Discovery and structure-activity relationships of a novel class of quinazoline glucokinase activators

Article abstract of DOI:10.1016/j.bmcl.2009.08.064

We describe design, syntheses and structure-activity relationships of a novel class of 4,6-disubstituted quinazoline glucokinase activators. Prototype quinazoline leads (4 and 5) were designed based on the X-ray analyses of the previous 2-aminobenzamide lead classes. Modifications of the quinazoline leads led to the identification of a potent GK activator (21d).

Full text of DOI:10.1016/j.bmcl.2009.08.064

Bioorganic & Medicinal Chemistry Letters 19 (2009) 5531–5538
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Discovery and structure–activity relationships of a novel class
of quinazoline glucokinase activators
*
Tomoharu Iino , Yasuhiro Sasaki, Makoto Bamba, Morihiro Mitsuya, Akio Ohno, Kenji Kamata,
Hideka Hosaka, Hiroko Maruki, Mayumi Futamura, Riki Yoshimoto, Sumika Ohyama, Kaori Sasaki,
Masato Chiba, Norikazu Ohtake, Yasufumi Nagata, Jun-ichi Eiki, Teruyuki Nishimura
Banyu Tsukuba Research Institute, Banyu Pharmaceutical Co. Ltd, Okubo-3, Tsukuba 300-2611, Ibaraki, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
We describe design, syntheses and structure–activity relationships of a novel class of 4,6-disubstituted
quinazoline glucokinase activators. Prototype quinazoline leads (4 and 5) were designed based on the
X-ray analyses of the previous 2-aminobenzamide lead classes. Modifications of the quinazoline leads
led to the identification of a potent GK activator (21d).
Received 24 June 2009
Revised 3 August 2009
Accepted 14 August 2009
Available online 21 August 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Glucokinase
Glucokinase activator
Glucose lowering efficacy
Log D
Aqueous solubility
4,6-Disubstituted quinazoline
Type 2 diabetes (T2D), a disease characterized by hyperglyce-
mia (elevated blood glucose concentrations), is becoming more
prevalent as a result of the recent dramatic rise in obesity levels.
Current antidiabetic drugs to treat this disease include metformin,
insulin, thiazolinediones, alpha-glucosidase inhibitors, sulfonylu-
reas and DPPIV inhibitors. Despite these multiple treatment op-
tions, it is difficult to effectively treat T2D by single treatment
option in the long term.1–3 Therefore, there is an unmet medical
need for the development of new, safe and effective antidiabetic
therapies with novel and multiple mode of action.
potent GK activation and glucose lowering effect in a rat OGTT
model. Moreover, the crystal structure of 1 with GK protein re-
vealed a unique binding mode at an allosteric site distinct from
the glucose binding and catalytic sites. This structure elucidation
S
S
N
HN
Me
O
N
HN
Me
N
HO
O
S
O
Glucokinase (GK), a glucose-phosphorylating enzyme, repre-
sents an attractive target for T2D therapies,4,5 because it plays a
critical role in whole-body glucose control through its actions in
multiple organs. In particular, in the b-cells of the pancreas, GK acts
as the glucose sensor that determines the threshold for insulin
secretion, while in the liver, this enzyme is rate-determining for
glucose metabolism.6–10 As a result of promising preclinical data,
many pharmaceutical companies have actively pursued the pro-
gram aiming at the development of GK activators (GKAs).10–18 Of
these, several companies including Roche, Astra-Zeneca and OSI/
Prosidion have entered their compounds into clinical study.12,14
We previously reported a 2-aminobenzamide class of allosteric
GKAs exemplified by compound 1 (Fig. 1).15 Compound 1 showed
N
N
O
NH2
Compound 1
MeO2S
Compound 2
S
Me
N
HN
S
Me
S
N
N
O
N
N
Compound 3
F
* Corresponding author. Tel.: +81 3 6272 2012; fax: +81 3 6238 9097.
