Discovery of BR102375, a new class of non-TZD PPARγ full agonist for the treatment of type 2 diabetes

Article abstract of DOI:10.1016/j.bmcl.2019.06.027

As a potential treatment of type 2 diabetes, a novel PPARγ non-TZD full agonist, compound 18 (BR102375) was identified from the original lead BR101549 by the SAR efforts of the labile metabolite control through bioisosteres approach. In vitro assessments

Full text of DOI:10.1016/j.bmcl.2019.06.027

Bioorganic&MedicinalChemistryLettersxxx(xxxx)xxx–xxx
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Discovery of BR102375, a new class of non-TZD PPARγ full agonist for the
treatment of type 2 diabetes
Wonken Chounga, Deokmo Yanga, Hakdo Kima, Hyukjoon Choia, Bo Ram Leea, Min Parka,
Su Min Janga, Jae Soo Lima, Woo Sik Kima, Kyung-Hee Kimb, Jungwook Chinb, Kyungjin Jungb,
Geumwoo Leeb, Eunmi Hongb, Tae-ho Jangb, Jeongmin Joob, Hayoung Hwangb,
⁎
Jayhyuk Myunga, Seong Heon Kima,
a Central Research Center, Boryung Pharmaceuticals Co. Ltd., Republic of Korea
b New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation (DGMIF), Republic of Korea
A R T I C L E I N F O
A B S T R A C T
Keywords:
As a potential treatment of type 2 diabetes, a novel PPARγ non-TZD full agonist, compound 18 (BR102375) was
identified from the original lead BR101549 by the SAR efforts of the labile metabolite control through bioi-
sosteres approach. In vitro assessments of BR102375 demonstrated its activating potential of PPARγ comparable
to Pioglitazone as well as the induction of related gene expressions. Further in vivo evaluation of BR102375 in
diabetic rodent models successfully proved its glucose lowering effect as a potential antidiabetic agent, but the
anticipated suppression of weight gain was not evident. The X-ray co-crystal analysis of BR102375-PPARγ LBD
unexpectedly revealed binding modes totally different from those of BR101549, which was found, instead,
closely resembled to those of TZD full agonists.
Drug discovery
Antidiabetics
PPARγ agonist
Non-TZD full agonist
Since aging population has grown rapidly, the adequate control of
chronic diseases has become major concern for the entire society not
only to meet the needs of the aging population, but also to keep the
potential economic burden from the medical expense as low as af-
fordable. As a major culprit to threat the normal life style of, in parti-
cular, the senior population, the prevalence of diabetes has risen ra-
pidly and it is reported to be the seventh leading cause of death in
2030.1 Type 2 diabetes is a chronic disease of impaired blood glucose
control either by insufficient secretion of insulin from the pancreatic
beta-cells or decreased insulin sensitivity.2 More seriously, type 2 dia-
betes also enables onset of scores of devastating complications in-
cluding cardiovascular disease,3 chronic kidney disease, stroke and
blindness.4 Besides the tremendous efforts to promote the life style to
prevent the disease, the relentless efforts to expand the treatment op-
tions of type 2 diabetes still have been listed high priority in drug
discovery research.
known PPARγ full agonists to this date are based on common scaffold
called thiazolidinedione (TZD) which was deemed to contribute to the
characteristic binding modes critical to draw the full effect of the pro-
tein.6 However, the concerns from the toxicities unleashed in clinical
application limited their therapeutic use by the Black Box Warning
label or market withdrawal. To avoid the side effects suspected to be
ascribed to the transcriptions caused by full agonism of TZD scaffold,
studies to identify non-TZD PPARγ agonists produced a few promising
candidates with partial agonism. Despite their weaker transcriptional
activation, the selective PPARγ modulators (SPPARMs) indeed showed
efficacy in animal models with even less adverse effects culminating in
progress into clinical trials. However, partial agonism of PPARγ was
eventually demonstrated not enough to show efficacy in the clinical
settings and currently none of the non-TZD PPARγ agonists has
achieved FDA approval.7
In our previous studies8,9 to find additional therapeutic indications
as part of the “Value Expansion” efforts of our original anti-hyperten-
sive ARB (angiotensin receptor blocker) Fimasartan (brand name: Ka-
narb) which has been approved by Korean FDA in 2010, a potent PPARγ
agonist (BR101549) has been identified (Fig. 1). Due to its ester moiety,
BR101549 proved itself metabolically unstable releasing the corre-
sponding carboxylic acid which was suspected to be further
Among the many biological targets for the treatment of type 2
diabetes explored hitherto, a nuclear receptor peroxisome proliferator-
activated receptorγ (PPARγ) could be listed as one of the most suc-
cessful targets for which various effective modulators have been de-
veloped. Despite the target relevant adverse effects, some of them such
as Rosiglitazone and Pioglitazone could reach the market.5 All of the
⁎ Corresponding author.
E-mail address: rose1998@boryung.co.kr (S.H. Kim).
https://doi.org/10.1016/j.bmcl.2019.06.027
Received 12 February 2019; Received in revised form 14 June 2019; Accepted 19 June 2019
0960-894X/©2019ElsevierLtd.Allrightsreserved.
Pleasecitethisarticleas:WonkenChoung,etal.,Bioorganic&MedicinalChemistryLetters,https://doi.org/10.1016/j.bmcl.2019.06.027

