The discovery of MK-4256, a potent SSTR3 antagonist as a potential treatment of type 2 diabetes

Article abstract of DOI:10.1021/ml300063m

A structure-activity relationship study of the imidazolyl-β- tetrahydrocarboline series identified MK-4256 as a potent, selective SSTR3 antagonist, which demonstrated superior efficacy in a mouse oGTT model. MK-4256 reduced glucose excursion in a dose-dependent fashion with maximal efficacy achieved at doses as low as 0.03 mg/kg po. As compared with glipizide, MK-4256 showed a minimal hypoglycemia risk in mice.

Full text of DOI:10.1021/ml300063m

Letter
pubs.acs.org/acsmedchemlett
The Discovery of MK-4256, a Potent SSTR3 Antagonist as a Potential
Treatment of Type 2 Diabetes
Shuwen He,*,† Zhixiong Ye,† Quang Truong,† Shrenik Shah,† Wu Du,† Liangqin Guo,†
Peter H. Dobbelaar,† Zhong Lai,† Jian Liu,† Tianying Jian,† Hongbo Qi,† Raman K. Bakshi,†
Qingmei Hong,† James Dellureficio,† Alexander Pasternak,† Zhe Feng,† Reynalda deJesus,† Lihu Yang,†
Mikhail Reibarkh,† Scott A. Bradley,† Mark A. Holmes,† Richard G. Ball,† Rebecca T. Ruck,‡
Mark A. Huffman,‡ Frederick Wong,‡ Koppara Samuel,§ Vijay B. Reddy,§ Stan Mitelman,§
Sharon X. Tong,§ Gary G. Chicchi,∥ Kwei-Lan Tsao,∥ Dorina Trusca,∥ Margaret Wu,∥ Qing Shao,∥
Maria E. Trujillo,∥ George J. Eiermann,∥ Cai Li,∥ Bei B. Zhang,∥ Andrew D. Howard,∥ Yun-Ping Zhou,∥
Ravi P. Nargund,† and William K. Hagmann†
Departments of †Medicinal Chemistry, ‡Process Research, §Drug Metabolism and Pharmacokinetics, and ∥Diabetes Research, Merck
Research Laboratories, 126 East Lincoln Avenue, Rahway, New Jersey 07065, United States
S
* Supporting Information
ABSTRACT: A structure−activity relationship study of the imidazolyl-β-tetrahydrocarboline series
identified MK-4256 as a potent, selective SSTR3 antagonist, which demonstrated superior efficacy in a
mouse oGTT model. MK-4256 reduced glucose excursion in a dose-dependent fashion with maximal
efficacy achieved at doses as low as 0.03 mg/kg po. As compared with glipizide, MK-4256 showed a
minimal hypoglycemia risk in mice.
KEYWORDS: SSTR3, antagonist, type 2 diabetes, β-tetrahydrocarboline
ype 2 diabetes mellitus (T2DM) is a carbohydrate
metabolism disorder characterized by high blood glucose
cells, thus minimizing the potential risk associated with
hypoglycemia. Loss of GDIS from the pancreatic β-cell is a
primary defect responsible for the onset and progression of
T2DM.9 Oral agents that stimulate insulin secretion, such as
sulfonylureas, have proven efficacious in glucose lowering.
However, these agents stimulate the β-cell to secrete insulin
continuously, regardless of prevailing glucose levels, thereby
promoting hypoglycemia and accelerating the loss of islet
function.10 Thus, oral agents that induce GDIS have the
potential to replace sulfonylureas as a first-line therapy for the
treatment of T2DM. To that end, DPP-4 inhibitors represent a
major breakthrough such that they selectively enhance insulin
secretion in the presence of hyperglycemia by increasing plasma
levels of active GLP-1.11,12 DPP-4 inhibitors thus avoid the risk
of hypoglycemia commonly seen with sulfonylureas. Novel
agents with a GDIS mechanism may offer better efficacy and/or
durability, both as monotherapy and in combination.
