A novel series of indazole-/indole-based glucagon receptor antagonists

Article abstract of DOI:10.1016/j.bmcl.2015.08.015

A novel, potent series of glucagon receptor antagonists (GRAs) was discovered. These indazole- and indole-based compounds were designed on an earlier pyrazole-based GRA lead MK-0893. Structure-activity relationship (SAR) studies were focused on the C3 and C6 positions of the indazole core, as well as the benzylic position on the N-1 of indazole. Multiple potent GRAs were identified with excellent in vitro profiles and good pharmacokinetics in rat. Among them, GRA 16d was found to be orally active in blunting glucagon induced glucose excursion in an acute glucagon challenge model in glucagon receptor humanized (hGCGR) mice at 1, 3 and 10 mg/kg (mpk), and significantly lowered acute glucose levels in hGCGR ob/ob mice at 3 mpk dose.

Full text of DOI:10.1016/j.bmcl.2015.08.015

Bioorganic & Medicinal Chemistry Letters xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
A novel series of indazole-/indole-based glucagon receptor
antagonists
⇑
Songnian Lin , Fengqi Zhang, Guoqiang Jiang, Sajjad A. Qureshi, Xiaodong Yang, Gary G. Chicchi,
Laurie Tota, Alka Bansal, Edward Brady, Maria Trujillo, Gino Salituro, Corey Miller, James R. Tata,
Bei B. Zhang, Emma R. Parmee
Early Development and Discovery Science, and Preclinical Development, Merck Research Laboratories, 2015 Galloping Hill Rd, Kenilworth, NJ 07033, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel, potent series of glucagon receptor antagonists (GRAs) was discovered. These indazole- and
indole-based compounds were designed on an earlier pyrazole-based GRA lead MK-0893. Structure–
activity relationship (SAR) studies were focused on the C3 and C6 positions of the indazole core, as well
as the benzylic position on the N-1 of indazole. Multiple potent GRAs were identified with excellent
in vitro profiles and good pharmacokinetics in rat. Among them, GRA 16d was found to be orally active
in blunting glucagon induced glucose excursion in an acute glucagon challenge model in glucagon recep-
tor humanized (hGCGR) mice at 1, 3 and 10 mg/kg (mpk), and significantly lowered acute glucose levels
in hGCGR ob/ob mice at 3 mpk dose.
Received 1 June 2015
Revised 29 July 2015
Accepted 6 August 2015
Available online xxxx
This publication is dedicated to Professor
Iwao Ojima on the occasion of his 70th
birthday
Ó 2015 Elsevier Ltd. All rights reserved.
Keywords:
Glucagon receptor antagonist
Indazole
Indole
Diabetes
Glucose lowering
Type 2 Diabetes Mellitus (T2DM) is a growing worldwide epi-
demic currently affecting an estimated 300 million people.1
Despite a number of diabetic therapies available nowadays, there
remains a significant unmet medical need for additional therapies.2
T2DM is partially characterized by elevated and dysregulated hep-
atic glucose production (HGP). Glucagon is a 29-amino acid pep-
tide that acts as a major counter-regulatory hormone to insulin,
and stimulates gluconeogenesis and glycogenolysis in liver and
thus increasing HGP.3 Studies in type 2 diabetic subjects have
demonstrated a causal role for glucagon in promoting excessive
glucose production.4 An inappropriately high rate of HGP is the
predominant cause of fasting hyperglycemia and a major contrib-
utor to the postprandial hyperglycemia characteristic of T2DM.5
It is therefore postulated that blocking the action of the glucagon
receptor would lead to improved glycemic control in T2DM
patients.6
antagonists (GRAs) as potential treatments for T2DM over the last
two decades.6,7 Clinical data on one of the early GRAs, Bay 27-9955
(1) was reported and an acute effect was observed with the com-
pound in blocking glucagon-induced glucose increase in healthy
volunteers.8 A series of b-alanine acid containing urea based
GRAs such as NNC 25-0926 (2) was later reported by Novo-
Nordisk.9–11 Various scaffold changes replacing the urea core while
keeping the b-alanine moiety by many groups have since been
reported in patent applications7 and literature (e.g., GRA 3 reported
by Pfizer12). Prominent examples of this include several GRA clin-
ical candidates, such as MK-0893 (4, Merck)13 and likely
LY2409021 (Eli Lilly).14
With the continued interest in the area of developing novel
GRAs as a potential treatment for T2DM, we designed a novel series
of GRAs possessing an indazole or an indole/azaindole core (5,
Fig. 1) as intrigued by the presence of a unique 5-naphthylpyrozole
moiety in the core structure of MK-0893. In this Letter, we would
like to discuss the synthesis and the structure–activity relationship
(SAR) studies of this series of GRAs, leading to the identification of
several potent compounds which demonstrated excellent in vitro
and in vivo profiles.
