Discovery of a Novel Series of Orally Bioavailable and CNS Penetrant Glucagon-like Peptide-1 Receptor (GLP-1R) Noncompetitive Antagonists Based on a 1,3-Disubstituted-7-aryl-5,5-bis(trifluoromethyl)-5,8-dihydropyrimido[4,5-d]pyrimidine-2,4(1H,3H)-dione Co

Article abstract of DOI:10.1021/acs.jmedchem.6b01706

A duplexed, functional multiaddition high throughput screen and subsequent optimization effort identified the first orally bioavailable and CNS penetrant glucagon-like peptide-1 receptor (GLP-1R) noncompetitive antagonist. Antagonist 5d not only blocked e

Full text of DOI:10.1021/acs.jmedchem.6b01706

Brief Article
pubs.acs.org/jmc
Discovery of a Novel Series of Orally Bioavailable and CNS Penetrant
Glucagon-like Peptide‑1 Receptor (GLP-1R) Noncompetitive
Antagonists Based on a 1,3-Disubstituted-7-aryl-5,5-
bis(trifluoromethyl)-5,8-dihydropyrimido[4,5‑d]pyrimidine-
2,4(1H,3H)‑dione Core
Kellie D. Nance,∇,§ Emily L. Days,∥ C. David Weaver,‡,∥ Anastasia Coldren,⊥ Tiffany D. Farmer,⊥
Hyekyung P. Cho,‡,§ Colleen M. Niswender,‡,§,○ Anna L. Blobaum,‡,§ Kevin D. Niswender,*,†,#
and Craig W. Lindsley*,‡,§,∥,∇
†Department of Medicine, Division of Diabetes, Endocrinology and Metabolism, ‡Department of Pharmacology, §Vanderbilt Center
for Neuroscience Drug Discovery, ∥Vanderbilt Institute of Chemical Biology, and ⊥Vanderbilt Diabetes Center, Vanderbilt University
School of Medicine, Nashville, Tennessee 37232, United States
#Tennessee Valley Healthcare System, ∇Department of Chemistry, and ○Vanderbilt Kennedy Center, Vanderbilt University,
Nashville, Tennessee 37232, United States
S
* Supporting Information
ABSTRACT: A duplexed, functional multiaddition high
throughput screen and subsequent optimization effort
identified the first orally bioavailable and CNS penetrant
glucagon-like peptide-1 receptor (GLP-1R) noncompetitive
antagonist. Antagonist 5d not only blocked exendin-4-
stimulated insulin release in islets but also lowered insulin
levels while increasing blood glucose in vivo.
insulinism.16 Disruption of GLP-1R signaling in the CNS, via
knockout of the GLP-1R in Sim1 neurons, supports a role for
INTRODUCTION
■
The glucagon-like peptide-1 receptor (GLP-1R) is a family B
GLP-1R inhibition in acute and chronic stress as well as
G-protein-coupled receptor (GPCR) and a critical incretin
anxiety.16 While synthetic peptide ligands, such as EX-9,
hormone-responsive receptor with diverse physiological
functions in the periphery.1,2 GLP-1R is a major focus of
address the short half-life of endogenous GLP-1, adverse
events, iv administration, and limited CNS penetration limit
therapeutic discovery for type II diabetes, where it plays a
their utility for target validation studies and recapitulation of
critical role in the potentiation of insulin secretion and
genetic studies.18,19 To address these issues, efforts have been
suppression of glucagon secretion.3,4 However, GLP-1R is
directed toward the development of orally bioavailable, non-
also located within the central nervous system (CNS) in
peptide ligands, particularly small molecule positive allosteric
multiple brain regions important for appetite, movement, and
cognition.5−7 As a family B GPCR, GLP-1R is activated by four
modulators (PAMs) and noncompetitive antagonists/negative
allosteric modulators (NAMs), for use as in vivo proof of
endogenous GLP-1 peptides (GLP-1 (1−37), GLP-1 (7−37),
GLP-1 (1−36) amide, and GLP-1 (7−36) amide) and a fifth
concept tool cpompunds.20−22
structurally related peptide, oxyntomodulin.8,9 To date, the
We recently reported on a duplexed (GLP-1R and glucagon
receptor (GCGR)) triple-add, functional high-throughput