T
levels (hyperglycemia) resulting from the body's deficiency in
insulin production and utilization.1 Diabetes has become a
worldwide epidemic, affecting 6.4% of the adult population in
the developed world. It is predicted that the number affected
will grow to 7.7% by 2030.2 Among all of the diabetes cases,
more than 90% of the patients have T2DM (noninsulin-
dependent diabetes).3 Diabetes causes significant morbidity and
mortality. Diabetic retinopathy is the number one cause of
preventable blindness in the developed countries, while diabetic
kidney disease often leads to end stage renal failure.4,5 Despite
the availability of a range of agents for the treatment of T2DM
(e.g., sulfonylureas, metformin, PPARγ-selective agonists, and
DPP-4 inhibitors), a high proportion of the diabetic patients are
undertreated, failing to achieve or maintain glycemic targets. In
addition, many current therapies have significant limitations
and/or liabilities, particularly in terms of disease modification
and durability.6−8 Therefore, effective treatment of T2DM
continues to be a huge, unmet medical need.
Somatostatin (also known as growth hormone-inhibition
hormone or somatotropin release-inhibiting factor, SRIF)
One strategy for the discovery of safe, effective treatments of
Received: March 9, 2012
Accepted: May 7, 2012
T2DM is the development of novel agents that promote
glucose-dependent insulin secretion (GDIS) from pancreatic β-
© XXXX American Chemical Society
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Figure 1. Imidazolyl β-carboline SSTR3 antagonists.
a
Table 1. Profile of C-1 Monosubstituted Imidazolyl β-Carbolines
human SSTR3
functional cAMP
antagonism IC50 (nM)
(% inh.)
mouse SSTR3
functional cAMP
antagonism IC50 (nM)
(% inh.)
compd
no.
binding
IC50 (nM)
binding
IC50 (nM)
MK-499 binding reduction of glucose excursion in mouse ipGTT at
b,c
assay, Ki (nM)
10 mg/kg oral dose (drug level)
1
2
3
4
5
6
14
11 (87%)
5.7 (119%)
9.3 (102%)
33 (93%)
19 (102%)
58 (76%)
8.9
1.7
4.0
4.8
16 (98%)
26 (108%)
4.4 (67%)
26 (66%)
18 (103%)
29 (92%)
369
377
75% (3.8 μM)
79% (4.6 μM)
91% (1.2 μM)
84% (1.6 μM)
2.8
6.9
7.2
19
300
2189
385
d
d
ND
ND
9.2
8.1
2206
87% (0.2 μM)
a
b
Assay protocols are provided in the Supporting Information. In vitro assay results are the average of at least three duplicates. Mice were challenged
c
d
with ip injection of 2 g/kg dextrose. Drug level refers to the concentration of the compound in plasma 2.5 h postoral dosing at 10 mg/kg. Not
determined.
derived its names from its ability to inhibit the release of growth
hormone from the anterior pituitary gland.13 Two active forms
of somatosatin are produced by alternative cleavage: 14 amino
acids (SRIF-14) and 28 amino acids (SRIF-28). Somatostatin
also suppresses the production of the pancreatic hormones
(e.g., insulin and glucagon), has a role in the central nervous
system as a neurotransmitter, is involved in the regulation of
gastric secretion, and may regulate cell proliferation. The
functions of somatostatin are mediated through five G-protein
coupled receptors (SSTR1−SSTR5).
We had found that antagonism of SSTR3 has the potential to
be a novel GDIS mechanism for the treatment of T2DM.14
SSTR3 is highly expressed in β-cells of human and rodent islets.