With this, there have been many Letters detailing efforts to
identify both small and large molecule glucagon receptor
⇑
Corresponding author. Tel.: +1 908 740 0585; fax: +1 908 740 3126.
E-mail address: songnian.lin@merck.com (S. Lin).
http://dx.doi.org/10.1016/j.bmcl.2015.08.015
0960-894X/Ó 2015 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Lin, S.; et al. Bioorg. Med. Chem. Lett. (2015), http://dx.doi.org/10.1016/j.bmcl.2015.08.015

2
S. Lin et al. / Bioorg. Med. Chem. Lett. xxx (2015) xxx–xxx
F
Bromination at the benzylic position of 4-alkylbenzoic acids 9 was
HO
OH
achieved with NBS and benzoyl peroxide, and the resulting 10 was
coupled with b-alanine ethyl ester to afford amides 11. Indazoles 8
were then alkylated at the N-1 position with benzylbromides 11 in
the presence of Cs2CO3 in DMF to provide 12. Suzuki couplings of
12 with Ar1B(OH)2 catalyzed by Pd(Ph3P)2Cl2 preferentially at the
3-postion of the indazole (resulted in the partial hydrolysis of ethyl
ester), followed by a second Suzuki coupling with Ar2B(OH)2 at the
5-, 6-, or 7-position of the indazole core under similar conditions
were then performed. The sequential Suzuki couplings provided
desired bis-substituted indazoles 13–16 in moderate to good yields
over two steps. To facilitate the chiral resolution of the racemic
compounds, the acids were converted to methyl esters by simple
treatment with TMSCHN2 in MeOH/THF, and re-hydrolyzed back
to acids after chiral separation.15
To synthesize the 7-azaindole based compound 22, Suzuki cou-
pling of 6-chloro-7-azaindole 17 with 4-CF3O-phenylboronic acid
was carried out in the presence of Pd(dppf)Cl2ÁCH2Cl2 to supply
biaryl 18 in quantitative yield (Scheme 2). Iodination at the C-3
position resulted 3-iodo-7-azaindazole 19. Alkylation of the N-1
position of 19 with bromide 11a, prepared similarly to 11 as shown
in Scheme 1, provide iodide 20 in 82% yield. Suzuki coupling of 20
with 5-trifluoromethyl-2-methoxyphenylboronic acid afforded
tert-butyl ester 21 in high yield, which was hydrolyzed to provide
desired acid 22 after chiral resolution.16
Cl
H
N
O
O
N
OH
N
O
H
Cl
(+)
1
2
NNC 25-0926
Bay 27-9955
F3C
OH
O
H
N
N
N
N
H
O
3
(Pfizer)
Cl
Cl
Ar1
X
Ar2
N
N
Y
N
OH
H
N
R
MeO
O
O
4
5
MK-0893
Figure 1. Structures of several key glucagon receptor antagonists.
Similarly, synthesis of indole-based compound 30 is shown in
Scheme 3. Briefly, 6-bromoindole 23 was alkylated at the N-1 posi-
tion with bromide 24, and the resulting indole 25 was iodinated at
the C-3 position to afford 26. Suzuki coupling of 26 with 5-trifluo-
romethyl-2-methoxyphenylboronic acid afforded methyl eater 27,
which was hydrolyzed to acid 28, and coupled with b-alanine ethyl
ester to provide 29. The second Suzuki coupling of 29 with substi-
tuted phenylboronic acids followed by ester saponification
afforded desired compounds 30.
The synthesis of the indazole-based GRAs is shown in Scheme 1.
Treatment of 5-bromo-, 4-bromo-, or 3-bromo-2-fluorobenzalde-
hydes 6 with methoxyamine in the presence of K2CO3, followed
by refluxing with hydrazine in DME afforded corresponding 5-,
6-, or 7-bromoindazoles 7 in good yields. Iodination of 7 with
iodine/KOH in DMF provided 3-Iodoindazoles 8 in excellent yields.
