Diamine derivatives as novel small-molecule, potent, and subtype-selective somatostatin SST3 receptor agonists

Article abstract of DOI:10.1021/ml500079u

A novel class of small-molecule, highly potent, and subtype-selective somatostatin SST3 agonists was discovered through modification of a SST3 antagonist. As an example, (1R,2S)-9 demonstrated not only potent in vitro SST3 agonist activity but also in viv

Full text of DOI:10.1021/ml500079u

Letter
pubs.acs.org/acsmedchemlett
Diamine Derivatives as Novel Small-Molecule, Potent, and Subtype-
Selective Somatostatin SST3 Receptor Agonists
Derun Li,*,† Zhicai Wu,† Yang Yu,† Richard G. Ball,† Liangqin Guo,† Edward Sherer,† Shuwen He,†
Qingmei Hong,† Zhong Lai,† Hongbo Qi,† Quang Truong,† David X. Yang,† Gary G. Chicchi,‡
Kwei-Lan Tsao,‡ Dorina Trusca,‡ Maria Trujillo,‡ Michele Pachanski,‡ George J. Eiermann,‡
Andrew D. Howard,‡ Yun-Ping Zhou,‡ Bei B. Zhang,‡ Ravi P. Nargund,† and William K. Hagmann†
‡
†Departments of Medicinal Chemistry and Diabetes Research, Merck Research Laboratories, 126 East Lincoln Avenue, Rahway,
New Jersey 07065, United States
S
* Supporting Information
ABSTRACT: A novel class of small-molecule, highly potent,
and subtype-selective somatostatin SST3 agonists was
discovered through modification of a SST3 antagonist. As an
example, (1R,2S)-9 demonstrated not only potent in vitro
SST3 agonist activity but also in vivo SST3 agonist activity in a
mouse oral glucose tolerance test (OGTT). These agonists
may be useful reagents for studying the physiological roles of
the SST3 receptor and may potentially be useful as therapeutic
agents.
KEYWORDS: Somatostatin, GPCR, somatostin receptor subtype 3 (SST3), small-molecule SST3 agonists
agonist activity.13 The objective to identify orally bioavailable
omatostatins (somatotropin-release inhibiting factors
S[SRIF]) are a family of cyclopeptides that are produced low molecular weight antagonists/agonists is also desirable.
Herein, we report the discovery of potent SST3 small-molecule
agonists.
by normal endocrine, gastrointestinal, immune, and neuronal
cells, as well as by certain tumors.1,2 The actions of SRIF are
mediated by five distinct somatostatin receptors (SST1−5) that
belong to the seven-transmembrane, G-protein-coupled
receptor (GPCR) family.3,4 SRIF exhibits multiple biological
functions such as inhibition of the release of growth hormone,
insulin, glucagon,5 and gastrin.6 SRIF also acts as a neuro-
modulator in the central nervous system (CNS).7,8 Various
SRIF-related peptides, including SRIF-14 and SRIF-28,
containing 14 and 28 amino acids, respectively, have been
identified.9 The pan-antisecretory profile of natural SRIF-14 has
led to exploratory clinical trials for the treatment of a range of
conditions, including diabetes (types I and II), hypersecretory
tumors, such as growth hormone-secreting pituitary adenomas,
gastrinomas, insulinomas, glucagonomas, and VIPomas, and
gastrointestinal disorders.9,10 These studies also showed that
the full therapeutic potential of SRIF cannot be exploited owing
to its short plasma half-life (<3 min).11 Peptide analogues of
SRIF with enhanced metabolic stability have been developed
for clinical use. For example, cyclic peptide analogue SMS 201−
995 (octreotide) was introduced into clinical practice as an
injectable depot formulation for the treatment of acromegaly
(growth hormone oversecretion), diarrhea associated with
vasoactive intestinal peptide-secreting tumors (VIPomas), and
carcinoid syndrome.12 There is also strong interest in
developing subtype selective, small molecule ligands to reduce
the side effects that are associated with pan-somatostatin
Somatostatin receptor subtype 3 (SST3) has been shown to
be present in brain, pituitary, stomach, pancreas, thymus,
thyroid, prostate, and vascular endothelial cells. In addition to
suppressing the secretion of several hormones, SST3 is
implicated in apoptotic signaling and proliferation, and several
studies have indicated that this signaling proceeds via
modulation of phosphotyrosine phosphatase activity and
localization. Preclinical studies assessing angiogenesis and