majority of agonists and antagonists ligands to study GLP-1R
function are peptides, and several synthetic peptidic drugs, such
screen that identified both small molecule PAM and antagonist
leads, leading to the development of the in vivo active GLP-1R
as exenatide and liragulitide administered by subcutaneous
PAM 1 (Figure 1).23,24 As our screen also identified antagonist
hits, we were surprised to find that very few small molecule
GLP-1R antagonists, such as 2 (IC50 = 21 μM) and 3, have
been described in the primary literature (another, PNU-
injection, have been developed.10−12 A peptide-based antago-
nist, exendin (9−39) or EX-9, has also been employed in proof-
of-concept studies wherein it has demonstrated effects on
feeding in rodents; however, EX-9 cannot be administered
orally.13,14 Recently, clinical studies have demonstrated efficacy
for GLP-1R antagonism by EX-9 in patients suffering from
hyperinsulinemia,15 as well as infants with congenital hyper-
Received: November 21, 2016
Published: January 19, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.jmedchem.6b01706
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Journal of Medicinal Chemistry
Brief Article
gem-di-CF3 is maintained, could be accessed in three synthetic
steps (Scheme 1). The R3 substituent is introduced in the first
a
Scheme 1. Synthesis of GLP-1R Antagonists 5
Figure 1. Structures of our GLP-1R PAM 1 and reported small
molecule antagonists 2 and 3. Very little data (pharmacology or
DMPK) are known regarding the reported GLP-1R antagonists.
126814, has only been disclosed in an abstract without
structure) and without detailed drug metabolism and
pharmacokinetics (DMPK) or in vivo efficacy data.17 Thus,
we decided to pursue the discovery of small molecule GLP-1R
noncompetitive antagonists and report here on the discovery of
a novel series that is highly selective, orally bioavailable, and
CNS penetrant with robust efficacy in vivo for use as in vivo
tool compounds.
a
Reagents and conditions: (a) DCM, 95−98% (crude); (b)
(CF3O)2O, pyridine, ether, 94−97% (crude); (c) triethylamine,
DMF, 24−36%.
RESULTS AND DISCUSSION
Chemistry. The HTS campaign afforded one small
molecule chemotype 4 (Figure 2), based on an unusual 1,3-
■
step in the form of primary carboxamide 6. Condensation with
1,1,1,3,3,3-hexafluoropropan-2-one 7 affords intermediate 8
which then eliminates to provide the substituted N-(perfluoro-
propan-2-yllidine)amide 9. Both 8 and 9 were unstable and
were carried on crude into the condensation step. Thus,
condensation of crude 9 with an appropriately substituted 6-
amino-1,3-substituted-pyrimidine-2,4(1H,3H)-dione 10 deliv-
ers analogs 5. Overall yields were modest (∼24%) for the three-
step sequence, and all requisite intermediates were commer-
cially available.25
Structures and GLP-1R antagonist activities of representative
analogs 5 are highlighted in Table 1. Limited examples are
highlighted, as SAR was steep, and the majority of analogs were
inactive (IC50 > 10 μM). When R1 = H (e.g, 4, 5a, and 5b),
weak partial antagonists resulted, but 5a, wherein R2 is benzyl
and R3 is 2-thienyl, delivered a GLP-1R antagonist more potent
(GLP-1 (7−36) amide, IC50 = 1.3 μM, pIC50 = 5.89 0.04,
Table 1. Structures and Activities of Analogs 5
Figure 2. (A) Structure of GLP-1R antagonist HTS hit 4 and the four
areas to evaluate in the optimization campaign (5). (B) Concen-
tration−response curve (CRC) for inhibition of GLP-1 activation of
GLP-1R by 4 (IC50 = 5.9 μM, pIC50 = 5.23 0.09, 16.8 6.3 GLP-1
min). (C) CRC for inhibition of exendin-4 (EX-4) activation of GLP-1
by 4 (IC50 = 5.8 μM, pIC50 = 5.24 0.08, 23.9 5.5 GLP-1 min).