The compounds thus synthesized were first evaluated in vitro
using both binding and functional assay formats.13 The binding
MeONH2.HCl,
I
O
F
K2CO3, DME,
40 oC;
I2, KOH
DMF, rt
N
H
O
Br
N
Br
O
Br
N
H
H2N-NH2,
reflux
N
F3C
H
B(OH)2
O
76-90%
60-85%
Pd(dppf)Cl2 CH2Cl2,
NaHCO3, DME/H2O, 90 o
quantitiative
6
7
8
N
H
N
N
H
C
Cl
N
F3C
O
18
H2N
OEt
17
O
NBS
EDC, HOBt
DIEA
O
O
OH
BzOOBz
OH
N
H
OtBu
I
R
R
CCl4, reflux
20 min
CH2Cl2, rt
91-100%
R
11a R = n-Pr
Cs2CO3, DMF, 60 oC, 4 h
82%
Br
I2, KOH
Br
N
N
10
9
84-95%
DMF, rt
83%
H
F3C
O
19
I
O
O
N
Br
F3C
OMe
I
N
H
OEt
8
, Cs2CO3
N
OEt
R
B(OH)2
H
DMF, 60 o
2 h
C
N
Pd(dppf)Cl2 CH2Cl2
R
Br
N
O
N
OtBu
H
N
NaHCO3, DME/H2O, 90 o
90%
C
O
F3C
71-87%
12
11
O
O
O
Ar1
20
Ar2
Pd(Ph3P)2Cl2, Ar1-B(OH)2
N
*
F3C
NaHCO3, DME/H2O; 90 o
C
N
OR'
H
N
Pd(Ph3P)2Cl2, Ar2-B(OH)2
R
O
NaHCO3, DME/H2O, 90 o
35-78% (2 steps)
C
OMe
O
13-16
R' = H
TMSCHN2
N
N
OR' 21
R' = t-Bu
H
THF/MeOH (1/1)
i) Chiral HPLC;
ii) NaOH
i) Chiral HPLC;
ii) TFA, CH2Cl2
*
F3C
N
R' = Me
R' = H
O
22
R' = H
O
O
Scheme 1. Synthesis of indazole GRAs 13–16.
Scheme 2. Synthesis of azaindole GRA 22.
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S. Lin et al. / Bioorg. Med. Chem. Lett. xxx (2015) xxx–xxx
3
Table 1
Br
24
SAR on the position of Ar2 on indazole
O
N
Br
OMe
NIS/DMF
F3C
O
60 oC, 4 h
60%
N
H
Br
NaH/DMF, rt, 2 h
68%
OMe
25
23
OMe
5
6
Ar2
N
F3C
N
OH
7
H
N
F3C
OMe
B(OH)2
Pd(dppf)Cl
I
O
OMe
O
2
N
Br
Na CO , DME,
O
2
3
N
Br
Compound
Position
Ar2
hGCGR
binding (nM)
hGCGR
cAMP (nM)
60 oC, 12 h
40%
O
OMe
26
OR'
13a
13b
13c
13d
13e
13f
C-5
C-6
C-7
C-5
C-6
C-7
4-MeO-Ph
4-MeO-Ph
4-MeO-Ph
4-Me-Ph
4-Me-Ph
4-Me-Ph
10
4.0
1700
7.0
2.0
26
11
2700
17
5.0
27
28
R' = Me
R' = H
aq. NaOH
F3C
quantitative
780
3800
OMe
β-Ala-OEt
N
Br
OEt
EDC, HOBt
DIEA, CH Cl
H
N
2
2
Table 2
hGCGR activity of indole-, 7-azaindole-, and indazole-based GRAs
O
78%
O
29
F3C
Ar -B(OH)
Pd(dppf)Cl
1)
2
2
OMe
2
Na CO , DME, 60 oC, 16 h
2
3
Ar2
N
OH
O
H
2) aq. NaOH, MeOH
72-83%
N
O
30
Compound
X/Y
Ar2
hGCGR
hGCGR
binding (nM)
cAMP (nM)
Scheme 3. Synthesis of indole GRA 30.
13b
30aa
13e
30ba
16a
22
N/CH
CH/CH
N/CH
CH/CH
N/CH
CH/N
4-MeO-Ph
4-MeO-Ph
4-Me-Ph
4-Me-Ph
4-CF3O-Ph
4-CF3O-Ph
4.0
8.0
2.0
4.0
1.0
12
11
130
5.0
48
5.6
360
affinity of compounds for the human glucagon receptor (hGCGR)
was determined by their ability to displace [125I] Glucagon from
hGCGR using a membrane preparation from a CHO cell line
expressing the human GCGR (CHO hGCGR). The functional activity
was assessed by the ability of these compounds to inhibit gluca-
gon-induced cAMP production in a cell line expressing hGCGR.
