Design, synthesis and SAR of novel glucokinase activators

Article abstract of DOI:10.1016/j.bmcl.2013.01.093

Guided by co-crystal structures of compounds 15, 22 and 30, an SBDD approach led to the discovery of the 6-methyl pyridone series as a novel class of GKAs that potently activate GK in enzyme and cell assays. Anti-diabetic OGTT efficacy was demonstrated with 54 in a mouse model of type 2 diabetes.

Full text of DOI:10.1016/j.bmcl.2013.01.093

Bioorganic & Medicinal Chemistry Letters 23 (2013) 2166–2171
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Design, synthesis and SAR of novel glucokinase activators
b,
Zacharia S. Cheruvallath a, , Stephen L. Gwaltney II , Mark Sabat a, Mingnam Tang a, Jun Feng c,
,
⇑
Haixia Wang a, Joanne Miura a, Prasuna Guntupalli d, , Andy Jennings a, David Hosfield e,
,
Bumsup Lee f, , Yiqin Wu g,
a Takeda California, 10410 Science Center Drive, San Diego, CA 92121, USA
b Global Blood Therapeutics, 400 East Jamie Court, Suite 101, South San Francisco, CA 94080, USA
c Wellspring Biosciences, 3210 Merryfield Row, San Diego, CA 92121, USA
d RQX Pharmaceuticals, 11099 North Torry Pines Road, Suite 290, La Jolla, CA 92037, USA
e Ben May Cancer Institute, University of Chicago, USA
f Kolon Life Science, Inc., 7FL Kolon Tower Annex, 38 Byeoryangsangga 2-Ro, Gwacheon-Si, Gyeonggi-Do 427-709, Republic of Korea
g Quanticel Pharmaceuticals Inc., 9393 Towne Centre Drive, Suite 110, San Diego, CA 92121, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Guided by co-crystal structures of compounds 15, 22 and 30, an SBDD approach led to the discovery of
the 6-methyl pyridone series as a novel class of GKAs that potently activate GK in enzyme and cell assays.
Anti-diabetic OGTT efficacy was demonstrated with 54 in a mouse model of type 2 diabetes.
Ó 2013 Elsevier Ltd. All rights reserved.
Received 5 December 2012
Revised 17 January 2013
Accepted 22 January 2013
Available online 4 February 2013
Keywords:
Glucokinase activator
Structure-based drug design
OGTT
Type 2 diabetes
6-Methyl pyridone
Type 2 diabetes (T2D) affects more than 150 million people
worldwide and is increasing at an alarming rate due to the ongoing
obesity epidemic.1 While there are several classes of diabetic ther-
apies available, they do not achieve adequate glycemic control, and
hence there is a need for the development of safe and effective
therapies with a novel mode of action.2–5
in the patent literature and multiple compounds have been evalu-
ated in the clinic.16
O
Glucokinase (GK), a member of the hexokinase family, is pre-
dominantly expressed in the liver, pancreatic b-cells, brain and
gut where it catalyzes the phosphorylation of glucose to glucose-
6-phosphate.6,7 GK plays an important role in the control of
whole-body glucose homeostasis by enhancing glucose stimulated
insulin release from the pancreatic b-cells and promoting glycogen
synthesis in the liver.8–10 Glucokinase activators (GKAs) have also
been shown to increase hepatic glucose uptake and reduce hyper-
glycemia in multiple animal models of T2D. GKAs may represent a
novel approach for the treatment of T2D.11 Following the initial
discovery of an allosteric activator binding site 20 Å removed from
the glucose binding site by Grimsby et al.,12 there have been many
publications from pharmaceutical companies targeting this site
with GKAs (Fig. 1).13–15 There are greater than 100 reports of GKAs
H
N
N
H
N
Cl
N
N
O
O
S
O
S
S
O
O
O
Roche RO-28-1675 (1)
Roche Piragliatin (2)
O
O
OH
O
N
N
N
H
N
O
N
S
F
S
N
H
NH2
O
O
Astra-Zeneca (3)
Banyu-Merck (4)
⇑
Corresponding author.