GloSensor cAMP assay in TREx293 HEK cells was conducted; n = 3.
disubstituted-7-aryl-5,5-bis(trifluoromethyl)-5,8-dihydro-
pyrimido[4,5-d]pyrimidine-2,4(1H,3H)-dione core that proved
to be a weak partial GLP-1R antagonist for the native agonist
GLP-1 (IC50 = 5.9 μM, pIC50 = 5.23 0.09, 16.8 6.3 GLP-
1min) and the synthetic agonist exendin-4, EX-4 (IC50 = 5.8 μM,
pIC50 = 5.24 0.08, 23.9 5.5 GLP-1 min), employing native
cAMP as a readout. Moreover, 4 was inactive at the closely
related glucagon receptor (IC50 > 30 μM). On the basis of
nonpeptidic structure, we assumed the hit was a non-
competitive antagonist, but we would require more potent
analogs to confirm the mode of inhibition. Moreover, early
DMPK profiling in rat showed that 4 was a moderately cleared
compound in vivo (CLp = 36.4 mL min−1 kg−1) with a 2.4 h
half-life and possessed exceptional oral bioavailability (F =
100%). Figure 2 also highlights key areas of 4 to be evaluated in
the chemical optimization program. Analogs 5, wherein the
a
GLP-1R IC50, pIC50, and GLP-1 min (%) in TREx293 HEK cell line
with GloSensor cAMP assay upon activation with an EC80 of GLP-1
(7−36) amide; n = 3. GLP-1R IC50, pIC50, and GLP-1 min (%) in
TREx293 HEK cell line with GloSensor cAMP assay upon activation
b
with an EC80 of EX-4; n = 3. Data reported as average SEM.
B
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Journal of Medicinal Chemistry
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36.2 1.9 GLP-1 min; exendin-4, IC50 = 1.5 μM, pIC50 = 5.82
0.06, 32.0 2.4 GLP-1 min) than the lead 4. Replacing H
with Me at R1 led to a significant increase in GLP-1 antagonist
potency, as highlighted by submicromolar analogs 5c (GLP-1
(7−36) amide, IC50 = 0.61 μM, pIC50 = 6.22 0.03, 16.4 1.5
GLP-1 min; exendin-4, IC50 = 0.69 μM, pIC50 = 6.16 0.04,
15.5 1.7 GLP-1 min) and 5d (GLP-1 (7−36) amide, IC50
=
0.65 μM, pIC50 = 6.19 0.03, 20.9 1.4 GLP-1 min; exendin-
4, IC50 = 0.69 μM, pIC50 = 6.16 0.05, 19.7 2.1 GLP-1 min).
However, neither analog completely inhibited the GLP-1
response, suggesting that they are partial antagonists, or
antagonists with limited negative cooperativity, in this cAMP
assay. Alkyl moieties larger than methyl at R1 lost 5- to 20-fold
potency. Thus, we advanced 5c and 5d in an effort to rapidly
identify an in vivo tool compound for proof-of-concept
studies.25
Molecular Pharmacology. As mentioned previously, SAR
was driven in human TREx293 HEK cells by measuring cAMP
levels using a GloSensor cAMP reporter.25 Responses were
assessed in response to inhibition of an ∼EC80 concentration of
either GLP-1(7−36) amide or exendin-4. Importantly, this new
series of GLP-1R.antagonists did not display probe dependence
(Figure 3), affording comparable IC50 values with the native
Figure 4. Progressive fold-shift studies with 5c and 5d. (A) Increasing
concentrations of 5c in the presence of a fixed CRC of GLP-1 (7−36
amide) inducing a dose-dependent decrease in the GLP-1 max,
consistent with noncompetitive inhibition. (B) Increasing concen-
trations of 5d in the presence of a fixed CRC of GLP-1 (7−36 amide)
inducing a dose-dependent decrease in the GLP-1 max, consistent with
noncompetitive inhibition, n = 3.