Both binding and functional activities are expressed as values of
IC50. All data reported are from the more active enantiomers tested
unless otherwise noted.
Based on the structure homology of MK-0893 and indazole
GRAs designed, it is obvious that the C-3 aryl (Ar1) of 5 is critical
for the activity against the hGCGR. However, it is not as clear as
to where the second aryl substituent (Ar2) should be placed on
the indazole ring. We therefore set out to compare all C-5, C-6,
and C-7 positions of indazole. As shown in Table 1, we were
pleased to find that all indazole-based GRAs were active in vitro
against the hGCGR. However, it is clear from the SAR that C-7 is
the least preferred position for the second aryl substitution (13c
and 13f). While both C-5 and C-6 afforded GRAs with potent activ-
ity, C-6 position seems to be more preferred with an edge over C-5
position (13b vs 13a, and 13e vs 13d).
With the identification of the C-6 position being the preferred
position for the 2nd aryl substitution, we set out to find out how
the indazole core compared to other 6/5 ring systems such as
indole or azaindole (Table 2). Interestingly, while head to head
comparison of C-3/C-6 substituted indazoles with corresponding
indoles showed very similar activity in binding to the hGCGR,
indoles exhibited ca. 5-fold weaker potency in the cAMP functional
assay (13b vs 30a, and 13e vs 30b). Indazole 16a was found to be a
very potent GRA in both binding assay (IC50 = 1 nM) and cAMP
functional assay (IC50 = 5.6 nM). However, moving the nitrogen at
a
Compounds were tested as a racemic mixture.
indazole 2 position to 7 position, in another word, replacement
of indazole core of 16a with a 7-azaindole core, resulted in signif-
icant loss of hGCGR activity (binding IC50 = 12 nM, cAMP
IC50 = 360 nM for 7-azaindole indole 22). Obviously, the indazole
core is the most preferred scaffold for hGCGR activity among the
three heterocycles studied.
Aryl substitution on the C-3 position of indazole was then
examined for their hGCGR activity (Table 3). In general, most of
the aryl groups, including substituted phenyl, pyridinyl, or
pyrimidinyl groups, are tolerated. Evidently, phenyl groups substi-
tuted with simple halides, a methoxyl group, or a trifluoromethyl
group is more likely to provide GRAs with good potency (14a–f,
and 14l–m). A polar substitution on the phenyl group is usually
less preferred (14g, 14p, and 14q), and often resulted in weaker
functional activity (14g and 14q). Similarly, placement of substi-
tuted pyridines (14h–k) and pyrimidine (14r) generally afforded
compounds with weaker hGCGR activity. Not surprisingly, 14a,
an analog of 16a with a 1-MeO-4-CF3O-phen-2-yl group at C-3
position, exhibited best functional activity (cAMP IC50 = 11 nM)
among all aryl groups tested, and excellent binding activity
(IC50 = 7.0 nM).
The 1-MeO-4-CF3O-phen-2-yl group was then selected for the
C-3 position when we investigated the aryl substituents at the
C-6 position of indazole. As shown in Table 4, C-6 position seems
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4
S. Lin et al. / Bioorg. Med. Chem. Lett. xxx (2015) xxx–xxx
Table 3
Table 5
SAR on the C-3 position of indazole
SAR on the N-1 benzylic position of indazole
F3C
Ar1
N
N
OMe
OH
H
N
N
F3CO
O
N
OH
H
N
O
Me
R
O
Ar1
hGCGR
hGCGR
O
Compound
binding (nM)
cAMP (nM)
Compound
R
hGCGR binding (nM)
hGCGR cAMP (nM)
14a
14b
14c
14d
14e
14f
14g
14h
14i
14j
14k
14l
14m
14n
14o
14p
14q
14r
1-MeO-4-CF3O-Ph-2-yl