E-mail address: tomoharu_iino@merck.com (T. Iino).
Figure 1. Structures of GK activators 1–3.
0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2009.08.064

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T. Iino et al. / Bioorg. Med. Chem. Lett. 19 (2009) 5531–5538
S
N
R
N
O
HN
N
Cl
I
I
I
(a)
(b)
OH
NH2
N
N
R
11: R = H
12: R = Me
9
10
S
N
N
HN
N
Me
N
S
(c)
4: R = H
5: R = Me
N
N
Scheme 1. Reagents and conditions: (a) (1) HCONH2, 160 °C, 93%; (2) POCl3, reflux, CH3CN, 81%; (b) thiazol-2-ylamine or 4-methylthazol-2-ylamine, phenol, 120 °C, 28%; (c)
4-methyl-1,2,4-triazol-3-ylthiol, CuI, Cs2CO3, DMA, 140 °C, 40%.
OH
O
Cl
HO
HO
AcO
(a)
(b)
N
OH
NH2
N
N
N
13
14
15
S
N
S
N
Me
Me
N
HN
N
N
HN
N
(c)
(d)
HO
O
R
17a, 18, 19
16
6-8
SO2Me
17a: 2-Fluoro(methylsulfonyl)benzene
18: 1,2-Difluorobenzene
6: R =
7: R =
8: R =
19: 1,4-Difluorobenzene
F
F
N Me
N Me
N
N
HN
HN
N
(e)
(d)
17a-17o
HO
O
N
N
R
15
N
20
21a-21o
17a: 2-Fluoro(methylsulfonyl)benzene
17b: 1,2,4-Trifluorobenzene
17d: 2,3-Difluoro(methylsulfonyl)benzene
17e: 3-Chloro-2-fluoro(methylsulfonyl)benzene
17f: 2-Fluoro-3-(methylsulfonyl)toluene
17g: 4-Fluoro-3-(methylsulfonyl)toluene
17h: 3-Cyano-2-fluorotoluene
17i: 2-Chloropyridine
17j: 2-Chloropyrazine
17k: 4-Chloropyrimidine
17l: 3-Fluoro-2-chloropyridine
17m: 2,3-Dichloropyridine
17n: 3-Bromo-2-chloropyridine
17o: 2-Chloro-3-(dimethylcarbamoyl)pyridine
SO2Me
SO2Me
SO2Me
SO2Me
21e: R =
21j: R =
21f: R =
21k: R =
21d: R =
21i: R =
21a: R =
21b: R =
Cl
F
F
Me
F
CN
Cl
SO2Me
N
21g: R =
21h: R =
N
N
N
N
Me
Me
Br
N
CONMe2
N
F
21n: R =
21o: R =
21l: R =
21m: R =
N
N
Scheme 2. Reagents and conditions: (a) HCONH2, 160 °C, 77%; (b) (1) Ac2O, Py, rt; (2) SOCl2, cat. DMF, reflux, 89%; (c) (1) 4-methylthiazol-2-ylamine, phenol, 120 °C; (2) aq
NH3, MeOH, 28%; (d) t-BuOK, DMA,130 °C, 20–50%; (e) (1) 3-amino-1-methylpyrazole, phenol, 80 °C; (2) aq NH3, MeOH, 50%.
has provided helpful information to further perform SAR study.