tumorigenesis in both cultured endothelial cells and in vivo
tumor xenograft models have suggested that SST3 agonists may
be useful in cancer therapy.14−16 To date only one small-
molecule peptidyl partial SST3 agonist, L-796,778 (Ki = 24 nM,
Figure 1), has been discovered about two decades ago.13
Recently, Moinet et al. reported the discovery of imidazolyl
derivatives that bind selectively to SST3 with moderate affinity
(Figure 2).17 To introduce conformational rigidity, 1 was
submitted to Pictet−Spengler cyclization to afford the
corresponding tetrahydro-beta-carbolines, represented by 2.18
Biological studies showed that 2 exhibited high affinity to
human SST3 (h-SST3, Ki = 0.64 nM) and acted as a potent
SST3 antagonist by inhibiting SRIF-14 (1 nM) induced
Received: February 21, 2014
Accepted: April 24, 2014
Published: April 24, 2014
© 2014 American Chemical Society
690
dx.doi.org/10.1021/ml500079u | ACS Med. Chem. Lett. 2014, 5, 690−695

ACS Medicinal Chemistry Letters
Letter
Figure 1. Structure of L-796,778 and its inhibition constant (Ki) on
somatostatin subtype receptor-3 (SST3).
Figure 3. Racemic diamine analogues, and h-SST3 binding affinity and
agonist/antagonist activity.
similar binding and agonist activity profile. Rapid structure−
activity relationship (SAR) development revealed that 4-
fluorophenyl analogue 9 showed single digit nanomolar h-
SST3 affinity. More interestingly, it is a potent SST3 agonist
with EC50 = 2.9 nM (97% activation at 2 μM). Replacement of
the indole with a dichlorophenyl moiety gave 10, which is also a
potent SST3 agonist.
Improvements in h-SST3 binding affinity and/or agonist/
antagonist activities were modulated by changing the
substitution on the benzylamine. The compounds and SST3
results are listed in Table 1. It is clear that variation at this
position has a strong influence on SST3 affinity. The simple
Figure 2. Analysis of tetrahydro-beta-carboline 2 lead to diamine
analogues.
reduction of cAMP accumulation induced by forskolin (1 μM)
in CHO-K1 cells expressing human SST3. The molecular
constraint introduced into 1 to afford 2 suggests the spatial
orientation of the two N-Hs created by this rigidity might be a
key interaction for high affinity.
Table 1. Human SST3 Binding Affinity and Agonist Activity
of Racemic Aminoamides 11a−j
We were interested in simplifying this class of compounds to
identify novel small molecule SST3 ligands. Incising C4 of 2
and introducing additional ring constraints would give a
diamine, such as 3 (Figure 2), with a rigid orientation of the
two N−Hs. Another advantage of this system is the diamines
would expedite rapid analogue synthesis for biological
evaluation (e.g., 4).
The initial synthesis of analogues began with monoacylation
of cis-1,2-diaminocyclohexane 5.19 Reductive amination of
aminoamide 6 afforded the desired racemic diamine analogues
(Scheme 1).20
a
Scheme 1. Synthesis of Diamine Analogues
a
Reagents and conditions: (a) 9-BBN, THF, rt, 1 h, then ArCOCl, rt,
2 h; (b) RCHO, NaBH(OAc)3, DCE, rt, overnight; or RCHO, 4 Å
MS, MeOH, overnight, then NaBH4.
Analogue 3 afforded modest binding affinity to human SST3
(h-SST3) (Figure 3).21 Interestingly, when 3 was evaluated for
functional activity, it showed no antagonist activity and was
unable to block the inhibitory effect of SRIF-14. However, 3
alone showed weak agonist activity by reducing the cAMP
production elicited by forskolin. Its close analogue 8 showed a
691
dx.doi.org/10.1021/ml500079u | ACS Med. Chem. Lett. 2014, 5, 690−695

ACS Medicinal Chemistry Letters
Letter
methylphenyl analogue (11a) shows modest SST3 affinity and
agonist activity. Different substituted phenyl analogues with
different electron properties (11b−e) had modest SST3 affinity
but maintained agonist activity. However, benzoic acid
analogue (11f) was not tolerated. Extension of the linkage to
a two-carbon linkage (11g) had a small effect on affinity. The
sterically bulky tert-butyl analogue (11h) showed modest
affinity. Both the affinity and agonist activity were lost when
heterocyles like thiazole (11i) and pyridone (11j) were
incorporated.
