Discovery of a novel phenylethyl benzamide glucokinase activator for the treatment of type 2 diabetes mellitus

Article abstract of DOI:10.1016/j.bmcl.2012.11.018

Novel benzamide derivatives were synthesized and tested at in vitro assay by measuring fold increase of glucokinase activity at 5.0 mM glucose concentration. Among the prepared compounds, YH-GKA was found to be an active glucokinase activator with EC₅₀ of 70 nM. YH-GKA showed similar glucose AUC reduction of 29.6% (50 mg/kg) in an OGTT study with C57BL/J6 mice compared to 29.9% for metformin (300 mg/kg). Acute treatment of the compound in C57BL/J6 and ob/ob mice elicited basal glucose lowering activity. In subchronic study with ob/ob mice, YH-GKA showed significant decrease in blood glucose levels and no adverse effects on serum lipids or body weight. In addition, YH-GKA exhibited high bioavailability and moderate elimination in preclinical species.

Full text of DOI:10.1016/j.bmcl.2012.11.018

Bioorganic & Medicinal Chemistry Letters 23 (2013) 537–542
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Discovery of a novel phenylethyl benzamide glucokinase activator for the
treatment of type 2 diabetes mellitus
⇑
Kaapjoo Park , Byoung Moon Lee, Young Hwan Kim, Taedong Han, Wonhui Yi, Dong Hoon Lee,
Hyun Ho Choi, Wonee Chong, Chun Ho Lee
Yuhan Research Institute, 416-1, Gongse-dong, Giheung-gu, Yongin-si, Gyeonggi-do, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
Novel benzamide derivatives were synthesized and tested at in vitro assay by measuring fold increase of
glucokinase activity at 5.0 mM glucose concentration. Among the prepared compounds, YH-GKA was
found to be an active glucokinase activator with EC50 of 70 nM. YH-GKA showed similar glucose AUC
reduction of 29.6% (50 mg/kg) in an OGTT study with C57BL/J6 mice compared to 29.9% for metformin
(300 mg/kg). Acute treatment of the compound in C57BL/J6 and ob/ob mice elicited basal glucose lower-
ing activity. In subchronic study with ob/ob mice, YH-GKA showed significant decrease in blood glucose
levels and no adverse effects on serum lipids or body weight. In addition, YH-GKA exhibited high bio-
availability and moderate elimination in preclinical species.
Received 21 September 2012
Revised 16 October 2012
Accepted 7 November 2012
Available online 16 November 2012
Keywords:
Glucokinase
Glucokinase activator
GKAs
Ó 2012 Elsevier Ltd. All rights reserved.
YH-GKA
T2DM
Type 2 diabetes mellitus
OGTT
Type 2 diabetes mellitus (T2DM) is a rapidly growing public
epidemic which affects over 300 million people worldwide. Rates
of diabetes have increased noticeably over the last 50 years with
the similar trend of increasing rates of obesity, which is thought
to be one of the primary causes of type 2 diabetes.1 The first line
oral therapy for type 2 diabetes mellitus (T2DM) is metformin
and second line oral therapies2 are sulfonylureas (SU), dipeptidyl
peptidase-4 (DPP-4) inhibitors and thiazolidinediones (TZD) in
combination with metformin. However, currently available anti-
diabetic agents have limited long-term efficacy and trade-offs in
efficacy and safety/tolerability. Therefore, the clinical need for im-
proved T2DM therapies remains high and diabetes patients are ea-
ger to have novel therapeutic options to safely achieve tight
glycemic control.
Glucokinase (GK) is a hexokinase isozyme (hexokinase IV, hexo-
kinase D) with 465 amino acids (molecular weight = 50 kD). Gluco-
kinase facilitates phosphorylation of glucose to glucose-6-
phosphate (G6P), which is the first step of both glycogen synthesis
and glycolysis. Glucokinase exists in cells in the liver, pancreas, gut,
and brain of humans and most other vertebrates. Compared to
other hexokinases, glucokinase has a lower affinity for glucose
and its activity is localized to a few cell types. Due to this reduced
affinity for glucose, the activity of glucokinase varies substantially
with the concentration of glucose. Furthermore, unlike other hexo-
kinases, glucokinase is not inhibited by its product, glucose-6-
phosphate3 and distinctively, glucokinase shows moderate cooper-
ativity with glucose with a Hill coefficient (nH) of about 1.7.4 Be-
cause of this moderate cooperativity, classical Michaelis-Menten
kinetics do not apply to the kinetic interaction of glucokinase with
glucose.5 So, instead of using a Km for glucose, a half-saturation le-
vel S0.5, which is the concentration at which the enzyme is 50% sat-
urated and active, is used for glucokinase. Glucokinase acts as a
glucose sensor regulating hepatic glucose metabolism to provide
approximately 95% of the hexokinase activity in hepatocytes.4 In
addition, glucokinase activity serves as a key control for glucose-
dependent insulin secretion in islet beta cells.6 Glucokinase activa-
tor (GKA) is expectedly associated with a dual mechanism for low-
ering blood glucose concentration by the enhancement of insulin
secretion from pancreatic beta cell and glucose uptake in the liver.