Silencing the expression of SSTR3 with siRNA significantly
enhanced GDIS in a rat insulinoma cell line, INS-1 cells. The
importance of SSTR3 in regulating GDIS and glucose
homeostasis was further supported by the fact that a selective
SSTR3 antagonist enhanced GDIS in mouse islets and reduced
blood glucose levels during a glucose tolerance test (GTT)
(Figure 1).15 The glucose lowering was not observed with
SSTR3 knockout mice.15 Mechanistically, SSTR3 signals
primarily through Gαi-mediated inhibition of cAMP produc-
tion. Therefore, antagonists of SSTR3 most likely enhance
GDIS by increasing intracellular cAMP levels in pancreatic β-
cells, a mechanism that is similar to GLP-1 analogues, which is
proven to be a glucose-dependent mechanism.16
Two different structural classes of selective small molecule
SSTR3 antagonists have been disclosed, imidazolyl-β-carbolines
derived from D-Trp and substituted decahydroisoquino-
lines.17−21 While both structural classes offer potent, selective
SSTR3 antagonists, these compounds have not been reported
as potential treatments of T2DM. Starting with the imidazolyl-
β-carboline class, compound 1 was found to be a potent and
selective SSTR3 antagonist.15 It demonstrated good inhibition
(75%) of glucose excursion in the mouse ipGTT (intra-
peritoneal glucose tolerance test) model at 10 mg/kg oral dose
(Table 1). The efficacy was mediated through SSTR3 since the
inhibition of glucose excursion was not observed in the SSTR3
B
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Table 2. PK Parameters of 4 and 6
mg/kg
oral dose
compd no.
species
iv dose
oral AUC(0−t) (μM h)
iv t1/2
iv CL (mL/min kg)
Vdss (L/kg)
F (%)
a
4
4
6
6
6
6
mouse
4
1
4
1
1
1
10
2
4.11
1.38
7.73
4.36
27.6
12.4
2.24
2.26
2.58
8.14
6.69
8.08
99.6
25.3
39.9
9.67
1.78
2.79
10.8
4.59
7.21
5.83
0.87
1.75
100
47
76
58
67
51
a
rat
a
mouse
10
2
a
rat
b
dog
2
b
rhesus
2
a
b
The compound was dosed as 1.0 mg/mL solution in EtOH:PEG400:water (2:23:75). The compound was dosed as 4.0 mg/mL solution in
EtOH:PEG400:water (10:40:50).
a
Table 3. Profiles of Disubstituted Imidazoyl β-Carbolines
human SSTR3
mouse SSTR3
compd
no.
binding
IC50 (nM)
functional cAMP antagonism
IC50 (nM) (% inh.)
binding
IC50 (nM)
functional cAMP antagonism MK-499 binding
reduction of glucose excursion in mouse
b
IC50 (nM) (% inh.)
assay, Ki (nM)
oGTT at 1 mg/kg oral dose
c
7
8
0.76
0.66
1.1
7.3 (91%)
0.95 (83%)
1.1 (107%)
3.6 (77%)
ND
0.36
0.61
1.2
2.4 (101%)
0.46 (87%)
3.7 (130%)
4.8 (92%)
44
1701
1638
462
ND
109%
63%
81%
80%
68%
9
10
11
12
13
2.3
0.94
0.74
0.97
0.78 (75%)
0.70 (103%)
1.2 (69%)
0.50
0.46
0.59
0.14 (68%)
0.48 (113%)
1.3 (133%)
543
2616
1403
71%
a
b
Assay protocols are provided in the Supporting Information. In vitro assay results are the average of at least three duplicates. Mice were challenged
c
with oral dose of 5 g/kg dextrose. Not determined.
knockout mouse. However, 1 has strong binding to hERG as
shown in a MK-499 binding assay.22,23 Herein, we describe
improved efficacy in this series with a reduced off-target
activities (especially hERG) that led to a potential development
candidate.
that diastereomer 6 has less activity in the MK-499 binding
assay.
Compounds 4 and 6 were further evaluated in pharmaco-
kinetic (PK) studies (Table 2). In rodents, 6 showed lower
clearance and ∼2−3-fold higher exposures after oral dosing
than 4. Compound 6 was further tested in higher species and
exhibited excellent PK profiles in both dog and rhesus with long
half-lives and excellent oral exposures.
An interesting observation was made with compound 7
where the C1 position has a diphenyl substitution pattern.
Compound 7 is more potent than the monosubstituted
compounds on SSTR3 in vitro assays (Table 3), but 7 does
afford potent binding in MK-499 binding assay.
