene and ammonium acetate and removal of water via
Dean−Stark trap at reflux afforded imidazole 7. Removal of the
Boc group (TFA) was followed by Pictet−Spengler cyclization
with commercially available or routinely prepared aldehydes.
Cyclization generally led to predominantly one isomeric
product. Poitout and Thurieau observed the same for
compound 3 and assumed that the major isomer had the
trans stereochemistry; however, they did not offer any evidence
to support this assignment.15 On the basis of a strong NOE in
the 1D NOE NMR spectrum between the two methine protons
in major isomer 5a, we have established that the relative
stereochemistry must be cis instead. A second NOE study with
a related analogue (not shown) also demonstrated that the
major isomer is cis, giving us added confidence that, for these
analogues, the Pictet−Spengler reaction produces predom-
inantly the cis isomers. In some cases, further elaboration was
performed under routine conditions (for example, when the 1-
substituent was Boc-piperidine, the Boc was removed, and
further acylation or sulfonylation could be performed).
Compounds 5a−n were evaluated in a sst3 binding assay,17
a
cAMP assay measuring sst3 functional antagonism potency
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ACS Medicinal Chemistry Letters
Letter
a
Table 1. Human sst3 Binding and Functional Data and hERG Binding Data for 3 and 5a−n
IC50 (nM)
sst3 cAMP
b
analogue (n is 1 except as noted)
X
sst3 binding
hERG binding
3
CH2
O
0.8 (5; SD 0.3)
14 (425; SD 4.6)
390 (2)
45 (2)
26 (2)
77 (2)
380 (2)
730 (2)
64 (2)
5a (cis)
22 (417; SD 17)
1200 (1)
19 (1)
5b (trans)
O
5c, n is 0 isomer 1
O
5d, n is 0 isomer 2
O
63 (2)
30 (1)
25 (2)
5e
S
1.7 (1)
10 (1)
120 (2)
5f isomer 1
SO
SO
SO2
220 (1)
21 (1)
380 (2)
24 (2)
5g isomer 2
100 (2)
100 (2)
5h
5i
120 (2)
7 (2)
290 (2)
1000 (2)
220 (2)
46 (2)
NBoc
5j
NH
63 (1)
5100 (2)
9800 (1)
3500 (2)
700 (2)
240 (2)
5k
5l
NAc
16 (2)
NSO2Me
NCO2Me
NCONHMe
44 (2)
5m
5n
4 (2)
66 (2)
35 (2)
180 (2)
a
b
Numbers in parentheses represent numbers of determinations and standard deviation (SD), when calculable. hERG binding data were obtained by
measuring displacement of 35S-MK499 from HEK-293 cells stably expressing hERG.19
Table 2. Pharmacokinetic Properties of Compounds 3, 4,
and 5a in C57BL/6N Mice
5e, 5g, and 5k). Generally, the directional changes in sst3
a
binding affinity and functional potencies for each analogue
track together, but that is not the case for all molecules.
Structural changes among the series may affect ligand−receptor
on-rates, off-rates, or both and, as such, can have differential
effects on the binding affinities and functional antagonism
potencies determined in the two different assay formats,
wherein the binding assay is a competition readout at steady-
state equilibrium, while the cAMP assay is an accumulation
challenge assay following prebinding of the test molecule.
Installation of a heterocycle, in some cases, also led to a modest
to substantial reduction in binding affinity for the hERG
channel (analogs 5a, 5j, 5k, 5l, and 5m), demonstrating the
feasibility of improving selectivity over hERG in the β-carboline
sst3 antagonist class through incorporation of heteroatoms into
this fragment. As indicated above, Pictet−Spengler cyclization
led to predominantly one stereoisomer product, which in the
case of compound 5a, we have established to be cis.
Comparison of the potency of the isomerically pure cis (5a)
and trans (5b) isomers indicated that the major cis isomer is
more potent in both the sst3 binding and the functional assays.