other GLP-1R agonists, as well as our previously reported GLP-
1R PAM (1), have been shown to potentiate glucose-induced
insulin secretion in primary mouse pancreatic islets.22,26,27 On
the basis of the ability of 5c and 5d to inhibit EX-4 activation of
GLP-1R, we next examined if the antagonist could block EX-4
stimulated insulin secretion in this model (Figure 5). As
Figure 5. Glucose-stimulated insulin secretion in primary mouse islets
in the presence of 10 nM EX-4 under low and high glucose conditions.
Both antagonists, 5c and 5d (at 1 μM), blocked the potentiation of
insulin secretion by EX-4: (∗) significantly different from 11.0 mM
EX-4 by two-way ANOVA followed by Sidak’s multiple comparison
test.
Figure 3. Molecular pharmacology of 5c and 5d. (A) Concentration−
response curve (CRC) for inhibition of GLP-1 (7−36 amide)
expected, EX-4 potentiates insulin secretion upon low and high
glucose stimulation, and this effect is completely blocked by 5c
and 5d. Therefore, the inhibitory activity measured in our cell-
based assay translated into the standard ex vivo model.
activation of GLP-1 by 5c (IC50 = 0.60 μM, pIC50 = 6.22
0.03,
16.4 1.5 GLP-1 min). (B) CRC for inhibition of EX-4 activation of
GLP-1 by 5c (IC50 = 0.69 μM, pIC50 = 6.16 0.04, 15.5 1.7 GLP-1
min). (C) CRC for inhibition of GLP-1 (7−36 amide) activation of
GLP-1 by 5c (IC50 = 0.6 μM, pIC50 = 6.19 0.03, 20.9 1.4 GLP-1
min). (D) CRC for inhibition of EX-4 activation of GLP-1 by 5c (IC50
= 0.69 μM, pIC50 = 6.16 0.05, 19.7 2.1 GLP-1 min). GloSensor
cAMP assay in TREx293 HEK cells was conducted; n = 3.
Drug Metabolism and Disposition. With robust activity
in cells and in primary tissue, we next evaluated 5c and 5d in a
panel of DMPK assays to assess their utility as in vivo probes
(Table 2).25 In general, 5c and 5d displayed attractive in vitro
DMPK properties (reasonable cLogPs, measurable free drug
levels and predicted hepatic clearance). Of note, 5d was stable
in rat microsomes and possessed low predicted hepatic
clearance in human microsomes (2.03 mL min−1 kg−1). For
first generation tool compounds, the CYP450 profiles were
acceptable. For example, 5d showed no inhibition of 3A4 or
2D6 (IC50 > 30 μM), weak activity against 1A2 (IC50 = 4 μM),
but potent inhibition of 2C9 (IC50 = 410 nM). In general, this
chemotype displayed inhibition of CYP 2C9. In a 3 mg/kg oral
plasma/brain distribution study, 5d was highly CNS penetrant
(Kp = 1.45) and clearly orally bioavailable from the high total
plasma (45 ng/mL) and brain (65.1 ng/g) concentrations. In
an in vivo rat PK study, 5d showed a good in vitro/in vivo
correlation (IVIVC) with a CLp of 4.79 mL min−1 kg−1, a long
agonist or the synthetic agonist EX-4. As 5c and 5d displayed
only partial antagonism and due to the steep SAR and low
molecular weight (MWs of 440−450) for a class B GPCR
ligand, we assumed that these were noncompetitive antagonists.