However, there is a potential toxicity concern associated with an
aniline moiety contained in the structure of 1.19,20 Therefore, a
new structure class without the aniline group was strongly desired
to further develop GKAs. We have developed heteroaromatic
amides GKAs represented by compounds (2 and 3) and reported

T. Iino et al. / Bioorg. Med. Chem. Lett. 19 (2009) 5531–5538
5533
F
OH
F
O
F
O
F
CN
Cl
CN
(a)
N
(b)
N
NH2
NO2
23
22
24
N Me
N
F
HN
N
(c)
O
F
N
21b
CHO
N Me
N Me
Cl
OH
N
N
HN
N
CHO
N
HN
N
O
O
(e)
N
N
20
N
(d)
N
26
21P
Scheme 3. Reagents and conditions: (a) (1) 2,6-difluorophenol, Cs2CO3, DMF, 80 °C; (2) H2, 10% Pd–C, THFMeOH, rt, 3 h; (b) HCO2H, 110 °C, 14 h; (c) (1) SOCl2, cat. DMF, 80 °C;
(2) N-methylpyrazole, phenol, 120 °C; 30 min; (d) t-BuOK, DMA, 130 °C, 45%; (e) NaBH4, MeOH, 55%.
R
Cl
N
SO2Me
O
HN
N
AcO
(a) or (b)
(c)
N
N
F
method(a): 25a, 25b, 25f, 25g
method(b): 25c, 25d, 25e, 25h
15
25a-25h
N
S
Me
Me
NH 25c: R =
25d: R =
25h: R =
N
Et 25b: R =
25f: R =
25a: R =
N
N
N
N
N
N
N
N
Cl
25e: R =
25g: R =
N
N
N
N
Scheme 4. Reagents and conditions: (a) (1) RNH2, phenol, 120 °C; (2) aq NH3, MeOH, 50%; (b) RNH2, Pd2(dba)3 (0.1 equiv), BNAP (0.1 equiv), Cs2CO3 (2 equiv), toluene, 3 h,
120 °C; (2) aq NH3, MeOH, 50%; (c) 2,3-difluoromethanesulfonylbenzene, t-BuOK, DMA,130 °C, 25–50%.
previously.16,18 Here we described the design and synthesis of a
novel class of 4,6-disubstituted quinazoline GK activators which
eliminate the aniline group of the lead compound (1), and thus
overcome any potential toxicity issue.
yield. Coupling of 15 with 2-amino-4-methylthiazole led to 16 in a
moderate yield. Finally, nucleophilic aromatic substitution reaction
of 16 with 2-fluoro(methanesulfonyl)benzene 17a, 1,2-difluoro-
benzene 18 and 1,4-difluorobenzene 19 afforded quinazoline
derivatives (6–8), respectively.
General synthetic methods of quinazoline derivatives (4–8,
21a–o, 25a–h) are summarized in Schemes 1–4. A key quinazoline
intermediate (10) was prepared from commercially available 2-
amino-5-iodobenzoic acid 9 by the following two step sequences
(Scheme 1); (1) quinazoline ring closure by treatment with
HCONH2 at 160 °C, (2) chlorination by POCl3 in CH3CN at reflux.
This intermediate (10) was regio-selectively coupled with
2-aminothiazole or 2-amino-4-methylthiazole to afford 6-iodo-4-
(thiazol-2-ylamino)quinazoline (11) or 6-iodo-4-(4-methylthia-
zol-2-ylamino)quinazoline (12). Subsequently, these quinazoline
compounds were coupled with 4-methyl-4H-1,2,4-triazole-3-thiol
at the 6-position to produce the derivatives (4 and 5), respectively.
Similarly, 6-hydroxy-4-(4-methylthiazol-2-ylamino)quinazoline
intermediate 16 was prepared from 2-amino-5-hydroxybenzoic
acid 13 (Scheme 2). More specifically, 4,6-dihydroxyquinazoline
14 was treated with acetic anhydride in pyridine to protect the
hydroxyl group at the 6-position as an acetate. Subsequently, the
hydroxyl moiety at the 4-position was chlorinated by thionyl
chloride to afford 6-acetoxy-4-chloroquinazoline 15 in an excellent
The 4-(1-methylpyrazol-3-ylamino)quinazoline derivatives
(21a–o) were prepared from 6-hydroxy-4-(1-methylpyrazol-3-yla-
mino)quinazoline 20 in a similar manner described for the synthe-
sis of 6 in 20–50% yields. Due to extremely low yield in the
nucleophilic aromatic substitution (SNAr) reaction of 16, an alter-
native synthetic method was developed (Scheme 3). More specifi-
cally, SNAr reaction of 2,6-difluorophenol with commercially
available 4-chloro-2-cyanonitrobenzene provided 23 in a 50%
yield. Catalytic hydrogenation of the nitro group followed by qui-
nazoline ring closure reaction (HCO2H, 110 °C) led to 24 in a 40%
yield. Compound 24 was converted into 21c by the following
methods; (1) SOCl2 in the presence of catalytic amount of DMF,
(2) 3-amino-1-methylpyrazole in phenol at 80 °C. Hydroxymethyl
derivative (21p) was prepared from formyl intermediates by
reduction reaction.