W. Choung, et al.
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Fig. 1. Major metabolites of BR101549 and the bioisosteres approach.
metabolized toward potentially toxic reactive acyl glucuronide. A series
of Met ID studies indeed demonstrated the formation of acyl glucur-
onide from the carboxylic acid metabolite. To overcome the liability,
SAR efforts were first focused on modification of ester alkyls hoping to
suppress the degradation by sterically bulkier alkyl groups. Though
there appeared some improved results, the intrinsic tendency prone to
hydrolysis to the carboxylic acid seemed inevitable and subsequently
the concern of toxic acyl glucuronide formation prohibited further ex-
ploration of the ester series. As an alternative and perhaps more reliable
option to avoid the reactive acyl glucuronide formation, while main-
taining the encouraging PPARγ activity of the ester derivatives, appli-
cation of bioisosteres for ester functionality was explored.
Table 1
Comparison of PPARγ activation of 5-ring heteroaromatics.
Ar
Comp. No R1
R2
Amax of PPARγ vs.
Telmisartan (%)†
5-Ring heteroaromatics have been used in a wide range of appli-
cations in medicinal chemistry to provide solutions of the issues faced
in various discovery programs.10 Among those applications, they have
often proved themselves successful as bioisosteres of ester moiety
mainly to avoid rapid hydrolysis, which attracted us to explore 5-ring
heteroaromatics as a surrogate of ester functionality of BR101549. As
shown in Fig. 1, a total of six 5-ring heteroaromatics containing three
heteroatoms have been selected and assessed for the transcriptional
activation of PPARγ relative to the partial agonist Telmisartan.11,12 For
the comparison of relative transcriptional effects, a few derivatives with
representative alkyl substitutions were prepared for each series of 5-
ring heteroaromatics.
4
5
isopropyl methyl
79
93
methyl
methyl
6
7
methyl
methyl
methyl
61
71
4-fluorophenyl
8
9
isopropyl methyl
80
isopropyl 4-methoxyphenyl 73
10
11
12
isopropyl methyl
methyl methyl
isopropyl t-butyl
79
As summarized in Table 1, 1,2,4-thiadiazoles, A (compounds 4–5),
1,3,4-triazoles, B (compounds 6–7), 1,3,4-oxadiazoles, C (compounds
8–9), and 1,3,4-thiadiazoles, D (compounds 10–11) demonstrated re-
latively weak activation versus Telmisartan regardless of substituents
on R1 (methyl, isopropyl) and R2 (methyl, 4-fluorophenyl, 4-methox-
yphenyl) with the exception of compound 12 (R2 = t-Bu). Since com-
pound 12 containing sterically demanding t-butyl group on R2 un-
leashed exceptional activity, bulkier groups such as t-butyl and
isopropyl have been applied to the next heteoaromatic motif, 1,2,4-
71
180
13
14
15
methyl
methyl
methyl
t-butyl
258
233
150
207
136
331
isopropyl
2-fluorophenyl
16
17
18
isopropyl methyl
methyl
methyl
methyl
t-butyl
†
The Amax value is a percentage value calculated relative to Telmisartan.
2