Figure 1. Structures of selected glucokinase activators.
Present address.
0960-894X/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2013.01.093

Z. S. Cheruvallath et al. / Bioorg. Med. Chem. Lett. 23 (2013) 2166–2171
2167
Arg 63
GK. The energy minimized model indicated hydrogen bonding be-
tween the amide NH and the thiazole N with the backbone atoms
of Arg63, a hydrophobic interaction of the isopropyl methyl group
hydrophobic
back pocket
N
O
H
with the GK back pocket and a p-stacking interactions with Trp99.
H
N
N
To test our hypothesis, we synthesized compounds 5–8 follow-
ing either literature precedents19 or the approach shown in
Scheme 1. Coupling of commercially available compound 8a with
2-aminothiazole gave amide 8b, which upon treatment with HCl/
dioxane gave intermediate 8c. Amide coupling of 8c with anthra-
nilic acid gave 8d, which upon treatment with CDI gave the cy-
clized target quinazoline-2,4-dione 8.19b Encouraged by the data
for compound 8, we next aimed to improve the potency of this
chemotype by incorporation of substituents on the quinazoline-
2,4-dione ring and replacement of the isobutyl chain with groups
of increased steric bulk that would interact with the hydrophobic
back pocket of GKA.
As seen from the data in Table 1, replacement of the isopropyl
group with the cyclohexyl group (compound 9) improved potency
20-fold, whereas use of the phenyl moiety (compound 10) led to a
>20-fold reduction in potency. With the cyclohexyl group of com-
pound 9 fixed, we examined substituents R1 and R2 on the quinaz-
oline-2,4-dione core. Of the analogs examined in this series,
compound 16 was the most potent. Analogous to compounds 1,
and 2, the S isomer was the more potent isomer of the pair.13,14
An insight into the binding of these compounds was obtained
by an X-ray co-crystal structure of 15 bound in the open form of
GK as shown in Figure 3.20 The interactions observed in this co-
crystal structure were consistent with our hypothesis. The amide
NH and the thiazole N form hydrogen bonds with the backbone
atoms of Arg63. The cyclohexylmethyl group forms hydrophobic
interactions in the GK back pocket, and the quinazoline-2,4-dione
R
Trp 99
O
S
O
O
N
N
N
N
O
S
N
N
H
O
O
O
6
7
5
8
EC50 = 7.9 µM
µ
EC50 = >100 µM
EC50 = > 100
M
EC50 = 10 µM
Figure 2. Initially designed GKAs.
All GKAs increase the binding affinity for glucose (S0.5);17 how-
ever, they vary in their modulation of the maximum velocity (Vmax
)
of glucokinase. We divided our GKAs into three classes based on
their effect on GK catalytic activity at saturated glucose concentra-
tions. Activators that enhanced enzyme catalytic turnover at satu-
rated glucose concentrations were denoted Class 1 activators,
whereas activators that did not alter enzyme catalytic turnover
were called Class 2 and compounds that reduced enzyme catalytic
turnover were labeled Class 3. While Class 2 activators may
provide benefit to diabetic patients due to activation of GK at mod-
erate glucose concentrations, Class 1 activators may be more effec-
tive at high glucose concentrations. Class 3 activators can only
activate GK at relatively low glucose concentrations and hence
may not be effective in controlling hyperglycemia.