Therefore, Glucokinase has been an attractive target for anti-
diabetic therapy. Several glucokokinase activators (GKAs) have
advanced to clinical studies and have shown to lower both fasting
and postprandial glucose in healthy subjects and T2DM patients.
Hypoglycemia has been revealed as one of main adverse effects
of GKAs. To overcome this hypoglycemia issue, several clinical
strategies have been employed including dose titration and more
frequent dosing times. Initially, Yuhan adopted this dose titration
clinical strategy to reduce the possibility of hypoglycemia caused
⇑
Corresponding author. Tel.: +82 31 899 4274; fax: +82 31 275 6145.
E-mail address: kaapjoo@yuhan.co.kr (K. Park).
0960-894X/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2012.11.018

538
K. Park et al. / Bioorg. Med. Chem. Lett. 23 (2013) 537–542
by GKA. Recently, two strategies have been employed to reduce the
potential for inducing hypoglycemia. One strategy is the design of
partial activators that improve the dependence of enzymatic activ-
ity on various physiological glucose levels. The other is to make li-
ver selective glucose activators7–9 that restrict the main enzyme
activity at liver since hypoglycemia risk is postulated to result from
the increase of pancreatic insulin secretion at low glucose levels.
Based on the dual action of hepatic and pancreatic effects, GKAs
represent novel and promising approach for the treatment of type 2
diabetes. Many small molecule allosteric activators of this enzyme
have been investigated by numerous pharmaceutical companies
in the past decade.10–12 Selected representative small molecule
GKAs are shown in Figure 1. Since Grimsby reported small molecule
allosteric GKAs in 2003,13 a phenylacetamide series of activators
including clinical candidate 2,14 have been identified. Also, a variety
of other GKAs have been reported, such as benzamides (1,4–7)15–19
and imidazolylacetamide (8).7 In 2009, Banyu scientists reported
the co-crystal structure of glucokinase-compound 1 complex that
revealed binding mode at an allosteric site of glucokinase. Having
this structural information available to us, the rational compound
modification for further improvements to the compound-target
binding motifs has been performed in short time. Herein we report
the discovery of YH-GKA, a benzamide gulcokinase activator, as a
potential preclinical candidate for the treatment of T2DM.
The benzamide scaffold was chosen as a starting point for the
synthesis of selective GKAs which would bind to the allosteric
binding site of the protein and achieve anti-hyperglycemic effects.
Various benzamide derivatives were prepared based on the bind-
ing mode analysis from the X-ray structure of the allosteric binding
site of glucokinase as shown in Figure 2. The A-part of the molecule
is required to have both hydrogen bond donor (NH) and hydrogen
bond acceptor (@N) to bind to Arg63 favorably. The B moiety is re-
quired to be of small size with potential hydrophobic interactions
with Tyr214, Tyr215 and Leu451. The C-pocket of the enzyme is
fairly large and long and the end part of C-moiety has the potential
for a hydrogen bonding interaction with Arg250 in order to in-
crease binding affinity.
Figure 2. Synthetic strategy for benzamide GKAs.
Hundreds of benzamide derivatives having various A-, B-, and
C-part substituents have been synthesized at Yuhan.20 (R)-(ꢀ)-1-
Methoxy-2-propanoxy group was identified as an optimum moiety
through initial diversification of B-part while A- and C-parts were
limited. Then A-part had been investigated thoroughly by intro-
ducing a variety of aryl or hetero-aromatic groups. Finally, C-part
was optimized by prioritizing compounds based on in vitro po-
tency, physicochemical property and in vivo activity. The synthesis
of selected compounds, pyrazol benzamide series and carboxypyri-
dine benzamide series, is described in Scheme 1. Mitsunobu
reaction of dimethyl 5-hydroxy isophthalate with (R)-(ꢀ)-1-meth-
oxy-2-propanol gave benzoic acid 9. Reduction of 9 followed by
acetylation provided ester 11. Amide coupling of 11 with 1-
methyl-1H-pyrazol-3-ylamine and the hydrolysis of resulting ester
12 followed by the treatment with PBr3 yielded benzyl bromide 13.