On the basis of the comparable functional potency and 5-fold
weaker hERG binding affinity (hERG IC50 = 380 nM) of
compound 5a as compared to 3, we decided to further profile
it. Compound 5a was found to have good selectivity against the
other human somatostatin receptor subtypes in binding assays
(sst1, sst2, sst4, and sst5 IC50 values all >1 μM). Because our
pharmacodynamic model was established in mice, we evaluated
compound 5a in the mouse sst3 binding and cAMP-based
AUCN po
Cmax po
Vdss
Cl
t1/2
no. F %
(μM h/mg)
(nM)
(L/kg) (mL/min/kg)
(h)
3
4
15
4
0.07
0.06
1.3
60
130
840
8.1
0.7
1.6
95
31
15
0.14
0.54
1.6
5a
45
a
Mouse compound exposures were analyzed in blood; iv and po doses
were 1 and 2 mg/kg, respectively.
Figure 2. Effect of compound 5a (10 μM) on GSIS in pancreatic β-
cells from normal C57BL/6J mice (n = 4).
against SS-14,18 and a hERG binding assay.19 The resulting IC50
values for each assay are displayed in Table 1. Replacement of
the cyclohexyl moiety in 3 with a variety of saturated
heterocycles led, in general, to loss of binding potency (with
the exception of compound 5e, which had similar binding
potency). Despite this, a number of analogues retained
equivalent or better potency as compared to 3 in the assay
measuring functional antagonism activity (analogues 5a, 5c, 5d,
functional assays (sst3 binding IC50 = 8.9 nM, sst3 cAMP IC50
=
16 nM), where it demonstrated equivalent potency to that
observed on the human receptor. When screened against other
mouse somatostatin receptor subtypes, it maintained good sst3
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ACS Medicinal Chemistry Letters
Letter
Figure 3. Evaluation of 2 and 10 mg/kg doses of compound 5a in
ipGTT and OGTT tests in C57BL/6N Tac mice following dextrose
(dex) challenge. *p < 0.05, **p < 0.005 vs dextrose alone. Treatment
= trt.
Figure 4. Evaluation of compound 5a (10 mg/kg) in ipGTT studies in
wild-type and sst3 knockout mice challenged with 2 g/kg dextrose
(dex). *p < 0.05 vs dextrose alone. Treatment = trt.
secretion. GSIS is decreased significantly (by 39%) in the
presence of the somatostatin agonist octreotide; however, 5a
(at 10 μM) can partially overcome the effect of 50 nM
octreotide on GSIS. GLP-1 serving as the positive control (at
10 nM) elevates GSIS as expected.
subtype selectivity (IC50 msst1, msst2, msst4, and msst5 all >10
μM). It demonstrated weaker potency as compared to
compound 3 in the L type Ca2+ channel binding assay (Ca2+
IC50 = 1.9 μM). In a pharmacokinetic study in mice, compound
5a had a reduced clearance rate, increased half-life, higher oral
bioavailability, and significantly higher plasma exposures (po)
as compared to parent compounds 3 and 4 (Table 2).