Based on crystal structures of GK both in the absence of glucose
and in the presence of glucose and a GKA, Kamata et al. proposed a
model to explain the observed positive cooperativity of GK with re-
spect to glucose.18 In the absence of glucose, or at very low glucose
concentrations, GK exists in a low energy, super open, inactive con-
formation in which the two lobes of the kinase are widely sepa-
rated and the allosteric binding pocket is not accessible. The
open and closed conformations of GK are stabilized by binding of
GKA’s that result in the increase in affinity of GK for glucose and
are favored at high concentrations of glucose. GKAs bind to the
allosteric pocket located in the hinge region between the two
lobes.
forms aromatic
p-stacking interactions with Trp99. Compound
16, which places the methylsulfonyl group in the same position
as that in compound 1, maintains similar potency consistent with
a hydrogen bond interaction of the sulfone oxygen with the side
chain of Gln98 as seen in compound 1.12
Since attempts to further improve the potency of compound 16
failed, we evaluated alternative heterocyclic scaffolds to replace
the quinazoline-2,4-dione core. Molecular modeling21 based on
our crystal structure of compound 15 suggested that scaffold
morphing of the quinazoline-2,4-dione to the quinazoline scaffold
could be tolerated. In order to evaluate the potential of this scaf-
fold, we synthesized the quinazolinones by cyclization of the
appropriate intermediate (8d) by treatment with triethyl orthofor-
mate19b as shown in Scheme 2.
In this Letter, we describe our preliminary efforts to identify and
optimize novel, potent and orally bioavailable GKAs for the treat-
ment of T2D.19 Our analysis of GKAs reported in the literature to
bind to the allosteric site of GK,11–15 led us to the design of com-
pounds 5–8 as novel GKAs (Fig. 2). Molecular modeling20 of these
analogs suggested a complementary fit in the allosteric site of
Compound 18 showed potency comparable to that of com-
pound 1 (Table 2). To facilitate further optimization of the scaffold,
we obtained a co-crystal structure of compound 22 bound to GK
H
H
N
OH
a
b
N
N
BocHN
N
H2N
HCl
BocHN
O
O
S
O
S
8a
8b
8c
O
O
H
H
N
N
N
N
c
d
N
N
H
O
S
O
S
N
H
O
NH2
8d
8
Scheme 1. Reagents and conditions: (a) isobutyl chloroformate, NMM, 2-aminothiazole, THF; (b) 4 N HCl in dioxane; (c) 2-aminobenzoic acid, HBTU, TEA, DMF; (d) CDI,
dioxane,
D
.

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Z. S. Cheruvallath et al. / Bioorg. Med. Chem. Lett. 23 (2013) 2166–2171
Table 1
Selected data for quinazoline-2,4-dione analogs
R
O
H
R1
R2
N
N
N
O
S
N
H
O
R3
R3
Compd
R
R1
R2
EC50
(lM)
% Maximum activation
1
0.5
7.9
4.0
>100
50
1.0
2.0
10
98
67
46
0
28
22
59
65
127
37
8a
iPr
H
H
H
H
H
H
OMe
F
H
H
H
H
H
H
H
H
H
H
H
H
H
Cl
9
Cyclohexyl
Phenyl
iPr
Cyclohexyl
Cyclohexyl
Cyclohexyl
Cyclohexyl
Cyclohexyl
10
11
12
13
14
15
16a
MeSO2
Cl
H
H
3.1
0.63
MeSO2
a
Racemic.
complementary fit in the allosteric site of GK and mimic the qui-
nazoline core to yield potent GKAs.
Analogous to the synthesis of the quinazoline-2,4-diones, the
commercially available amino acid 30a was converted to the thia-
zole amide 30b and deprotected to afford 30c. Amide coupling of
30c with a Boc-protected glycine gives intermediate 30d. After
treatment with TFA to remove the Boc group, cyclization to the
ketopiperazine intermediate 30e was achieved by treatment with
dibromoethane in the presence of K2CO3.22–24 The intermediate
30e was treated with a variety of sulfonyl chlorides to yield com-
pounds 30–42 shown in Scheme 3.