Having identified the indole (9) and 3,4-dichlorophenyl (10)
moieties as optimal substitution on the amine, efforts to study
the SAR of the amide moiety were initiated. 3,4-Dichlorobenzyl
was held constant on the amine end because of its chemical
stability. The synthesis began from Boc-protected racemic cis-
1,2-diaminocyclohexane. Reductive amination of racemic 12
gave 13. Removal of the Boc protecting group of 13, followed
by monoacylation afforded the desired analogues 15a−g
(Scheme 2).
analogue (10) in terms of affinity and agonist activity. 2-
Naphthyl analogue (15d) further boosted both SST3 affinity
and potency as an agonist. Putting an additional fluorine atom
on the 6 position (15e) did not enhance binding/agonism. 2-
Quinoline analogue (15f) was much less potent compared with
2-naphthyl analogue (15d). 1-Naphthyl analogue (15g) was
also less active.
The SAR of the diamine backbone was then explored (Figure
4). Interestingly, the racemic trans-cyclohexane diamine
analogue (16) was equal potent as the cis-analogue (9),
despite the very different orientation of the N−Hs in these two
compounds. All four enantiomeric isomers of cyclopentane
diamine analogues (17−20) were prepared starting from
commercially available starting materials. In general, the amides
with the absolute R configuration are more potent than those
with the S configuration (17 vs 18 and 19 vs 20). This suggests
that the more potent isomer of analogue 9 has the R
configuration at the amide. Unlike six- and five-membered
analogues, both of the racemic cis- and trans-cyclopropane
diamine analogues (21 and 22) lost SST3 affinity and only
showed weak agonist activity. Acyclic diamine analogue 23 also
lost SST3 affinity.
a
Scheme 2. Synthesis of 15
This study suggested that the cyclohexane backbone is the
optimal structural motif for SST3 affinity. We also studied the
orientations of two N−Hs by changing 1,2 diamines to 1,3 and
1,4 diamines. The cis- and trans-isomers of 24 and 25 lost SST3
affinity and only showed weak agonist activity. Rigid phenyl
diamine analogue 26 lost SST3 binding affinity.
Variations of the linkage on the cyclohexane ring were
investigated next to better understand the role of the two N−
Hs (Figure 5). The analogues were prepared as racemic isomers
for synthetic expedience. Reductive amination of 9 with
formaldehyde gave amine 27, which showed modest SST3
binding affinity and agonist activity.
a
Reagents and conditions: (a) 3,4-dichlorobenzaldehyde, NaBH-
(OAc)3, DCE, rt, overnight; (b) 4 N HCl in dioxane, MeOH, rt,
overnight; (c) RCOCl, CH2Cl2, rt, 2 h.
Diamide 28 greatly lost SST3 binding affinity. Replacement
of the N−H with oxygen gave 29, which also lost binding
affinity and most agonist activity. These all suggested that basic
N−H may play an important role in the binding and functional
activities of these aminoamides, presumably through hydrogen
bonding. Replacement of amide with ester (30) greatly lost
SST3 binding affinity and all functional activity. While urea 31
maintained binding affinity and modest agonist activity,
carbamate analogue 32 only showed weak agonist activity.
The reverse amide, cis- and trans-β-amino acid analogues 33
and 34 were also synthesized. Interestingly, 33 showed modest
SST3 binding and agonist activity. Unlike the diamine
analogues, where cis- and trans-analogues (9 and 16) showed
similar activity, the trans-analogue 34 was much less potent.