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Table 4
Table 2
Oral rodent PK of compounds 18 and 19.
Activation of PPARγ with 1,2,4-oxadiazole derivatives.
Comp. No. Species (10 mpk) t1/2 (h) Tmax (h) Cmax (ng/mL)
AUClast
(ng·h/mL)
18
19
Rat
1.78
1.18
0.82
0.30
0.33
0.33
1318
949
889
584
581
Mouse
Mouse
547
group was fixed to methyl and isopropyl and the agonist potential was
measured as a ratio of activation versus Pioglitazone, a TZD full agonist
(Table 2). As expected from the results shown in Table 1, compounds 16
and 18 indeed enabled to activate PPARγ to the level of Pioglitazone
(93% and 98%, respectively). However, they disclosed more than 3-fold
difference of potency, EC50, as compound 18 revealed excellent EC50
value of 0.28 μM versus 1.05 μM of compound 16. Subsequent R1 re-
placement of methyl in compound 18 by isopropyl improved Amax in ca.
30% but with compromised EC50 of 0.59 μM (2-fold decrease) (com-
pound 19). On the contrary to the t-butyl (R2) series (compounds 18 vs
19), the other examples including the compounds 20–25 containing
cyclopropyl, benzyl, and 4-fluorobenzyl groups on R2 clearly demon-
strated the positive effects of bulkier R1 (isopropyl) on EC50s, though
the effects were found overall weaker than the t-butyl analogs. Re-
garding PPARγ activation, unlike the EC50s, the series of compounds
were unable to disclose clear SAR tendency with the exception of 4-
fluorobenzyl derivatives which showed relatively weaker activation
potential (compounds 24–25). Continued tendency of weaker activa-
tion of 4-fluorobenzyl derivatives was also observed in the other elec-
tron deficient fluorobenzyl derivatives such as 3-fluorobenzyl and 3,5-
difluorobenzyl compounds, 27 and 28, respectively. Despite the cross
substitutions of R1 and R2 relative to compound 16, compound 26 re-
mained its decent EC50 and Amax values similar to compound 16. Ad-
ditional hydrogen bonding acceptor represented by the ether func-
tionalities of compounds 29 and 30 was not found beneficial to EC50s as
well as activation potentials. Overall, the potency (EC50) seemed im-
proved when R1 is isopropyl versus methyl while no such tendency was
observed on the efficacy (Amax). In terms of R2 variations, alkyls, par-
ticularly branched ones proved their beneficial effects not only to the
Amax but to the EC50 as well. Largely based on the submicromolar po-
tencies as well as high activation potentials, compounds 18
(EC50 = 0.28 μM, Amax ratio = 98%) and 19 (EC50 = 0.59 μM, Amax
ratio = 123%) were selected to proceed for further evaluation.
Comp. No R1
R2
EC50
Amax of PPARγ vs.
Pioglitazone (%)†,‡
(μM)†
16
18
19
20
21
22
23
24
25
26
27
28
29
30
isopropyl methyl
methyl t-butyl
1.05
0.28
0.59
4.25
2.55
1.75
1.14
2.41
1.48
1.32
1.39
93
98
isopropyl t-butyl
123
89
methyl
cyclopropyl
isopropyl cyclopropyl
102
105
92
methyl
benzyl
isopropyl benzyl
methyl
4-fluorobenzyl
81
isopropyl 4-fluorobenzyl
80
methyl
methyl
methyl
methyl
methyl
isopropyl
101
82
3-fluorobenzyl
3,5-di-fluorobenzyl 1.38
72
methoxyethyl
4.21
3.39
68
methoxymethyl
60
†
EC50 and Amax were obtained through reporter gene analysis by measuring
concentration dependent luciferase induction in cell lines (Indigo USA) trans-
fected with PPRE and luciferase genes.
‡
The Amax value is a percentage value calculated relative to Pioglitazone.
oxadiazole, E (Fig. 1). As expected, compounds 13 and 14 disclosed
excellent activation effects measured as Amax ratios of 258% and 233%,
respectively. Even aromatic substitution on R2 with 2-fluorophenyl re-
vealed Amax ratio of 150% which is definitely superior to the similar
analogs of other heteroaromatic series (compounds 7 and 9). The en-
couraging results of 1,2,4-oxadiazole (E) spontaneously led us to exploit
the reversed 1,2,4-oxadiazole (F) relative to the substitution pattern of
R1 and R2. Indeed, even the subtle variation explicitly revealed the
superior effects of reversed 1,2,4-oxadiazole (F) motif on PPARγ acti-
vation. Comparison of compound 16 (R2 = Me, Amax ratio = 207%)
and compound 18 (R2 = t-butyl, Amax ratio = 331%) to the derivatives
with same substituents on R1 and R2 in other heteroaromatic series
clearly demonstrated the enhanced effect of the reversed 1,2,4-ox-
adiazole (F) motif. As such, the comparison of PPARγ activation among
various 5-ring heteroaromatics apparently revealed superior activity of
1,2,4-oxadiazoles over the others. In particular, the series of 1,2,4-ox-
adiazole isomer F which seemed more potent than isomer E was chosen
for further SAR evaluation. The potency improvement caused by the
subtle configurational change derived by mutual exchange of hetero
atoms (N and O) in isomer F was intrigued but found inexplicable via
docking analysis.
Further in vitro profiling (Table 3) and in vivo PK (Table 4) eva-
luation of compounds 18 and 19 revealed their similar properties in
terms of CYP inhibitions, liver microsomal stabilities, and mouse PK,
which were predictable from the similarity of the molecular structures.
Compound 18 could maintain its edge to the compound 19 in the field
of hERG inhibition. The fact that both compounds had unexpectedly
low liver microsomal stabilities, particularly in rodent models, at least,
seemed to have plausible correlation with the modest plasma exposure
levels (Table 4) suggesting a tip helping to improve the poor exposure
in later SAR attempts. Mostly due to the advantage in hERG profile
(8.3% inhibition at 10 μM) versus compound 19 (16% inhibition at
10 μM), compound 18 was selected to proceed for further in vivo effi-
cacy studies to complete proof-of-concept (POC) evaluation. Although
Based on the results in Table 1 and our previous report,9 the R1
Table 3
In vitro profiling of compounds 18 and 19.
Comp. No
hERG (%)†
Microsomal stability (% remaining @30 min)
CYP inhibition (% remain activity @10uM)
M
R
D
H
1A2
2C9
2C19
2D6
3A4
18
19
8.3
16
11
24
12
13
11
13
17
12
88
92
57
33
84
78
93
89
64
50
†
% inhibition at 10 μM.
3