As analysis of the data from Table 3 shows, multiple heterocy-
clic sulfonamides were well tolerated at position 4 of the ketopip-
erazine scaffold (compounds 35–40) with the cyclopentyl
sulfonamide being the most potent of the variants made at that po-
sition (compound 32). The 25-fold improvement in potency of
compound 32 compared to compound 30 is hypothesized to be
due to the hydrophobic interaction of the cyclopentyl group with
Pro66 as can be envisioned by the co-crystal structure of com-
pound 3025 bound in the allosteric site of GK (Fig. 5).20 In addition
to the H-bond and hydrophobic interactions, the pucker of the
ketopiperazine ring positions the sulfonamide group such that it
forms H-bonds with both the OH group of Tyr214 and the back-
bone amide of Trp99. Interaction with Tyr214 provides an addi-
tional interaction in the allosteric site of GK that is not observed
with previous compounds. Unfortunately compound 32 also
Figure 3. Co-crystal structure of compound 15 in the GK allosteric site.
(Fig. 4).20 In addition to the customary H-bonds to Arg63 and the
hydrophobic interaction in the back pocket, when compared to
the quinazoline-2,4-dione ring of compound 15, the F atom of
compound 22 is directed towards the backbone NH of Gln98. By
binding in this orientation, the C7 atom is directed towards a pock-
et formed by Val101, Tyr215, and Leu451, suggesting small hydro-
phobic groups at this position (R2) could increase activator
potency.
Consistent with this hypothesis, a 50-fold improvement in
potency was obtained by the introduction of a methyl amide at
R2 of the quinazoline ring and a Cl at R3 of the thiazole ring (24).
Substitution of the cyclohexyl ring with a THP group led to an 8
to 10-fold reduction in potency (19 ? 20 and 27 ? 28). Although
the binding affinity of compound 24 was attractive, it showed low
showed low human and rat microsomal stability (t <5 min).
½
Although the binding affinity of the quinazolinone and ketopip-
erazine scaffold was attractive, these analogs showed very poor
in vitro microsomal stability.
As we continued evaluating alternative templates, the 6-meth-
ylpyridone scaffold was docked into the allosteric site of GK. The
model suggested a highly complementary fit and so to examine
its potential, the 6-methylpyridones were synthesized using the
synthetic route shown in Scheme 4. Condensation of commercially
human and rat microsomal stability (t <5 min).
½
By exploiting in house crystallographic information, molecular
modeling21 suggested that a ketopiperazine ring would have a
R
R
O
O
H
R1
H
N
R1
R2
N
N
N
N
H
a
N
O
S
R2
NH2
O
S
R3
N
R3
17-29
8d
Scheme 2. Reagents and conditions: (a) triethyl orthoformate, TEA,
D.

Z. S. Cheruvallath et al. / Bioorg. Med. Chem. Lett. 23 (2013) 2166–2171
2169
Table 2
Selected data for quinazolinone analogs
Compd
R
R1
R2
R3
EC50
(
lM)
% Maximum activation
1
0.5
10
0.5
0.12
1.2
2
98
72
87
54
36
56
108
86
58
72
65
87
44
44
17
18
19a
20a
21a
22
23
24
25
26
27
28
29
Cyclohexyl
Cyclohexyl
Cyclohexyl
THP
Cyclohexyl
Cyclohexyl
Cyclohexyl
Cyclohexyl
Cyclohexyl
Cyclohexyl
Cyclohexyl
THP
H
H
H
H
Cl
F
Me
H
H
H
H
H
H
H
H
H
Cl
Cl
H
H
H
Cl
F
MeSO2
CyPrNHCO
CyPrNHCO
H
H
H
MeNHCO
CyPentylSO2
CyPentylSO2
EtSO2
EtSO2
CyPrSO2
4
2.5
0.079
0.31
0.4
0.63
5
Cl
F
F
Cyclopentyl
H
2
a
Racemic, Cy = cyclo.
The 6-methyl pyridone analogs showed binding affinities com-
parable to the quinazolinone and ketopiperazine analogs (Table 4).
In addition, in the enzyme assay, the Vmax of the 6-methyl pyridone
series resembled compound 1 which is a Class 1 activator unlike
the ketopiperazines which were found to be Class 2/3 activators.
The 6-methylpyridones strike a good balance between potency
and Vmax of glucokinase.