Since racemic 9 proved to be the optimal SST3 agonist, it
was separated into two enantiomers, by using SFC-HPLC with
a Chiralpak AS.22 One enantiomer was much more potent than
the other and since only limited material was separated, the less
potent enantiomer was subjected to recrystallization for single-
crystal X-ray analysis. The structure determination proved the
absolute configuration of the less potent enantiomer to be
(1S,2R) (Figure 6) thereby determining the configuration of
the potent enantiomer to be (1R,2S).22 The more potent
(1R,2S)-9 was then tested against human, rhesus monkey, and
dog SST3 in a binding assay and showed potent binding affinity
with Ki = 0.89, 1.8, and 0.74 nM, respectively. Compound
(1R,2S)-9 also exhibited potent agonist activities in human,
dog, and mouse SST3 agonist functional assays. Compound
(1R,2S)-9 was further profiled in a panel of cell lines expressing
Phenyl amide (15a), methoxyphenyl analogue (15b) showed
modest h-SST3 affinities and very little agonist activity (Table
2). 3,4-Difluorophenyl (15c) was comparable to 4-fluorophenyl
Table 2. Binding Affinity and Agonist Activity on h-SST3 of
Racemic 15a−g
692
dx.doi.org/10.1021/ml500079u | ACS Med. Chem. Lett. 2014, 5, 690−695

ACS Medicinal Chemistry Letters
Letter
Figure 4. Structures, binding affinity, and agonist activity of diamine backbone analogues.
Figure 6. X-ray crystal structure of (1S,2R)-9.
Figure 5. SAR of the linkages of diamine analogues.
the other four human receptor subtypes (h-SST1, 2, 4, 5). As
indicated in Figure 7, the selectivity of (1R,2S)-9 over h-SST1,
2, 4, 5 is excellent (>300-fold).
Since (1R,2S)-9 demonstrated highly potent in vitro SST3
agonist activity, its in vivo agonist activity was investigated.
Recently, antagonism of SST3 was reported to have the
potential to be a novel glucose-dependent insulin secretion
(GDIS) mechanism for the treatment of type 2 diabetes
mellitus (T2DM).23,24 SST3 is highly expressed in β-cells of
human and rodent islets. Silencing the expression of SST3 with
siRNA significantly enhanced GDIS in a rat insulinoma cell line,
INS-1 cells. The importance of SST3 in regulating GDIS and
glucose homeostasis was further supported by the reports that a
selective SST3 antagonist MK-425625 (Figure 8, human
Figure 7. Binding affinity and agonist activity for human, rhesus
monkey, dog, and mouse SST3 and other human somatostatin subtype
receptors. StD is standard deviation.
693
dx.doi.org/10.1021/ml500079u | ACS Med. Chem. Lett. 2014, 5, 690−695

ACS Medicinal Chemistry Letters
Letter
receptor and have the potential to be potent leads for
developing effective therapeutic agents including cancer
therapy.
ASSOCIATED CONTENT
■
S
* Supporting Information
Syntheses and characterization data for compound 9; X-ray and
assay protocols. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
Figure 8. Structure of MK-4256 and its human and mouse SST3
antagonism activity. StD is standard deviation.
*(D.L.) Tel: 908-740-7326. E-mail: derun_li@merck.com.
Notes
antagonism IC50, 0.95 nM (83% inhibition @ 2 μM), mouse
antagonism IC50, 0.46 nM (87% inhibition @ 2 μM), and
human agonism (6% activation @ 20 μM)) reduced blood
glucose levels (97% reduction of glucose excursion at 1 mg/kg)
during a mouse oral glucose tolerance test (OGTT) (Figure 9,
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Dr. Jian Liu at Merck Research Laboratories for
helpful discussions.
REFERENCES
■
(1) Hoyer, D.; Bell, G. I.; Berelowitz, M.; Epelbaum, J.; Feniuk, W.;
Humphrey, P. P.; O’Carroll, A. M.; Patel, Y. C.; Schonbrunn, A.;
Taylor, J. E.; Reisine, T. Classification and nomenclature of
somatostatin receptors. Trends Pharmacol. Sci. 1995, 16 (3), 86−88.
(2) Brazeau, P.; Vale, W.; Burgus, R.; Ling, N.; Butcher, M.; Rivier, J.;
Guillemin, R. Hypothalamic polypeptide that inhibits the secretion of
immunoreactive pituitary growth hormone. Science 1973, 179 (68),
77−79.