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Fig. 2. Effects of compound 18 (BR102375) on mRNA expressions, glucose uptake, and adipocyte differentiation. (for experimental details, see Supporting
Information)
the poor microsomal stability profiles and relatively low plasma con-
centrations were among concerns, the experiment was supported by the
reasoning that higher dosage would enable to provide exposure cov-
erage enough to show efficacious effect in comparison to the reference
agent, Pioglitazone, for the purpose of POC.
stimulated by insulin (Fig. 2B).15 Furthermore, the evaluation of PPARγ
adipogenic capacity inducible by BR102375 has proved its concentra-
tion-dependent, insulin-sensitive effects on adipogenesis, which was
found similar to the effect of Pioglitazone as evidenced in Fig. 2C.16 In
light of the cell based assessments carried out, it was inferred that
BR102375 would be possibly a full agonist of PPARγ with comparable
activation potential as Pioglitazone (Amax ratio = 98% of Pioglitazone,
Table 2).
Prior to the in vivo experiments, compound 18 (BR102375) was also
evaluated in cell-based studies13 with Pioglitazone as a reference
compound. The gene expression levels relevant to PPARγ activation
including AP2 and CD36 were indeed found significantly increased
compared to the control, almost reaching to the level of full agonist,
Pioglitazone (Fig. 2A).14 In the study of insulin sensitizing potential of
BR102375, the cell (3T3 L1 adipocyte) treated with BR102375 (10 μM)
revealed enhanced glucose uptake comparable to Pioglitazone when
The anti-diabetic efficacy of compound 18 (BR102375) was as-
sessed in genetically induced db/db mouse diabetes models.17 In the
14-day BID study,18 compound 18 (BR102375) (75 mpk, p.o., bid) has
revealed significant suppressive effect on random blood glucose in-
crease comparable to the effect of Pioglitazone (30 mpk, p.o., qd)
4