Thus, we performed progressive fold-shift experiments to
determine if the antagonists engender a parallel-rightward shift
of the agonist CRC (competitive inhibition) or a decrease in
GLP-1 max (noncompetitive). Here (Figure 4), a GLP-1 (7−
36) amide CRC was subjected to increasing concentrations of
5c or 5d, and a dose-dependent decrease in the GLP-1 max
response was noted, consistent with a noncompetitive/NAM
mechanism of action. Furthermore, both were inactive against
the closely related glucagon receptor (IC50 > 30 μM). EX-4 and
C
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Journal of Medicinal Chemistry
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Table 2. DMPK Profiles of 4, 5c, and 5d
parameter
4
5c
451.29
5d
440.73
MW
518.80
83.03
4.93
TPSA
cLogP
116.82
3.63
65.01
3.63
P450 inhibition (μM)
P450 (1A2, 2C9,
3A4, 2D6)
>30, 3.78,
16.44, 8.13
25.04, 0.47,
>30, 21.20
4.01, 0.41,
>30, >30
in vitro PK
rat CLHEP
a
27.8
8.9
35.9
0
(mL min−1 kg−1
)
a
human CLHEP
0
2.03
(mL min−1 kg−1
)
Figure 6. Effect of 5d on whole blood glucose and insulin levels in rats
upon oral dosing at 10 mg/kg. Rats with carotid cannulae surgically
implanted were randomized to receive 5d or vehicle 30 min prior to
glucose dose (2 g/kg) given by gavage at time 0. Carotid blood
samples were obtained at given intervals to assess whole blood glucose
and insulin. Rat were crossed over to other treatment 7 days later and
restudied. Area under the curve (AUC) was calculated for glucose and
insulin excursion, and the mean values were compared by Student’s t
test: (∗) p < 0.05. Glucose excursions were assessed by two-way
ANOVA, p < 0.0001 for drug interaction, (∗) Bonferroni post-test p <
0.01 at these time points.
rat plasma fu
0.002
0.003
0.005
0.005
0.011
0.007
human plasma fu
in vivo rat distribution (po, 3 mg/kg, 1 h)
plasma (ng/mL)
brain (ng/mL)
1145
37.1
76.7
2.4
45.0
65.1
1.45
brain/plasma (Kp) 0.03
0.02
in vivo rat PK (iv, 1 mg/kg; po, 3 mg/kg)
CLp
36.4
3.64
4.79
(mL min−1 kg−1
)
t1/2 (min)
Vss (L/kg)
F (%)
145
0.69
100
42
587
3.57
50
0.22
ND
EXPERIMENTAL SECTION
Chemistry. All compounds were purified to ≥95% as determined by
analytical LC/MS (214 nm, 254 nm, and ELSD) and H NMR. The
a
■
Stable in hepatic microsomes.
1
half-life (t1/2 = 9.8 h), and a modest volume of distribution (Vss
= 3.57 L/kg). Importantly, in a discrete rat oral (po) study, 5d
was found to be highly orally bioavailable (F = 50%). A
Eurofins lead profiling panel was performed against a
radioligand binding panel of 68 GPCRs, ion channels, and
transporters, and 5d displayed no significant off-target activity
(no inhibition of >50% at 10 μM).25,28 Thus, 5d emerged as
the ideal in vivo tool compound to probe the pharmacody-
namics efficacy of GLP-1R inhibition.25
In Vivo Pharmacology. With 5d in hand, an orally
bioavailable GLP-1R antagonist with excellent rat PK and
efficacy in primary tissues, we elected to determine if inhibition
of GLP-1R by 5d in vivo would impact glucose and insulin
levels.29 For this study, male Sprague-Dawley rats were
administered 10 mg/kg po of 5d and after 30 min were
challenged with glucose or vehicle po in an oral glucose
tolerance test (OGTT). As shown in Figure 6, 5d-treated
animals displayed a significant increase in blood glucose levels,
with a concomitant decrease in blood insulin levels, thereby
validating the inhibitors in vivo.25
general chemistry, experimental information, and syntheses of all other
compounds are supplied in the Supporting Information.