The benzyl bromide 13 was treated with triethylphosphite to give
phosphonate 14. Horner-Wadsworth-Emmons reaction between
14 and a variety of aldehydes provided various E-alkene benzam-
ides 15. Pyrazol benzoamides 15 were reduced by Pd/H2 to give
final products 16. Likewise, amide coupling of 11 with 6-aminoni-
cotinic acid methyl ester gave nicotinic ester 17. E-alkene
O
O
O
S
H
N
S
S
N
H
N
F
N
O
S
Cl
N
N
N
H
O
N
N
N
NH2
O
S
O
O
O
1 (Banyu-Merck)
3 PSN-GK1
2 Piragliatin
OH
O
O
O
O
N
N
O
O
O
N
N
N
H
HO
N
N
H
HO
O
N
N
H
O
O
F
O
O
S
N
O
O
F
6 GKA-60
4 AZD 1092
5 MK-0941
N
S
O
O
O
N
N
H
F
F
F
H
N
N
N
O
OH
N
O
O
S
O
O
8 (Pfizer)
7 GKA-71
Figure 1. Representative structures of GKAs.

K. Park et al. / Bioorg. Med. Chem. Lett. 23 (2013) 537–542
539
CO2Me
HO
O
CO2Me
O
CO2Me
O
O
b
a
92 %
74 %
CO2Me
CO2H
OH
O
10
Dimetyl 5-hydroxy
isophthalate
9
O
O
N
N
O
CO2H
O
O
d
e
N
N
c
O
N
H
O
N
H
49 %
O
33 %
98 %
O
O
O
Br
11
13
12
O
O
N
N
O
O
O
N
N
O
N
O
N
H
N
N
O
H
O
N
H
h
f
g
99 %
28 ~ 86 %
19 ~ 67 %
P(OEt)2
O
R
R
14
16
15
CO2Me
O
CO2Me
O
O
O
CO2H
O
O
N
N
O
O
H
i
e, f, g
O
N
H
N
16 %, 94%, 50 ~ 80%
62 %
O
O
O
11
17
R
18
CO2H
CO2H
O
O
O
O
O
N
N
O
N
H
N
H
h
43 ~ 77 %
j
63 ~ 88 %
R
R
O
H
F
F
19
20
was used in g )
( YH-GKA : If
Scheme 1. Reagents and conditions: (a) (i) (R)-(ꢀ)-1-methoxy-2-propanol, PPh3, DIAD, THF, (ii) KOH, MeOH, reflux; (b) 1 M BH3/THF; (c) (i) 3 N NaOH, THF, (ii) acetyl
chloride, CH2Cl2, pyridine, water; (d) 1-methyl-1H-pyrazol-3-ylamine, HOBT, EDAC, TEA, CH2Cl2, (e) (i) NaOMe, MeOH/THF, (ii) PBr3, THF; (f) triethylphosphite, reflux; (g)
aldehyde, t-BuOK, THF; (h) Pd/C, H2-gas, MeOH; (i) (i) SOCl2, reflux, (ii) 6-aminonicotinic acid methyl ester, pyridine; (j) 3 N NaOH, THF.
benzamides 18 were prepared by using the same reactions that
were used for the synthesis of 15. Nicotinic esters 18 were hydro-
lyzed to form carboxylic acids 19 and 19 were reduced by Pd/H2 to
give final products 20. The prepared benzamides were tested at
in vitro assay by measuring fold increase of glucokinase activity
at 5.0 mM glucose concentration.
Introduction of nitro, fluorine or methoxy groups in the termi-
nal phenyl ring of pyrazol benzamide derivatives increased po-
tency with EC50 of submicromolar activity (Table 1). Replacement
of the terminal phenyl ring with methyl pyridine group (16k) sus-
tained a good potency. 40-Substituent (16c) tended to give some-
what lower potency than 20- or 30-nitro substituent (16a, 16b).