(3) Olias, G.; Viollet, C.; Kusserow, H.; Epelbaum, J.; Meyerhof, W.
Regulation and function of somatostatin receptors. . Neurochem. 2004,
89, 1057−1091.
(4) Reisine, T.; Bell, G. I. Molecular biology of somatostatin
receptors. Endocr. Rev. 1995, 16 (4), 427−442.
(5) Mandarino, L.; Stenner, D.; Blanchard, W.; Nissen, S.; Gerich, J.;
Ling, N.; Brazeau, P.; Bohlen, P.; Esch, F.; Guillemin, R. Selective
effects of somatostatin-14, -25, and -28 on in vivo insulin and glucagon
secretion. Nature 1981, 291, 76−77.
(6) Bloom, S.; Mortimer, C.; Thorner, M.; Besser, G.; Hall, R.;
Gomez-Pan, A.; Roy, U.; Russel, R.; Coy, D.; Kastin, A.; Schally, A.
Inhibition of gastrin and gastric acid secretion by growth hormone
release-inhibiting hormone. Lancet 1974, 2, 1106−1109.
(7) Renaud, L.; Martin, J.; Brazeau, P. Depressant action of TRH,
LHRH and SRIF on activity of central neurons. Nature 1975, 255,
233−235.
Figure 9. Compound (1R,2S)-9 increased glucose excursion in mouse
oGTT model. For MK-4256, P < 0.005 via ANOVA and Dunnett’s
test.
(8) Dodd, J.; Kelly, J. Is somatostatin an excitatory transmitter in the
hippocampus? Nature 1978, 273, 674−677.
(9) Weckbecker, G.; Lewis, I.; Albert, R.; Schmid, H. A.; Hoyer, D.;
Bruns, C. Opportunities in somatostatin research: biological, chemical,
and therapeutic aspects. Nat. Rev. Drug Discovery 2003, 2, 999−1017.
(10) For a recent review of subtype selective somatostatin receptor
ligands see: Wolkenberg, S. E.; Thut, C. J. Recent progress in the
discovery of selective non-peptide ligands of somatostatin receptors.
Current Opin. Drug Discovery Dev. 2008, 11 (4), 446−457.
(11) Patel, Y. C.; Wheatley, T. In vivo and in vitro plasma
disappearance and metabolism of somatostatin-28 and somatostatin-14
in the rat. Endocrinology 1983, 112, 220−225.
the black bar represents the glucose excursion when the mice
were challenged orally with dextrose only (5 g/kg)).26
Therefore, SST3 agonists would, in theory, increase blood
glucose levels during OGTT. Indeed, when (1R,2S)-9 (10 mg/
kg) was subjected to mouse OGTT (by oral gavage, 30 min
prior to glucose loading), it increased blood glucose level by
28% (Figure 9) relative to dextrose alone. The plasma
concentrations of (1R,2S)-9 were determined at the completion
of the OGTT study (2.5 h postadministration) and found to be
low (0.007 μM).
In summary, a novel class of small-molecule, highly potent,
and subtype-selective somatostatin SST3 agonists has been
described. Compound (1R,2S)-9 also demonstrated in vivo
SST3 agonist activity in a mouse OGTT model. These agonists
are useful tools for studying the physiological roles of the SST3
(12) Bauer, W.; et al. SMS 201−995: a very potent and selective
analogue of somatostatin with prolonged action. Life Sci. 1982, 31,
1134−1140.
(13) Rohrer, S. P.; Birzin, E. T.; Mosley, R. T.; Berk, S. C.; Hutchins,
S. M.; Shen, D.-M.; Xiong, Y.; Hayes, E. C.; Parmar, R. M.; Foor, F.;
Mitra, S. W.; et al. Rapid identification of subtype-selective agonists of
the somatostatin receptor through combinatorial chemistry. Science
1998, 282, 737−740.
694
dx.doi.org/10.1021/ml500079u | ACS Med. Chem. Lett. 2014, 5, 690−695

ACS Medicinal Chemistry Letters
Letter
(14) Florio, T.; Morini, M.; Villa, V.; Arena, S.; Corsaro, A.;
Thellung, S.; Culler, M. D.; Pfeffer, U.; Noonan, D. M.; Schettini, G.;
Albini, A. Somatostatin inhibits tumor angiogenesis and growth via
somatostatin receptor-3-mediated regulation of endothelial nitric oxide
synthase and mitogen-activated protein kinase activities. Endocrinology
2003, 144 (4), 1574−1584.