4-Chloro-N-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-
benzamide (8d). To an oven-dried three-necked round-bottom flask
were added at room temperature 4-chlorobenzamide (311 mg, 2.0
mmol) and CH2Cl2 (5 mL). To one neck of the flask was added a
coldfinger with dry ice/isopropanol. The second neck was sealed with
a septum, and the last neck was attached to a lecture bottle of
hexafluoroacetone. The reaction was heated to 30 °C with stirring, at
which point hexafluoroacetone was bubbled into the mixture until a
vigorous reflux of the gas was observed. The resultant mixture was
stirred for 3 h until reaction completion was confirmed by LC/MS.
Upon completion, the reaction was purged with air to remove excess
hexafluoroacetone and concentrated in vacuo without heating to afford
1
the desired product as a white solid (635 mg, 99%). H NMR (400
MHz, CDCl3) δ (ppm): 8.84 (s, 1H), 7.60 (d, J = 8.4 Hz, 2H), 7.39
(d, J = 8.4 Hz, 2H), 7.14 (s, 1H). 13C NMR (100.6 MHz, CDCl3) δ
1
(ppm): 171.99, 140.45, 130.24, 129.47, 128.63, 121.11 (q, JC−F
=
2
288.9 Hz), 84.41 (sep, JC−F = 33.0 Hz). LRMS (ES+) found for
C10H6ClF6NO2 (M + H), 322.1.
4-Chloro-N-(perfluoropropan-2-ylidene)benzamide (9d). To
a round-bottom flask was added at room temperature 8d (635 mg,
1.97 mmol), which was dissolved in ether (10 mL). This was cooled
with stirring to 0 °C before adding trifluoroacetic anhydride (282 μL,
2.0 mmol) and pyridine (338 μL, 4.2 mmol) dropwise simultaneously.
The resultant mixture was slowly warmed to room temperature with
stirring over 2 h, and reaction completion was verified by LC/MS.
Upon completion, the mixture was diluted with ether (20 mL), filtered
to remove organic salts, and concentrated in vacuo without heating to
CONCLUSION
■
In summary, we have developed the first reported CNS-
penetrant and orally bioavailable small molecule GLP-1R
antagonist 5d, VU0650991. Molecular pharmacology studies
showed that 5d did not possess probe dependence, as it
blocked the activation of GLP-1R by endogenous agonist, GLP-
1 (7−36) amide, as well as the synthetic agonist, EX-4. This
new small molecule GLP-1R antagonist blocked the activity of
EX-4 in potentiating insulin secretion in primary mouse
pancreatic islets and reduced blood insulin levels while
increasing blood glucose levels in rats upon oral dosing.
There are a number of exciting therapeutic indications
(hyperinsulinemia, acute/chronic stress and anxiety) for a
centrally active GLP-1R antagonist, and these studies are in
progress and will be reported in due course.
1
afford the desired product as a colorless oil (580 mg, 97%). H NMR
(400 MHz, CDCl3) δ (ppm): 7.70 (d, J = 8.7 Hz, 2H), 7.44 (d, J = 8.7
Hz, 2H). 13C NMR (100.6 MHz, CDCl3) δ (ppm): 171.65, 162.83 (d,
1
2JC−F = 36.8 Hz), 140.27, 130.33, 129.43, 128.86, 121.11 (q, JC−F
=
289.5 Hz). LRMS (ES+) found for C10H4ClF6NO (M + 1 + MeOH),
336.0.
7-(4-Chlorophenyl)-1,3-dimethyl-5,5-bis(trifluoromethyl)-
5,8-dihydropyrimido[4,5-d]pyrimidine-2,4(1H,3H)-dione (5d).