Preparation of 4-heteroarylamino-6-(2-methanesulfonyl-6-flu-
orophenoxy)quinazoline derivatives (25a–h) was accomplished
by similar methods as described for 21a or a slightly modified pro-

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T. Iino et al. / Bioorg. Med. Chem. Lett. 19 (2009) 5531–5538
analysis revealed that the aniline NH of
1 interacted with
Arg63
Arg63
N
N
H
Me
S
Me
S
H
Tyr215-OH of GK via hydrogen bonding, and that another aniline
NH formed an intra-molecular hydrogen bond with the amide car-
bonyl group in 1 to fix the conformation and preferably bound to
Arg63 backbone. Based on these data, we further designed 4-(thia-
zolamino)-6-(N-methyl-1,2,4-triazol-5-ylthio)quinazoline (4) and
its 4-methylthiazol-2-ylamino analogue (5), in which we assumed
the nitrogen atom of the thiazole ring and thiazolamine NH was
favorably arranged to interact with Arg63 of GK and the nitrogen
atom at the 1-position of the quinazoline core interacted with
Tyr215-OH of GK. We speculate that the hydrogen bonding pattern
associated with Tyr215 changes on going from the 2-carbo-
xamidoaniline to the quinazoline (Fig. 2). In the first situation,
Tyr215 acts as an H-bond acceptor, while, in the second situation,
it acts as a H-bond donor.
O
O
N
N
H
H
N
N
Me
N
Me
N
S
S
O
N
N
N
N
H
N
N
H
N
H
O
OH
Tyr215
Tyr215
Figure 2. Design of novel quinazoline lead.
Table 1
These compounds (4 and 5) exhibited moderate GKA potency
(4: EC50 = 2.1 lM, 5: EC50 = 2.1 lM), indicating that the quinazoline
Profiles of compounds (4 and 5)
R
structure deserved attention as a novel class of GK activator leads
(Table 1). To optimize this novel lead class, we initially focused on
modifications at the 4- and 6-position of the quinazoline core.
In the previous SAR study of the 2-aminobenzamide class, it
was revealed that replacement of the triazol-2-ylthio group of
compound 1 with a substituted phenoxy moiety was feasible.15,17
We applied this approach to the modifications of the current qui-
nazoline leads (Fig. 3). Initially, the triazol-2-ylthio moiety in 5
was replaced with 2-(methylsulfonyl)phenoxy-(6), 2-fluorophen-
oxy-(7), or 4-fluorophenoxy-(8) group as representative surro-
gates. Interestingly, compounds 6 and 7 exhibited significant
N
N
S
HN
Me
N
S
N
N
N
Compd
R
2.5 mM Glc
10 mM Glc
a
b
a
b
EC50
(
l
M)
Emax
EC50
(
lM)
Emax
4
5
1
H
Me
—
2.1
2.1
0.42
0.69
0.67
1.0
0.21
0.92
0.14
0.47
0.70
1.0
improvement in GK activation (6: EC50 = 0.23
0.15 M) as compared with 5, while 8 had a comparable GK activa-
tion potency (8: EC50 = 1.0 M), suggesting that replacement of the
lM, 7: EC50 =
l
Compound 1 is the internal standard (EC50: 0.42 0.09 and 0.14 0.04).
l
n.t.: not tested.