(15) Srikant, C. B. Cell cycle dependent induction of apoptosis by
somatostatin analog SMS 201−995 in AtT-20 mouse pituitary cells.
Biochem. Biophys. Res. Commun. 1995, 209 (2), 400−406.
(16) Lattuada, D.; Casnici, C.; Venuto, A.; Marelli, O. The apoptotic
effect of somatostatin analog SMS 201−995 on human lymphocytes. J.
Neuroimmunol. 2002, 133, 211−216.
(17) Moinet, C.; Contour-Galcera, M.; Poitout, L.; Morgan, B.;
Gordon, T.; Roubert, P.; Thurieau, C. Novel non-peptide ligands for
the somatostatin sst3 receptor. Bioorg. Med. Chem. Lett. 2001, 11, 991−
995.
(18) Poitout, L.; Roubert, P.; Contour-Galcera, M.; Moinet, C.;
Lannoy, J.; Pommier, J.; Plas, P.; Bigg, D.; Thurieau, C. Identification
of potent non-peptide somatostatin antagonists with SST3 selectivity.
J. Med. Chem. 2001, 44, 2990.
(19) Zhang, Z.; Yin, Z.; Meanwell, N.; Kadow, J. F.; Wang, T.
Selective monoacylation of symmetrical diamines via prior complex-
ation with boron. Org. Lett. 2003, 5, 3399−3402.
(20) Abdel-Magid, A. F.; Carson, K. G.; Harris, B. D.; Maryanoff, C.
A.; Shah, R. D. Reductive amination of aldehydes and ketones with
sodium triacetoxyborohydride. Studies on direct and indirect reductive
amination procedures. J. Org. Chem. 1996, 61, 3489−3862.
(21) Protocols for somatostatin receptor cell line generation as well
as in vitro binding and functional assays can be found in the
Supporting Information.
(22) Details of the synthesis, separation of enantiomers, and the X-
ray structure analysis can be found in the Supporting Information.
(23) Li, J.; Zhou, Y.; et al. Manuscript in preparation.
(24) Pasternak, A.; Feng, Z.; de Jesus, R.; Ye, Z.; He, S.; Dobbelaar,
P. H.; Bradley, S. A.; Chicchi, G. G.; Tsao, K.; Trusca, D.; Eiermann,
G. J.; Li, C.; Feng, Y.; Wu, M.; Shao, Q.; Zhang, B.; Nargund, R. P.;
Mills, S. G.; Howard, A. D.; Yang, L.; Zhou, Y. Stimulation of glucose-
dependent insuline secretion by a potent, selective SST3 antagonist.
ACS Med. Chem. Lett. 2012, 3, 289−293.
(25) He, S.; Ye, Z.; Truong, Q.; Shah, S.; Du, W.; Guo, L.; Dobbelaar,
P. H.; Lai, Z.; Liu, J.; Jian, T.; Qi, H.; Bakshi, R. K.; Hong, Q.;
Dellureficio, J.; Pasternak, A.; Feng, Z.; DeJesus, R.; Yang, L.; Bradley,
S. A.; Holmes, M. A.; Ball, R. G.; Ruck, R. T.; Huffman, M. A.; Wong,
F.; Samuel, K.; Reddy, V. B.; Mitelman, S.; Tong, S. X.; Chicchi, G. G.;
Tsao, C.; Trusca, D.; Wu, M.; Shao, Q.; Trujillo, M.; Eiermann, G. J.;
Li, C.; Zhang, B.; Howard, A. D.; Zhou, Y.-P.; Nargund, R. P.;
Hagmann, W. K. The discovery of MK-4256, a potent SST3 antagonist
as a potential treatment of type 2 diabetes. ACS Med. Chem. Lett. 2012,
3, 484−489.
(26) For details on the glucose tolerance test models in mice please
see: 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.
695
dx.doi.org/10.1021/ml500079u | ACS Med. Chem. Lett. 2014, 5, 690−695