To a vial were added at room temperature 9d (580 mg, 1.91
mmol), 6-amino-1,3-dimethylpyrimidine-2,4(1H,3H)-dione (235 mg,
1.91 mmol), and triethylamine (39 μL, 0.29 mmol), which was then
D
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Journal of Medicinal Chemistry
Brief Article
dissolved in N,N-dimethylformamide (2 mL). This mixture was heated
to 100 °C with stirring for 3 h. Upon completion by LC/MS, the
mixture was diluted with 1:1 water/CH2Cl2 (20 mL) and extracted
three times with CH2Cl2 (5 mL). The combined organic layers were
washed twice with a 5% LiCl solution (10 mL), passed through a
phase separator to dry, and concentrated in vacuo. The brown residue
was purified by automated flash chromatography using 40−70% ethyl
acetate in hexanes to elute. Desired product was afforded as a pale
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1
yellow solid (202 mg, 24%). H NMR (400 MHz, CDCl3) δ (ppm):
7.83 (d, J = 8.7 Hz, 2H), 7.54 (d, J = 8.7 Hz, 2H), 6.70 (s, 1H), 3.65
(s, 3H), 3.37 (s, 3H). 13C NMR (100.6 MHz, CDCl3) δ (ppm):
159.60, 157.76, 153.32, 151.52, 140.55, 129.87, 129.80, 128.76, 122.51
(6) Perry, T.; Haughey, N. J.; Mattson, M. P.; Egan, J. M.; Greig, N.
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1
(q, JC−F = 290.2 Hz), 80.96, 65.67−65.03 (m), 30.49, 28.41. HRMS
(TOF, ES+) calcd for C16H11ClF6N4O2 (M + 1), 440.0477; found,
440.0475.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.jmed-
chem.6b01706.
■
S
(10) Edwards, C. M.; Stanley, S. A.; Davis, R.; Bynes, A. E.; Frost, G.
S.; Seal, L. J.; Ghatei, M. A.; Bloom, S. R. Exendin-4 reduces fasting
and postprandial glucose and decreases energy intake in healthy
volunteers. Am. J. Physiol.: Endocrinol. Metab. 2001, 281, E151−E161.
(11) Knudsen, L. B.; Nielsen, P. F.; Huusfeldt, P. O.; Johansen, N. L.;
Madsen, K.; Pedersen, F. Z.; Thogersen, H.; Wilken, M.; Agerso, H.
Potent derivative of glucagon-like peptide-1 with pharmacokinetic
properties suitable for once daily dosing administration. J. Med. Chem.
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Experimental procedures and spectroscopic data for
selected compounds and detailed pharmacology and
DMPK methods (PDF)
Molecular formula strings and some data (CSV)
AUTHOR INFORMATION
Corresponding Authors
*K.D.N.: phone, 615-936-0500; fax, 615-936-1667; e-mail,
kevin.niswender@vanderbilt.edu.
*C.W.L.: phone, 615-322-8700; fax, 615-343-3088; e-mail,
craig.lindsley@vanderbilt.edu.
ORCID
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(12) Derosa, G.; Maffioli, P. GLP-1 agonists exenatide and
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Craig W. Lindsley: 0000-0003-0168-1445
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was generously supported by resources of the
Tennessee Valley Healthcare System, NIH Grant GM06232
(C.W.L. and K.D.N.), the Warren Family and Foundation for
establishing the William K. Warren, Jr. Chair in Medicine
(C.W.L.), a Culpepper Medical Scholarship (K.D.N), American
Diabetes Association research award (K.D.N), Vanderbilt
Diabetes and Research Training Center Pilot and Feasibility
award (K.D.N.), and the Vanderbilt Diabetes and Research
Training Center (Grant DK020593).
ABBREVIATIONS USED
■
GLP-1, glucagon-like peptide-1; CRC, concentration−response
curve; PAM, positive allosteric modulator; PBL, plasma/brain
level
(17) Ghosal, S.; Packard, A. E. B.; Mahbod, P.; McKlveen, J. M.;
Seeley, R. J.; Myers, B.; Ulrich-Lai, Y.; Smith, E. P.; D’Alessio, D. A.;
Herman, J. P. Disruption of glucagon-like peptide 1 signaling in Sim1
neurons reduces physiological behavior reactivity to acute and chronic
stress. J. Neurosci. 2017, 37, 184−193.
(18) Gupta, V. Glucagon-like peptide-1 analogues: an overview.
Indian J. Endocrinol. Metab. 2013, 17, 413−421.
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