Compound 5a was used to evaluate the role of sst3 in GSIS
from the β-cell (Figure 2). In this assay,17 the effects of 5a at 10
μM, octreotide (octr, a peptide somatostatin agonist at 50 nM),
a combination of 5a (10 μM) and octreotide at 50 nM, and
negative (DMSO) and positive controls [glucagon-like peptide-
1 (GLP-1) at 10 nM] on pancreatic islets isolated from normal
C57BL/6J mice were determined in the presence of 2 and 16
mM glucose.20 As shown, 5a significantly enhances GSIS (at 16
mM glucose) relative to DMSO control (44% increase). On the
other hand, it did not affect the insulin secretion at basal (2
mM) glucose in this assay. This result provides evidence that
the sst3 antagonist only enhances GSIS, not basal insulin
On the basis of the favorable mouse in vitro sst3 potency, the
pharmacokinetic profile, and the effect on GSIS in isolated
mouse islets of compound 5a, we next sought to evaluate its
ability to improve glucose tolerance in ip and po glucose
tolerance test models (ipGTT and OGTT, respectively) in lean
C57BL/6N Tac mice fasted for 5−6 h before dextrose
challenge.21 Figure 3 shows that dextrose challenge causes
blood glucose excursion, which in both studies is ameliorated in
a dose-dependent fashion by predosing (1 h prior to challenge)
with compound 5a (2 and 10 mg/kg). To demonstrate that
these effects are mechanism-based, we evaluated compound 5a
in an ipGTT study simultaneously comparing effects in wild-
type and sst3 knockout mice. As shown in Figure 4, compound
5a reduced glucose excursion resulting from dextrose challenge
in the wild-type mice (26% reduction in total blood glucose
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Letter
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Synthesis of the Potent and Selective Somatostatin sst3 Receptor
Antagonist [4-(3,4-difluoro-phenyl)-piperazine-1-yl]-{(4S,4aS,8aR)-
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(17) For details of the sst3 binding assay and the GSIS assay with
pancreatic islets, see the Supporting Information and Merck & Co.,
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Thornberry, N. A.) Diagnosis and Treatment of Diabetes and Other
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AUC) but had no significant effect on glucose levels following
dextrose challenge in sst3 knockout mice. Blood insulin levels
were not monitored in this and other typical GTT studies to
avoid excessive stress to the animals and impacting glucose
readout. However, in a parallel study in wild-type and knockout
mice predosed at −60 min with 10 mg/kg of 5a, a 50%
elevation in plasma insulin levels was observed 10 min
postdextrose challenge in wild-type mice with no effect on
the knockout mice; however, because of variability, this effect
did not reach statistical significance (p = 0.12, n = 5).
In summary, we have recently shown for the first time that
the sst3 receptor mediates GSIS from pancreatic β-cells. To
provide pharmacological proof of principle for this observation,
we developed β-carboline imidazole-based selective sst3
antagonist 5a, with improved ion channel selectivity and
mouse pharmacokinetic characteristics as compared to
previously described structurally related antagonists 2−4. We
demonstrated that compound 5a enhances GSIS in pancreatic
β-cells and blocks glucose excursion induced by dextrose
challenge in ipGTT and OGTT models in mice. Moreover, we
provided strong evidence that these effects are mechanism-
based in an ipGTT study showing blockade of glucose
excursion in wild-type but not sst3 knockout mice. Thus, we
have shown that antagonism of sst3 represents a new GSIS
target with potential in treating T2DM.
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental details for the synthesis and characterization of
sst3 antagonist 5a, in vitro assays, GSIS assay with pancreatic
islets, and GTTs. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
(18) The sst3 cAMP functional assay is described in the Supporting
Information.
(19) Wang, J.; Della Penna, K.; Wang, H.; Karczewski, J.; Connolly,
T. M.; Koblan, K. S.; Bennett, P. B.; Salata, J. J. Functional and
pharmacological properties of canine ERG potassium channels. Am. J.
Phys. 2003, 284, H256−67.
■
Corresponding Author
*Tel: 732-594-3847. E-mail: alexander_pasternak@merck.com.
Notes
The authors declare no competing financial interest.
(20) Zhou, Y.-P.; Marlen, K.; Palma, J. F.; Schweitzer, A.; Reilly, L.;
Gregoire, F. M.; Xu, G. G.; Blume, J. E.; Johnson, J. D. Overexpression
of Repressive cAMP Response Element Modulators in High Glucose
and Fatty Acid-treated Rat Islets. J. Biol. Chem. 2003, 278, 51316−
51323.
(21) For details on the glucose tolerance test models in mice, please
see the Supporting Information and Tan, C. P.; Feng, Y.; Zhou, Y.-P.;
Eiermann, G. J.; Petrov, A.; Zhou, C.; Lin, S.; Salituro, G.; Meinke, P.;
Mosley, R.; Akiyama, T. E.; Einstein, M.; Kumar, S.; Berger, J. P.; Mills,
S. G.; Thornberry, N. A.; Yang, L.; Howard, A. D. Selective small-
molecule agonists of G protein-coupled receptor 40 promote glucose-
dependent insulin secretion and reduce blood glucose in mice.
Diabetes 2008, 57 (8), 2211−2219.
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