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Fig. 3. In vivo efficacy study of compound 18 (BR102375) in db/db mouse model (75 mpk, bid, n = 9): A) Blood glucose lowering effect, B) Body weight increase, C)
Oral glucose tolerance test (measured on day 14), D) Food intake (measured on day 7), (PGZ = Pioglitazone).
(Fig. 3A). In addition to the effect on glucose, compound 18
(BR102375) also disclosed similar findings in body weight gain with
Pioglitazone on day 14 (Fig. 3B). Oral glucose tolerance test (OGTT) on
day 14 also revealed decent effect of compound 18 (BR102375) on
insulin resistance almost identical to Pioglitazone (Fig. 3C). On the
other hand, the amount of food intake was found slightly diminished,
however, which was not deemed significant enough to unleash a con-
cern of potential toxic signal (Fig. 3D). The 2-week study indeed de-
monstrated the decent efficacy of BR102375 on mouse diabetes models,
however the failure to suppress the body weight gain was disappointing
in light of our proposed rational to leverage it as a distinguishable point
from TZD drugs to overcome their clinical unmet need, as was discussed
in our previous study.9 The original lead BR101549 (Fig. 1) exhibited
enhanced activation of PPARγ and animal efficacy with decent sup-
pression of weight gain versus Pioglitazone.
enabling interactions with Tyr473 and His449, the key H-bonding in-
teractions of TZD motif of TZD full agonists stabilizing AF2 residues.
The t-butyl 1,2,4-oxadiazole motif is seemed to occupy the opposite
site, where the oxadiazoledione of BR101549 was known to bind,
perching on the helix-5 by hydrophobic interactions with Ile330,
Ile326, and Met329 residues. No additional H-bonding interactions of
the heteroatoms in the 1,2,4-oxadiazole ring were identified. Although
it doesn’t seem to be significant, the butyl branch of pyrimidinone ring
seems approaching helix-6 to generate another hydrophobic interaction
with M364 residue. Indeed, it was unexpected that the oxadiazoledione
motifs in BR102375 and BR101549 were observed stabilizing com-
pletely different parts of the LBD and induced their discrete char-
acteristic modes of binding (Fig. 4B). Although it’s not verifiable yet, it
might be inferred that the sterically bulkier t-butyl moiety on 1,2,4-
oxadiazole of BR102375 versus relatively small ethyl ester of
BR101549, was unable to fit into the pocket formed by helix-6 and
helix-3. Instead, the t-butyl-1,2,4-oxadiazole could participate in the
other side hydrophobic stabilization process which might be further
facilitated by the interactions between the oxadiazoledione and Tyr473
and His449 of helix 12.
In order to further interrogate the mechanism behind the enhanced
activation potential of PPARγ, BR102375 has been subjected to co-
crystal formation with PPARγ ligand binding domain (LBD) and the X-
ray crystallography analysis. The study revealed, to our surprise, a to-
tally different pattern of binding mode of BR102375 in the LBD stabi-
lization from that of the precursor BR101549 (Fig. 4). On the contrary
to BR101549, BR102375 in PPARγ LBD explicitly showed the strong
interaction of its oxadiazoledione motif with the Tyr473 on helix 12
which has been widely recognized as a characteristic of full agonists
enabling enhanced PPARγ activation.19 The binding of BR102375
seems to be forked three-way with the pyrimidineone as a pivot aligned
along the helix 3 (Fig. 4A). Most prominently, the oxadiazoledione
motif is, through the biphenyl linker, projected toward the helix 12
All the compounds enlisted in Tables 1 and 2 have been prepared
according to the routes summarized in Scheme 1. Compounds con-
taining heterocyclic motifs, B,C,D and F were prepared in 2–3 steps
from the carboxylic acids 35 obtained by hydrolysis of the corre-
sponding esters 34 whose syntheses have been reported in our previous
publication8. The acids 35 were converted to the desired 1,2,4-ox-
adiazole system F derivatives by refluxing with SOCl2 in pyridine in the
presence of hydroxylamidines 33 with varied R2, which were prepared
5