As shown in Table 4, an increase in steric bulk on the sulfone at
position 4 of the pyridone led to an 80-fold increase in potency (43
? 44 ? 45). Unfortunately compound 45 showed low human and
rat microsomal stability (t <5 min). With the cyclopentyl group of
½
compound 45 fixed, we explored a variety of substituents at R and
R2 (46–52) to improve the microsomal stability of the compounds
while maintaining potency without any success. However, while
compound 54 was less potent than other compounds in this series,
it was found to combine the best balance of GK activation and
in vitro DMPK properties and hence was chosen for further profil-
ing in efficacy models. Compound 54 showed a half-life of 120 min,
35 min and 60 min respectively when incubated with MLM, RLM
and HLM. Its rat pharmacokinetic profile was characterized by an
oral half-life of 5.9 h, clearance of 69 mL/min/kg, volume of distri-
bution of 2.4 L/kg and an oral bioavailability of 36%.
Oral administration of 30 mg/kg of 54 in C57BL/6J mice resulted
in a significant glucose lowering effect. In addition, compound 54
administered at an oral dose of 30 mg/kg reduced glucose excur-
sion in an oral glucose tolerance test (OGTT) experiment in ob/ob
mice in a manner comparable to that of compound 1 (Fig. 6).
In summary, using co-crystal structures of compounds 15, 22 and
30, an SBDD approach led to the discovery of the 6-methylpyridone
Figure 4. Co-crystal structure of compound 22 in the GK allosteric site.
available 4-hydroxy-6-methyl-2H-pyran-2-one with an appropri-
ately substituted amino acid in the presence of a base gave the
intermediate 43b.26 Esterification, followed by treatment with
POCl3 and dimethylaniline in the presence of tetraethyl
ammonium chloride gave the 4-chloro-6-methylpyridone interme-
diate 43c.27 Displacement of the halide with thiolate followed by
oxidation with mCPBA gave the sulfone 43d. Hydrolysis of the ester
followed by amide coupling with the substituted 2-aminothiazoles
gave the desired 6-methylpyridone analogs.
R1
R1
R1
b
H
N
a
c
H
N
N
N
OH
H2N
BocHN
BocHN
.
O
S
HCl
O
S
O
R2
R2
30c
30b
30a
R1
R1
R1
O
H
N
N
O
O
f, g
d, e
H
H
O
N
N
N
N
N
S
N
NH
O
R2
O
O
N
HN
S
S
S
4
R2
R
R2
NHBoc
O
30e
30 (R = Me)
30d
Scheme 3. Reagents and conditions: (a) thiazol-2-amine, HBTU, TEA, DMF; (b) 4 N HCl in dioxane; (c) 2-((tert-butoxycarbonyl)amino)acetic acid, HBTU, TEA, DMF; (d) 4 N
HCl in dioxane; (e) 1,2-dibromoethane, K2CO3, dioxane, 100 °C; (f) sulfonyl chloride, TEA, DMAP, DCM; (g) chiral HPLC purification.

2170
Z. S. Cheruvallath et al. / Bioorg. Med. Chem. Lett. 23 (2013) 2166–2171
Table 3
Selected data for ketopiperazine analogs
Compd
R
R1
R2
EC50
(l
M)
% Maximum activation
1
0.5
1.6
0.25
0.063
0.79
2
0.31
0.2
98
64
64
33
22
21
36
44
33
39
62
54
25
45
30a
31a
32
33
34
35
36
37
38
39
40
41
42
Me
Cyhexyl
Cyhexyl
Cyhexyl
THP
H
H
H
Cl
Cl
H
H
H
H
H
H
H
H
Cyclopropyl
Cyclopentyl
Cyclopropyl
Me
3-Cl phenyl
3,5-diF phenyl
3-Me phenyl
2-F,4-Me phenyl
2-Furyl
THP
Cyhexyl
Cyhexyl
Cyhexyl
Cyhexyl
Cyhexyl
Cyhexyl
Cyhexyl
Cyhexyl
0.2
0.25
0.16
0.31
0.4
N-Me pyrazole
Bn
iPr
1
a
Racemic, cyhexyl = cyclohexyl.