Tri-fluorine substituted compound 16i exhibited a considerable
decrease in potency compared to mono- or di-fluorinated analogs
(16d–h). Reduction of E-alkenes (16d–j) to the corresponding al-
kanes (16l–q) resulted in retained potency. In order to improve phys-
icochemical property, pyrazol moiety in benzamide derivatives (16)
was replaced with nicotinic acid group (20) (Table 2). All mono-nitro
substituted analogs (20a–c) exhibited a good activity with EC50
<300 nM. Like pyrazol benzamide derivatives, tri-fluorine substituted
compound 20i exhibited a 6- to 14-fold decrease in potency relative
to mono- or di-fluorinated analogs (20d–h). The E-alkenes that
showed an EC50 <100 nM (20d, 20f, 20h, 20j) were further reduced
to the corresponding alkanes. Among the reduced compounds, only
20k (YH-GKA) exhibited a similar potency to the corresponding E-al-
kene 20h. YH-GKA (6-[3-[2-(2,6-difluoro-phenyl)-ethyl]-5-(2-meth-
oxy-1-methyl-ethoxy)-benzoyl-amino]-nicotinic acid) was found to
be the most active GKA with favorable physicochemical property.

540
K. Park et al. / Bioorg. Med. Chem. Lett. 23 (2013) 537–542
Table 1
Table 1 (continued)
In vitro glucokinase activity of pyrazole benzamide derivatives 16
a
Compound
R1
hGK EC50 (nM)
O
N
O
F
N
O
N
H
16p
855
135
R1
16a - q
F
F
a
Compound
R1
hGK EC50 (nM)
16q
O
16a
283
a
Mean of at least duplicate runs.
NO2
16b
16c
16d
16e
16f
239
852
80
Table 2
O2N
O2N
In vitro glucokinase activity of carboxypyridine benzamide derivatives 20
O
OH
O
O
O
N
N
H
F
R2
F
F
119
109
20a - k
Compound
R2
hGK EC50 (nM)a
F
20a
296
F
NO2
16g
16h
16i
200
161
848
20b
20c
20d
20e
20f
165
284
56
F
F
O2N
O2N
F
F
F
F
F
F
120
95
F
16j
115
132
F
O
F
16k
20g
20h
134
90
N
F
F
16l
217
216
184
F
16m
16n
F
F
F
F
F
20i
20j
778
83
F
F
F
F
16o
131
O

K. Park et al. / Bioorg. Med. Chem. Lett. 23 (2013) 537–542
541
Table 2 (continued)
Compound
R2
hGK EC50 (nM)a
F
F
20k
(YH-GKA)
70
a
Mean of at least duplicate runs.
Figure 5. Glucose lowering activity of YH-GKA in ob/ob mice.
Oral glucose tolerance test (OGTT) of YH-GKA at 50 mg/kg in
C57BL/J6 mice showed similar glucose area under the curve
(AUC) reduction of 29.6%, closely comparable to that of 29.9% for
metformin at 300 mg/kg. As shown in Figure 4, YH-GKA showed
the indication of hypoglycemia risk at 150 mg/kg. However, the
hypoglycemia risk diminished at 50 mg/kg and this dose was cho-
sen for further study in disease animal models. Acute treatment of
YH-GKA in C57BL/J6 and ob/ob mice induced basal glucose lower-
ing activity (data not shown). In a subchronic study with ob/ob
mice, YH-GKA showed significant decrease in blood glucose levels
(Fig. 5) and no adverse effects on serum lipids or body weight.
These studies strongly support our position that YH-GKA is a
promising candidate for a study in humans as a therapeutic agent
for type 2 diabetes mellitus.
In vitro metabolism studies for CYP inhibition and CYP induc-
tion were conducted using human liver microsomes and a PXR re-
porter gene assay. Metabolic stability studies were also performed
using liver microsomes from mouse, dog and human. Pharmacoki-
netics of YH-GKA in mice and dogs was determined following sin-
gle intravenous and oral administration. YH-GKA showed
acceptable metabolic stability across species with that more than
60% of compound remained after 1 h incubation. In vitro CYP inhi-
bition (CYP1A2, 2C9, 2C19, 2D6, 3A) and CYP induction (CYP3A4)
Figure 3. Glucose dependent insulin secretion.
An enzymatic glucokinase assay using purified recombinant hu-
man pancreatic glucokinase and liver glucokinase was used to
evaluate compounds. Selectivity against hexokinase 1 and 2 was
tested using enzymatic hexokinase 1 and 2 assays. MIN-6 cells,
mouse pancreatic beta-cell line, were used to evaluate the effect
of glucokinase activity on glucose dependent insulin secretion.