4-methyl-1,2,4-triazol-3-ylthio group with substituted phenoxy
moieties was tolerable (Table 2). These results prompted us to
further optimize the quinazoline leads. However, lipophilic com-
pounds, particularly neutral compounds, may worsen the aqueous
solubility, which influence their ADME aspects, posing challenges
for drug development.22 Therefore, during the modifications of
the quinazoline leads, we elected to pay attention to the physico-
chemical properties of compounds, particularly the lipophilicity
(clog P or measured log DpH 7.4) and aqueous solubility which was
measured in high-speed solubility screening assay using DMSO
solution of compounds.23,24
Our initial attempt was to focus on optimizing a substituent of
the phenoxy group at the 6-position of the quinazoline core whilst
holding a 1-methylpyrazol-3-ylamino group15 at the 4-position
constant, because this heteroaromatic amino group retained in
GKA potency and more importantly this would give rise to a more
hydrophilic nature as compared with the 4-methylthiazol-2-yla-
mino moiety. As a basis for initial attempts, we incorporated a
methylsulfonyl group into the 2-position (21a), or fluorine atoms
at the 2- and 4-positions (21b) or 2- and 6-positions (21c) of the
phenoxy group. The compound (21a) exhibited moderate GKA
a
Values are the means of two or more independent assays.
The maximal activating response elicited the compounds as a ratio of the
maximal response evoked by 1 at each concentration independently.
b
tocol utilizing the coupling reaction of 15 with heteroaromatic
amines in the presence of Pd2(dba)3 and BINAP.
Compounds prepared herein were evaluated in an in vitro GK
assay, which was conducted at two different glucose concentra-
tions (2.5 mM and 10 mM).10 These glucose concentrations simu-
late low and high blood glucose conditions, respectively. GK
activity of compounds was described as EC50 values and maximal
effective responses (Emax). For comparison of compounds in each
assay, the EC50 and Emax values of compound 1 were used as an
internal standard (Emax value of 1 = 1.0). We suppose that not only
the EC50 values, but also the Emax values of GK activators are impor-
tant for the efficacy of in vivo experiments.
As previously reported, the aniline NH2 group of compound 1
played a critical role in GK activation based on the crystal structure
analysis of GK and 1 complex and the SAR study around the 2-ami-
nobenzamide class.15,21 More specifically, the co-crystal structure
S
S
R1
Me
N
N
HN
HN
N
Me
N
O
S
N
N
R2
N
N
N
6: R2 = 2-(SO2Me)
7: R2 = 2-F
4: R1 = H
5: R1 = Me
8: R2 = 4-F
Figure 3. Design of novel quinazoline leads 4–8.

T. Iino et al. / Bioorg. Med. Chem. Lett. 19 (2009) 5531–5538
5535
Table 2
Profiles of compounds (6–8, 21a–q)
R2
HN
O
R1
N
N
Compd
R1
R2
2.5 mM Glc
10 mM Glc
Log Dc (pH7.4)
Aqueous solubilityd
(lM)
a
b
a
b
EC50
(lM)
Emax
EC50
(lM)
Emax
SO2Me
Me
6
0.23
0.80
0.08
0.73
4.3e
n.t.
N
S
F
Me
7
0.15
1.03
0.53
0.30
0.61
0.48
0.76
0.93
0.05
0.10
0.08
0.06
0.56
0.46
0.76
0.40
5.8e
n.t.
n.t.
2.5
41
N
N
S
Me
8
5.8e
F
S
SO2Me
Me
N
21a
21b
1.9 (3.0e)
N
N
F
Me
N
3.6
F
F
Me
N
21c
21d
0.09
0.14
0.96
0.88
0.03
0.04
0.84
0.88
3.7
1.9
7.2
N
N
F
SO2Me
Me
N
>170
F
SO2Me
Me
N
21e
21f
21g
0.32
0.45
5.1
0.92
1.1
0.08
0.11
0.57
0.90
1.1
2.3
2.1
n.t.