1-MeO-4-Cl-Ph-2-yl
1-MeO-4,5-diF-Ph-2-yl
1-F-4-CF3-Ph-2-yl
1-Cl-4-F-Ph-2-yl
1,2,5-TriF-Ph-3-yl
1-NH2CO-4-Cl-Ph-2-yl
4-MeO-pyridine-3-yl
3-MeO-pyridine-5-yl
2-MeO-pyridine-5-yl
2-MeO-pyridine-3-yl
2,4-DiCl-Ph
3-Cl-5-CF3-Ph
3-F-4-Cl-Ph
3,4,5-TriF-Ph
4-CN-Ph
4-(Me2N)CO-Ph
2-MeO-pyrimidine-4-yl
7.0
3.0
4.0
5.0
10
7.0
2.0
110
50
11
36
37
120
140
52
220
760
100
65
77
41
56
44
20
43
210
84
15b
16b
13e
16c
16d
16e
n-Butyl
i-Propyl
n-Propyl
Ethyl
Methyl
H
2.6
4.0
2.0
4.0
2.6
39
6.6
69
5.0
21
7.6
140
26
72
Table 6
hGIP cAMP activity of selected compounds
8.0
3.0
4.0
6.0
15
Compound
hGCGR cAMP (nM)
hGIPR cAMP (nM)
hGIPR/hGCGR
15a
15b
15g
16a
16d
14
1100
1000
750
1400
1300
79
150
94
250
170
6.6
8.0
5.6
7.6
40
35
Table 4
Table 7
Rat pharmacokinetic profiles of selected compoundsa
SAR on the C-6 position of indazole
F3C
Compound
Clp
(mL/min/Kg)
Vdss
(L/Kg)
t1/2
(h)
AUCN
MÁhÁKg/mg)
F (%)
(l
15a
15b
15g
16a
16d
1.7
3.9
7.5
2.2
6.3
0.67
1.0
0.72
1.3
6.4
4.0
4.7
9.7
1.5
4.0
1.2
0.30
2.0
2.0
27
17
9.0
19
44
OMe
N
Ar2
N
OH
H
N
0.65
O
O
a
Wistar rats dosed at 0.5 mg/kg iv and 2 mg/kg po. Clp, plasma clearance; Vdss,
volume of distribution at steady state; T1/2, half-life; AUCN, dose normalized area
under the plasma concentration versus time curve; F, oral bioavailability.
Compound
Ar2
hGCGR
hGCGR
binding (nM)
cAMP (nM)
15a
15b
15c
15d
15e
15f
15g
15h
15i
4-MeO-Ph
4-Me-Ph
4-MeS-Ph
phenyl
2-Cl-4-MeO-Ph
3-F-4-MeO-Ph
4-CF3O-Ph
4-CF3-Ph
2-MeO-pyridine-5-yl
3-F-5-Cl-Ph
1.9
2.6
1.5
3.0
4.0
1.5
0.8
1.6
3.4
7.0
4.0
3.5
14
6.6
9.0
18
18
18
8.0
14
24
46
18
26
hGCGR activity (16e, binding IC50 = 39 nM, cAMP IC50 = 140 nM).
This is consistent with the findings on the pyrazole-based GRAs
exemplified by MK-0893.13 Although there is no clear difference
among small alkyl groups investigated for the hGCGR binding
activity (binding IC50 = 2-4 nM), their cAMP functional activity sug-
gested that a n-butyl, n-propyl, and methyl group (15b, 13e, and
16d, cAMP IC50 = 6.6, 5.0, and 8.0 nM, respectively), is more pre-
ferred than an isopropyl or ethyl group (16b and 16c, cAMP
IC50 = 69 and 21 nM, respectively).
15j
15k
15l
5-Me-thiophen-2-yl
3,4,5-TriF-Ph
As the pyrazole-based GRAs were often found not to be highly
selective against human glucose dependent insulinotropic peptide
receptor (hGIPR), one of other class B GPCR’s,13 selected com-
pounds were screened in hGIPR cAMP assay to verify selectivity
of this series of GRAs. A compound’s hGIPR cAMP potency was
determined in CHO cells expressing human GIPR, measuring
cAMP production. As shown in Table 6, these indazole based
GRAs were found to be generally very selective against hGIPR, with
selectivity ranging from 79- to 250-fold.
Based on their favorable in vitro profiles, several compounds
were chosen for in vivo pharmacokinetic characterization in rat.
The pharmacokinetic parameters are summarized in Table 7. All
compounds studied exhibited relatively low clearance, and moder-
ate to long half-lives (1.5–9.7 h). Oral dosing of these compounds
to be more tolerant than the C-3 position, as all the aryl groups
examined exhibited potent hGCGR activity. Interestingly, even
methoxypyridinyl group (15i, binding IC50 = 3.4 nM), which is not
well tolerated in C-3 position (14j, binding IC50 = 26 nM), is well
accepted. 4-Methoxyphenyl (15a, binding IC50 = 1.9 nM), 4-
methylphenyl (15b, binding IC50 = 2.6 nM), and 4-trifluo-
romethylphenyl (15g, binding IC50 = 0.8 nM) groups, are among
the most preferred aryl groups identified at the C-6 position.