The change of basal blood glucose levels and oral glucose tolerance
(OGT) in non-diabetic (C57BL/J6) and diabetic (DIO, ob/ob) mice
after oral administration was evaluated. The levels of blood glucose
and OGT were measured in mice after repeated oral dosing. YH-
GKA showed human pancreatic glucokinase activity of
EC50 = 70 nM at 5.0 mM glucose with a half maximum saturation
concentration (S0.5) of 1.27 mM glucose and maximum reaction
rate (Vmax) of 130%. YH-GKA also activated human hepatic glucoki-
nase with an EC50 of 85 nM and did not affect hexokinase 1 and 2.
The compound increased insulin secretion from MIN-6 cells in a
glucose dependent manner (Fig. 3). It also improved oral glucose
tolerance in C57BL/J6 mice in a dose-dependent manner (Fig. 4).
suggested no inhibitory or induction effect up to 25–50
lM con-
centration of YH-GKA. Pharmacokinetic study of YH-GKA in mice
Glucose
Figure 4. Plasma blood glucose lowering effect of YH-GKA in C57BL/J6 mice OGTT.

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K. Park et al. / Bioorg. Med. Chem. Lett. 23 (2013) 537–542
and dogs established mean clearance ranging from 0.15 to 0.43 L/
h/kg, distribution volume ranging from 0.33 to 0.49 L/kg, elimina-
tion half-life ranging from 2.6 to 3.7 h, and bioavailability (F) rang-
ing from 66% to 144%. There was no significant pharmacokinetic
difference observed between mice and dogs. Overall, YH-GKA
exhibited high bioavailability and moderate elimination in preclin-
ical species. In vitro examination of CYP inhibition and induction
suggested that YH-GKA has low risk of drug–drug interactions in
humans. These results indicate that YH-GKA has a highly favorable
pharmacokinetic profile for an oral anti-diabetic agent. Unsurpris-
ingly, YH-GKA (EC50 = 70 nM, T1/2 = 2.6 h and F = 85% in dog) pos-
sesses comparable potency, physicochemical property and
Economy, Republic of Korea (C-2-1, 500108, 7007618). We thank
Mr. Kyeong Bae Kim and Dr. Su Youn Nam for their helpful
discussion.
References and notes
1. Kahn, S. E.; Hull, R. L.; Utzschneider, K. M. Nature 2006, 444, 840.
2. Lebovitz, H. E. Joslin’s Diabetes Mellitus, 14th ed.; Lippincott Williams & Wilkins:
Philadelphia, PA, 2005. P 687.
3. Ralph, E. C.; Thomson, J.; Almaden, J.; Sun, S. Biochemistry 2008, 47, 5028.
4. Matschinsky, F. M. Diabetes 1996, 45, 223.
5. Heredia, W.; Thomson, J.; Nettleton, D.; Sun, S. Biochemistry 2006, 45, 7553.
6. Matschinsky, F. M.; Glaser, B.; Magnuson, M. A. Diabetes 1998, 47, 307.
7. Pfefferkorn, J. A.; Guzman-Perez, A.; Litchfield, J.; Aiello, R.; Treadway, J. L.;
Pattersen, J.; Minich, M. L.; Filipski, K. J.; Jones, C. S.; Tu, M.; Aspnes, G.; Sweet,
L.; Liras, S.; Rolph, T. P., et al J. Med. Chem. 2012, 55, 1318.
pharmacokinetic profiles with 6 (GKA-60, EC50 = 90 nM, T1/2
=
4.9 h and F = 100% in dog)18 presumably due to the structural
similarity. Since Waring et al. recently reported that pyridine-5-
carboxylic acid containing GKAs (e.g., 6, GKA-60) might cause testic-
ular toxicology,21 the testicular toxicity test for YH-GKA will be
monitored carefully and the results will be reported in due course.
In summary, YH-GKA was found to be an active GKA with EC50
of 70 nM and showed glucose reduction of 29.6% (50 mg/kg) in an
OGTT study, equivalent to 300 mg/kg metformin. Acute treatment
in C57BL/J6 and ob/ob mice elicited basal glucose lowering activity.
Also YH-GKA showed significant decrease in blood glucose levels
and no adverse effects on serum lipids or body weight at a sub-
chronic study in ob/ob mice. In addition, YH-GKA exhibited high
bioavailability and moderate elimination in mice and dogs. In con-
clusion, YH-GKA is a promising preclinical lead candidate for type 2
diabetes mellitus. To identify additional preclinical GKA candidates
with better efficacy and improved safety profile without hypogly-
cemia risk, we are performing further lead optimization of the
benzamide scaffold by utilizing an innovative and translational
screening strategy containing optimized in vitro, ex vivo, in vivo
biological assays. The study results from this new strategy will
be reported soon.