2.8
N
N
N
Cl
SO2Me
Me
N
>170
n.t.
Me
SO2Me
Me
N
0.78
0.68
Me
CN
Me
N
21h
21i
0.07
2.0
0.91
0.74
0.01
0.2
0.85
0.57
3.4
2.1
7.0
N
N
Me
Me
N
>170
N
(continued on next page)

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T. Iino et al. / Bioorg. Med. Chem. Lett. 19 (2009) 5531–5538
Table 2 (continued)
Compd
R1
R2
2.5 mM Glc
10 mM Glc
Log Dc (pH7.4)
Aqueous solubilityd
(lM)
a
b
a
b
EC50
6.1
(
lM)
Emax
EC50
(lM)
Emax
Me
N
N
21j
0.71
0.80
0.53
1.9
140
N
N
N
N
N
N
N
N
N
Me
N
21k
21l
14
0.77
0.84
0.86
0.86
0.36
0.81
2.7
0.81
0.63
0.80
0.80
0.54
0.74
1.7
2.4
2.9
3.4
1.4
1.7
>170
15
N
F
Me
N
0.34
0.21
0.11
11
0.04
0.04
0.02
4.0
N
Cl
Br
Me
N
21m
21n
21o
21p
35
N
N
Me
N
16
CONMe2
Me
N
>170
>170
N
OH
Me
N
1.5
0.15
N
Compound 1 is the internal standard (EC50: 0.42 0.09 and 0.14 0.04).
n.t.: not tested.
a
Values are the means of two or more independent assays.
b
The maximal activating response elicited the compounds as a ratio of the maximal response evoked by 1 at each concentration independently.
c
d
e
Log D value is actually measured using reported method.24
Aqueous solubility is measured in high-speed solubility screening assay using DMSO solutions (values are the means of two independent assays).23
clog P.
potency as well as suitable lipophilicity (log DpH 7.4 = 1.9), whilst
the aqueous solubility was poor (2.5 M). The compound (21c)
had excellent GK activity, although it showed relatively high lipo-
philicity (log DpH 7.4 = 3.7) and low aqueous solubility (7.2 M).
Based on the GKA potency and physicochemical properties of
21a and 21c, a 6-[2-fluoro-6-(methylsulfonyl)phenoxy]quinazo-
line lead (21d) was designed and prepared. This compound
nyl)phenoxy was a well-balanced functional group in terms of
the GKA potency and physicochemical properties. With these data
in hand, we elected to focus further on the SAR study on the 4-sub-
stituent of the quinazoline core. Table 3 highlights the GKA
potency associated with the lipophilicity and aq solubility of the
4-substituted quinazoline leads. The results demonstrated that
21d was one of the well-balanced compounds in this class.
As a representative quinazoline GK activator, further character-
ization of 21d was conducted. The rat PK study revealed that 21d
was orally absorbed and exhibited good oral bioavailability (Table
4). The acute in vivo efficacy of 21d was evaluated in high fat diet
(HFD) mice.17 Administration of a 10 mg/kg oral dose of 21d com-
pared with vehicle alone (0.5% methylcellulose solution) delivered
a statistically significant reduction in plasma glucose levels (Fig. 4).
The glucose lowering effects of 21d was comparable or superior to
that of 2.