Our attention was then focused on the N-1 benzylic position of
indazole. As Table 5 shows, a small alkyl group at this position is
clearly preferred, as no substitution resulted in much weaker
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S. Lin et al. / Bioorg. Med. Chem. Lett. xxx (2015) xxx–xxx
5
Vehicle
Glucagon
Glucagon + 16d @ 10 mpk
Glucagon + 16d @ 3 mpk
Glucagon + 16d @ 1 mpk
GRA 16d was found to be orally active in blunting glucagon
induced glucose excursion in an acute glucagon challenge model
in hGCGR mice at doses as low as 1 mpk, and significantly lowered
acute glucose levels in hGCGR ob/ob mice at 3 mpk dose. Further
evaluations of these exciting new GRAs are underway and will be
reported in due course.
90
80
70
60
50
40
30
20
10
0
Acknowledgments
We thank Drs. Yusheng Xiong, James Mu, Ester Carballo-Jane,
and Ravi Nargund for their assistance and helpful discussion dur-
ing the preparation of the manuscript.
0
12
24
36
48
Time (min)
Supplementary data
Figure 2. Effect of compound 16d in acute glucagon-induced glucose levels in
hGCGR mice. Data represents mean SEM (n = 8À10).
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.bmcl.2015.08.
015. These data include MOL files and InChiKeys of the most
important compounds described in this article.
50
veh
16d @ 3.0 mpk
0
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***
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15. Enantiomers were separated by ChiralPack Column IA or IB, using heptane/IPA
(8–15%) as the eluents.
Time [h]
cpd dosed
Figure 3. Acute effect of compound 16d in ambient glucose in the hGCGR ob/ob
mice (N = 10–12 mice in each group). Compound was dosed orally at 0 h and food
was removed at 0 h. **p <0.01 and ***p <0.001 relative to control group at each time
point.
in rat also found them to possess good exposure and low/moderate
to good bioavailability (9–44%), consistent with their low
clearance.
Encouraged by these desired in vitro profile and pharmacoki-
netic properties, we studied compound 16d in an acute glucagon
challenge model in glucagon receptor humanized (hGCGR) mice.17
As shown in Fig. 2, compound 16d was found to be active in blunt-
ing glucagon-induced glucose excursion when dosed orally at 1, 3,
and 10 mg/kg (mpk) one hour prior to a glucagon challenge (IP, 15
l
g/kg). The drug levels at 60 min were found to be 0.18, 0.50, and
2.54 M for 1, 3, and 10 mpk dose groups, respectively.
l
Compound 16d was further evaluated for its efficacy in glucose
lowering in a hGCGR ob/ob mice13 in an acute model as shown in
Fig. 3. Compared to vehicle control group, compound 16d at 3 mpk
oral doses lowered blood glucose level significantly at all the time
points checked during the 6 h post treatment monitoring, high-
lighting the excellent efficacy of compound 16d in this ob/ob mice
model. The drug levels at 1, 3, and 6 h were found to be 0.40, 0.28,
and 0.12 lM, respectively.
In summary, a novel series of indazole- and indole-based com-
pounds was designed based on an earlier pyrazole-based GRA lead
MK-0893 and synthesized. Structure–activity relationship studies
of this series of compounds focused on the C3 and C6 positions
of the indazole core, as well as the benzylic position on the N-1
of indazole. Multiple potent GRAs were identified with excellent
in vitro profiles and good pharmacokinetics in rat. Among them,
16. Enantiomers of racemic 21 were separated by chiralPak OD-H column, using
7% IPA in heptane as eluent.
17. Qureshi, S. A.; Candelore, M. R.; Xie, D.; Yang, X.; Tota, L. M.; Ding, V. D.; Li, Z.;
Bansal, A.; Miller, C.; Cohen, S. M.; Jiang, G.; Brady, E.; Saperstein, R.; Duffy, J. L.;
Tata, J. R.; Chapman, K. T.; Moller, E. D.; Zhang, B. B. Diabetes 2004, 53, 3267.
Please cite this article in press as: Lin, S.; et al. Bioorg. Med. Chem. Lett. (2015), http://dx.doi.org/10.1016/j.bmcl.2015.08.015