The enhanced potency of 7 prompted further investigation
of compounds with disubstitution at the C-1 position (Table
3). The N-methyl pyrazole and 1,2,4-oxadiazole of compounds
4 and 6 were combined to afford potent isomers 8 and 9. Both
compounds maintain excellent in vitro potency and reduced
activity in the MK-499 binding assay. Screening in the original
mouse ipGTT model was replaced with an oral glucose
tolerance test (oGTT) due to the ease of the experimental
protocols and analogy to oGTT protocols carried out in human
clinical trials. Compound 9 reduced glucose excursion by 63%
at 1 mg/kg po, while compound 8 achieved complete ablation
of glucose excursion (109%) at the same dose.
The enantiomers 10 and 11 were also synthesized, starting
from D-Trp. Interestingly, compounds 10 and 11 have similar
SSTR3 potency as compounds 8 and 9. However, they suffer
from increased binding to hERG. Compounds 12 and 13,
which have two identical heterocycles moieties at the C1
position, were also synthesized. Although both compounds
maintain high SSTR3 in vitro potency, and they were less
efficacious in the mouse oGTT model than compound 8
following oral dosing at 1 mg/kg.
During SAR optimization of the substitution pattern on the
phenyl-imidazolyl ring, the more potent 4-fluorophenyl
analogue 2 was synthesized (Table 1). The SSTR3 binding
assay measures a compound's competitive displacement of
radiolabeled SRIF from cell membranes expressing human or
mouse SSTR3 receptor. The SSTR3 antagonist assay is a whole
cell functional assay in cells expressing the human or mouse
SSTR3 receptor that affords a compound's ability to inhibit the
SRIF-induced reduction of cAMP accumulation induced by
forskolin. The mouse ipGTT model measures the compound's
ability to reduce plasma glucose excursion induced by
intraperitoneal injection of dextrose. As compared with 1,
compound 2 has improved SSTR3 in vitro potency while
maintaining similar MK-499 binding. Both 1 and 2 worked in
the mouse ipGTT model, reducing the glucose excursion by 75
and 79%, respectively. Given the enhanced SSTR3 potency, the
para-F substitution was incorporated in later analogues.
The 1-(4-tetrahydropyranyl) group was replaced by a variety
of heterocycles to afford 3−6. Compounds 3 and 4 are a pair of
diastereomers incorporating N-methyl pyrazole at the C1
position of β-tetrahydrocarboline. They have similar SSTR3
binding potency, while 3 is slightly more potent in the SSTR3
functional antagonist assay. Both compounds worked in the
mouse ipGTT model with similar plasma drug exposure.
However, compound 4 is ∼7-fold less potent in MK-499
binding assay.
Similarly, the diastereomeric pair 5 and 6 with 1,2,4-
oxadiazole substitution was prepared. Analogous to the pair
of 3 and 4, compounds 5 and 6 have comparable profiles except
C
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Synthesis of all compounds was based on the Pictet−
Spengler cyclization of the phenyl imidazolyl tryptamine with
the corresponding aldehydes and ketones.17−19,24 The reaction
with aldehydes was a mild process, occurring at room
temperature, while the reaction with ketones required more
vigorous conditions (Scheme 1).
mg/kg oral dose, compound 8 achieved Cmax of 7, 88, and 493
nM, respectivley.
To demonstrate that the observed glucose lowering by
compound 8 was SSTR3-dependent, the effect of a maximally
efficacious dosage of 8 on blood glucose excursion during an
oGTT was investigated in SSTR3 KO mice (Figure 3).
Administration of 8 (1 mg/kg) and compound A (1 mg/kg;
des-F-sitagliptin, a DPP-4 inhibitor included as a positive
control) to age-matched C57BL/6N male WT mice signifi-
cantly inhibited blood glucose excursion by 112 and 91%,
respectively. When equivalent dosages were administered to
SSTR3−/− mice, 8 reduced glucose excursion by 28% (not
significant), while compound A retained its efficacy as expected
(reduced glucose by 109%).
a,b
Scheme 1. Synthesis of Imidazoyl Carboline
Compound 8 has excellent selectivity against other SSTR
subtypes based on in vitro assays (Table 5). In human receptor
Table 4. Pharmacokinetic Parameters of 8
a
Experimental details are included in the Supporting Information.