In conclusion, we designed and synthesized a novel class of
quinazoline GK activators based on the X-ray analysis data of the
2-aminobenzamide and related GK activators to eliminate the
aniline structure. Subsequent structure–activity relationship
studies of this class were performed with the aim of identifying a
potent and orally active GK activator having a suitable balance of
potency and physicochemical properties, leading to the discovery
of 6-[2-fluoro-6-(methylsulfonyl)phenoxy]-4-(1-methylpyrazol-3-
l
l
retained good GKA potency (EC50 = 0.14
city (log DpH7.4 = 1.9). Furthermore, it was worthy to note that 21d
exhibited an excellent aqueous solubility (>170 M). Replacement
lM) and suitable lipophili-
l
of the fluorine atom in 21d with a methyl group retained the good
aqueous solubility, while replacement of a chlorine atom led to a
dramatic decrease in the aqueous solubility.
Next, a heteroaryloxy group such as a pyridin-2-yloxy-(21i),
pyrazin-2-yloxy-(21j) or pyrimidin-4-yloxy-(21k) was incorpo-
rated in place of the phenoxy to improve the aq solubility. While
these compounds showed excellent aqueous solubility, they had
reduced GKA potencies. Since 21i had the best GKA potency among
these, a halogen atom was incorporated into the 3-position of
pyridine-2-yloxy moiety. The resulting compounds (21l and
21m) resulted in improvement in the GKA potency, while the aq
solubility was deteriorated.
Optimization studies on the 6-substitunet of the quinazoline
core described above indicated that 2-fluoro-6-(methylsulfo-

T. Iino et al. / Bioorg. Med. Chem. Lett. 19 (2009) 5531–5538
5537
Table 3
Profiles of compounds (25a–25h)
R
SO2Me
O
HN
N
N
F
Compd
R
2.5 mM Glc
M)
10 mM Glc
M)
Log Dc (pH7.4)
Aqueous solubilityd
(lM)
a
b
a
b
EC50
0.14
(
l
Emax
EC50
(l
Emax
Me
N
21d
25a
25b
25c
25d
25e
25f
0.88
0.04
0.03
0.04
0.04
0.88
1.9
2.4
1.8
3.1
3.6
2.0
2.2
2.5
n.t.
>170
>170
>170
68
N
Et
N
0.19
0.12
0.11
0.18
8.7
0.85
0.76
1.0
0.75
0.62
1.1
N
N
H
N
Me
N
N
S
N
0.60
0.56
0.87
0.75
0.85
33
0.34
0.25
0.86
0.54
0.87
41
0.24
0.07
0.04
0.95
>170
165
163
n.t.
N
N
N
0.57
0.31
6.1
N
N
Me
Cl
25g
25h
N
N
N
Compound 1 is the internal standard (EC50: 0.42 0.09 and 0.14 0.04).
n.t.: not tested.
a
Values are the means of two or more independent assays.
b
The maximal activating response elicited the compounds as a ratio of the maximal response evoked by 1 at each concentration independently.
c
Log D value is actually measured using reported method.24
Aqueous solubility is measured in high-speed solubility screening assay using DMSO solutions (values are the means of two independent assays).23
d
Table 4
Profiles of the representative quinazoline lead (21d) in SD rats
Me
N
N
N
SO2Me
O
HN
N
F
Compd
AUC0–1
(
lM h)
CLp (mL/min/kg)
T1/2 (h)
Vdss (L/kg)
Cmax
(lM)
Tmax (h)
F (%)
IV (1 mg/kg, 100% PEG)
PO (3 mg/kg, 0.5% MC)
6.3
13.3
6.8
—
1.3
—
0.5
—
—
5.8
—
0.9
—
71
F: oral bioavailability.
PEG: polyethylene glycol 400.
MC: methylcellulose.

5538
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Figure 4. Blood glucose levels of 21d in HFD mice.
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porating substituted aromatic and heteroaromatic rings into the
4- and 6-position of the quinazoline core part. Comparison studies
between 21d and the other types of GK activators such as com-
pounds (2 and 3) in vitro and in vivo are underway.
Acknowledgements
The authors are grateful to Analytical group for the analytical
and spectral studies. We would also like to thank Dr. P. Meinke
and Mr. K. Sato for critical reading of the Letter.
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