8. Massa, M. L.; Gagliardino, J. J.; Francini, F. Life 2011, 63, 1.
9. Bebernitz, G. R.; Beaulieu, V.; Dale, B. A.; Deacon, R.; Duttaroy, A.; Gao, J.;
Grondine, M. S.; Gupta, R. C.; Kakmak, M.; Kavana, M.; Kirman, L. C.; Liang, J.;
Maniara, W. M.; Munshi, S.; Nadkarni, S. S.; Schuster, H. F.; Stams, T.; Denny, I.,
St; Taslimi, P. M.; Vash, B.; Caplan, S. L. J. Med. Chem. 2009, 52, 6142.
10. (a) Fyfe, M. C. T.; Procter, M. J. Drugs Future 2009, 34, 641; (b) Matschinsky, F.
Nat. Rev. Drug Disc. 2009, 8, 399.
11. Iino, T.; Hashimoto, N.; Hasegawa, T.; Chiba, M.; Eiki, J.; Nishimura, T. Bioorg.
Med. Chem. Lett. 2010, 20, 1619.
12. Sidduri, A.; Grimsby, J. S.; Corbett, W. L.; Sarabu, R.; Grippo, J. F.; Lou, J.; Kester,
R. F.; Dvorozniak, M.; Marcus, L.; Spence, C.; Racha, J. K.; Moore, D. J. Bioorg.
Med. Chem. Lett. 2010, 20, 5673.
13. Grimsby, J.; Sarabu, R.; Corbett, W. L.; Hayne, N. E.; Bizzarro, F. T.; Coffey, J. W.;
Guertin, K. R.; Hilliard, D. W.; Kester, R. F.; Mahaney, P. E.; Marcus, L.; Qi, L. D.;
Soence, C. L.; Tengi, J.; Magnuson, M. A.; Chu, C. A.; Dvorozniak, M. T.;
Matschinsky, F. M.; Grippo, J. F. Science 2003, 301, 370.
14. Sarabu, R.; Tilley, J. W.; Grimsby, J. RSC Drug Discovery Ser. 2011, 4, 51.
15. Mitsuya, M.; Kamata, K.; Bamba, M.; Watanabe, H.; Sasaki, Y.; Sasaki, K.;
Ohyama, S.; Hosaka, H.; Nagata, Y.; Eiki, J.; Nishimura, T. Bioorg. Med. Chem.
Lett. 2009, 19, 2718.
16. Waring, M. J.; Johnstone, C.; McKerrecher, D.; Pike, K. G.; Robb, G. R. Med. Chem.
Commun. 2011, 2, 775.
17. Meininger, G. E.; Scott, R.; Alba, R.; Shentu, Y.; Luo, E.; Amin, H.; Davies, M. J.;
Kaufman, K. D.; Goldstein, B. J. Diabetes Care 2011, 34, 2560.
18. Pike, K. G.; Allen, J. V.; Caulkett, P. W.; Clarke, D. S.; Donald, C. S.; Fenwick, M. L.;
Johnson, K. M.; Johnstone, C.; McKerrecher, D.; Rayner, J. W.; Walker, R. P.;
Wilson, I. Bioorg. Med. Chem. Lett. 2011, 11, 3467.
19. Winzell, M. S.; Coghlan, M.; Leighton, B.; Frangioudakis, G.; Smith, D. M.;
Storlien, L. H.; Ahrén, B. Eur. J. Pharmacol. 2011, 663, 80.
20. Yi, W. -H.; Han, T. -D.; Lee, K. -Y.; Kim, Y. -H.; Jung, E. -H.; Lee, D. -H.; Park, Y. -
H.; Min, K. -N.; Kim, J. -K.; Lee, B. -K. WO 2011/081280 A2, 2011.
21. Waring, M. J.; Brogan, I. J.; Coghlan, M.; Johnstone, C.; Jones, H. B.; Leighton, B.;
Mckerrecher, D.; Pike, K. G.; Robb, G. R. Med. Chem. Commun. 2011, 2, 771.
Acknowledgments
This study was supported by a Grant of Chungcheong Leading
Industry Office for Medicine & Bio Projects, Ministry of Knowledge