Table 4
Selected data for 6-methyl pyridone analogs
Compd
R
R1
R2 EC50
(l
M) % Maximum activation
1
0.5
6.3
2
0.079
0.79
1.6
0.2
1
1.6
98
125
117
88
73
40
75
64
55
52
43
44
45
46a
47a
48a
49a
50a
51
52
53
54
55
Cyclohexyl
Cyclohexyl
Cyclohexyl
iPr
Cyclopropyl Cypentyl
Cyclopentyl Cypentyl
THP
n-pr
THP
THP
Me
Et
Cypentyl
Cypentyl
H
H
H
H
H
H
H
H
Cypentyl
Cypentyl
Cypentyl Cl 0.16
Cypentyl
F
F
0.5
68
109
77
Cyclopentyl Cypropyl
THP
Cyclopentyl Cypropyl Cl 0.16
0.63
Cypropyl Cl 1.2
90
a
Figure 5. Co-crystal structure of compound 30 in the GK allosteric site.
Racemic, cypentyl = cyclopentyl, cypropyl = cyclopropyl.
R
O
R
O
O
O
40000
O
OH
a
b, c
O
O
d, e
40000
N
N
30000
HO
p<0.01
p<0.01
HO
Cl
30000
43a
43b
43c
20000
20000
R
R
O
O
O
10000
10000
H
N
N
OMe
N
f, g, h
N
O
S
O
O
S
0
0
4
S
O
R1
R2
Vehicle Cpd 54
R1
Vehicle
Cpd 1
O
43d
43
Figure 6. Glucose AUCs of 1 and 54 following an oral administration to C57BL/6J
mice (dose 30 mg/kg for both compounds).
Scheme 4. Reagents and conditions: (a) amino acid, 1 N NaOH, reflux; (b) MeOH,
H2SO4, reflux; (c) POCl3, Et4NCl, dimethylaniline, ACN, 80 °C; (d) thiol, NaH, DMSO,
80 °C; (e) mCPBA, DCM; (f) 1 M LiOH, dioxane; (g) aminothiazole, HBTU, TEA, DMF;
(h) chiral HPLC purification.
assistance. The X-ray crystallography data reported here is based
on research conducted at the Advanced Light Source (ALS). ALS is
supported by the Director, Office of Science, Office of Basic Energy
Sciences, Materials Sciences Division, of the U.S. Department of En-
ergy (DOE) under Contract No. DE-AC03-76SF00098 at Lawrence
Berkeley National Laboratory. We thank the staff at ALS for their
excellent support in the use of the synchrotron beam lines. The
authors would like to thank Matt Marx and Gavin Hirst for help
with reviewing the document.
series as a novel class of GKAs. Example 54 from the 6-methylpyri-
done series was assessed in an in vivo model of T2D and
demonstrated potent activity. Future reports will describe further
modification of the 6-methylpyridones for optimization of in vivo
properties.
Acknowledgements
References and notes
The authors appreciate the drug discovery expertise of Jeffrey
Stafford. We thank Robert Skene, Gyorgy Snell, Lisa Rahbaek, Pam-
ela Farrell and Beverly Knight for their valuable experimental
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3. Nathan, D. M. N. Eng. J. Med. 2002, 347, 1342.
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5. Bell, D. S. Treat. Endocrinol. 2004, 3, 67.
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19. Patent applications describing our GKAs have been published. Full
experimental procedures for all analogs in this Letter are contained within
the patent applications: (a) Cao, S. X.; Feng, J.; Gwaltney, S. L.; Hosfield, D. J.;
Skene, R. J.; Stafford, J. A.; Tang, M. US200072811942.; (b) Cheruvallath, Z.;
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Miura, J.; Sabat, M.; Tang, M.; Wang, H. WO2008079787, WO2008/16107A2.
20. PDB ID code for compound 15 is 41SF, compound 22 is 41SE and compound 30
is 41SG.
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