Reaction conditions: CH2Cl2, TFA, RT for aldehyde; pyridine, 70−
b
mg/kg
100 °C for ketone.
oral
AUC(0−t)
(μM h)
iv CL
(mL/min
kg)
iv
oral
Vdss
F
species
dose dose
iv t1/2
(L/kg) (%)
With the excellent efficacy of 8, the compound was titrated in
a
the mouse oGTT assay (Figure 2). In this graph, the black bar
mouse
4
1
1
1
10
2
19.3
0.81
15.6
14.4
1.52
1.73
7.00
7.21
10.1
34.0
2.34
3.09
1.66
5.10
1.52
1.74
58
42
53
65
b
rat
c
dog
2
c
rhesus
2
a
The compound was dosed as 1.0 mg/mL solution in
b
EtOH:PEG400:water (2:23:75). The compound was dosed as 1.0
mg/mL solution in EtOH:PEG400:water (20:30:50). The compound
c
was dosed as 4.0 mg/mL solution in EtOH:PEG400:water (10:40:50).
a
Table 5. SSTR Subtype Selectivity of Compound 8
human functional cAMP
human
binding IC50
(nM)
antagonism IC50 (nM)
(% inh. at max. dose)
agonism IC50 (nM)
(% act. at max. dose)
receptor
b
b
SSTR1
SSTR2
SSTR3
SSTR4
SSTR5
2362
4025
0.66
384
ND
ND
b
c
ND
−9% at 5 μM
6% at 20 μM
Figure 2. Compound 8 dose dependently reduces glucose excursion in
the mouse oGTT model.
c
0.95 (83% at 2 μM)
c
c
42% at 20 μM
27% at 5 μM
c
c
533
34% at 5 μM
6% at 20 μM
a
Assay protocols are provided in the Supporting Information. In vitro
represents the glucose excursion when the mice were
challenged orally with 5 g/kg dextrose. It was clear that
compound 8 reduces the glucose excursion from 0.003 to 10
mg/kg in a dose-dependent manner. The plasma Cmax of 8 was
determined from parallel mouse PK studies. At 0.01, 0.1, and 1
b
assay results are the average of at least three duplicates. Not
determined. IC50 was not calculated.
c
Figure 3. Effects of 8 and DPP-4 inhibitor compound A (des-F sitagliptin) on oGTT glucose levels in SSTR3 KO and WT mice.
D
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binding assays, 8 has IC50 values >2 μM for SSTR1 and SSTR2.
Although the binding IC50 values on SSTR4 and SSTR5 are
below 1 μM, there is still >500-fold selectivity. Compound 8
was tested in functional antagonist assays against SSTR4 and
SSTR5. The IC50 values are greater than 5 μM (at least 5000-
fold selectivity). Compound 8 was also tested in functional
agonist assays against SSTR2 to 5. The data indicate that
compound 8 is not an agonist against these receptor subtypes.
Compound 8 was further characterized in PK studies in
preclinical species (Table 4). It has excellent oral bioavailability
across species with long half-lives and high drug exposures in
higher species (dog and monkey).
marketed sulfonylurea K+-ATP blocker, dosed at 10 mpk,
caused significant decreases of blood glucose levels, starting at
60 min after dosing of glipizide.
In conclusion, we discovered compound 8 (MK-4256) as a
potent antagonist of SSTR3. MK-4256 demonstrated excep-
tional SSTR3-mediated glucose-lowering efficacy in the mouse
oGTT model with minimal hypoglycemia risk. When combined
with a DPP-4 inhibitor, there is significant synergy in glucose-
lowering efficacy.25 MK-4256 was selected for further develop-
ment as a treatment for T2DM.26 Additional data will be
reported in due course.
ASSOCIATED CONTENT
* Supporting Information
A single crystal X-ray of compound 8 was obtained to allow
unambiguous structure determination (Figure 4). The structure
■
S
Syntheses and characterization data for compounds 2−13 and
assay protocols. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*Tel: 732-594-0881. Fax: 732-594-3007. E-mail: shuwen_he@
merck.com.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Dr. Charles W. Ross III at Merck Research
Laboratories for measuring the high resolution mass of 8
(MK-4256).
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■
Figure 4. X-ray structure of 8 (toluene solvent deleted for clarity).
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