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Fig. 4. A) Crystal structure of PPARγ ligand binding domain (LBD, in sky blue cartoon) with BR102375 (sticks colored orange) in the presence of SRC-1 coactivator
peptide, and its zoomed in view showing interacting residues. B) Overall structure of BR102375 (in orange) in the PPARγ LBD (in white cartoon). BR101549 (in
yellow) and Rosiglitazone (in magenta) are superimposed on the structure. (PDB ID 6ICJ, Diffraction resolution: 2.48 Å).
from the corresponding nitriles 31. Conversion of nitriles 31 into the
amidines 32 was achieved by the treatment of trimethylaluminum and
NH4Cl in toluene at room temperature. Coupling of resulting amidines
32 with the acids 35 using DIPEA and HBTU in DMF followed by cy-
clization with hydrazine gave the desired triazole compounds 6 and 7.
The acid intermediates 35 were also reacted with the acylhydrazines
with varied R2 to provide the corresponding acylhydrazide derivatives
36 which were cyclized with Lawesson’s reagent in THF when heated to
70 °C resulting in the 1,3,4-thiadiazole derivatives 10–12. The oxygen
analogs, 1,3,4-oxadiazoles 8 and 9 could be obtained by the reaction of
the acylhydrazides 36 with POCl3 in refluxing toluene. For the synthesis
of 1,2,4-thiadiazole derivatives 4 and 5, the thioamide intermediates 38
prepared from the esters 34 by the sequence of amide formation and
thiolation reacted with DMF-DMA in MeOH affording the thioacyla-
midine derivatives 39, which were next cyclized in the presence of
hydroxylamine and acetic acid in dioxane at 90 °C.20 Another 1,2,4-
oxadiazole isomer ring system E including compounds 13–15 was in-
stalled by the cyclization of the acyloxyamidine intermediate 41 pre-
pared from the ester 34 in 4 steps. Amination of 34 by treatment with
ammonia water, followed by POCl3 induced dehydration gave the de-
sired nitriles 40, which were converted to acyloxylamidines in two
steps via hydroxylamines including aqueous hydroxylamine refluxing
and coupling with the R2-carboxylic acids under EDCI-HOBt condition.
The final cyclization by refluxing with K2CO3 in toluene provided the
derivatives containing 1,2,4-oxadiazole isomer E.21
In summary, a new class of non-TZD PPARγ full agonist, BR102375
(compound 18), has been identified through the efforts to overcome
potential reactive metabolites formation by successfully replacing the
metabolically labile ester moiety of BR101549 with its bioisostere,
1,2,4-oxadiazole motif. BR102375 has exhibited excellent potency in
terms of EC50 and Amax, in particular, the activation potential of the
protein was found comparable to the full agonist, Pioglitazone, which
was further evidenced by the mRNA expression patterns and the char-
acteristic binding interactions uncovered by the X-ray co-crystal ana-
lysis. Despite its relatively undesired mouse PK exposure, BR102375
was found efficacious in preclinical diabetic mouse models when as-
sessed in high-dose oral settings. However the beneficial effect of effi-
cacy was compromised by absence of the anticipated effect of sup-
pressing body weight gain, which could be ascribed to the indifferent
profiles observed in cell based assessments and the key binding inter-
actions of BR102375 in PPARγ LBD, compared to those of the TZD full
agonists. Also noteworthy is the finding of substantial change in
binding modes induced by the replacement of ethyl ester of BR101549
with t-butyl-1,2,4-oxadiazole motif of BR102375.
6

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Scheme 1. General synthetic scheme, a) trimethylaluminum, NH4Cl, toluene, 25 °C, b) NH2OH in H2O, EtOH, reflux, c) 2.5 M NaOH in H2O, EtOH, 25 °C, d) EDCI,
HOBt, TEA, acylhydrazide, CHCl3, 25 °C, e) 33, SOCl2, pyridine, reflux, f) 32, DIPEA, HBTU, DMF, 25 °C, g) hydrazine, AcOH, reflux, h) POCl3, toluene, reflux, i)
Lawesson’s reagent, THF, reflux, j) 1 M ammonia in MeOH, 50 °C, k) DMFDMA, MeOH, 25 °C, l) NH2OH, 1,4-dioxane, 90 °C, then AcOH, m) 28% ammonia in H2O,
25 °C, n) POCl3, acetonitrile, reflux, o) HOBt, EDCI, TEA, carboxylic acid, CH2Cl2, 25 °C, p) K2CO3, toluene, reflux.
7

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Acknowledgments
8. Choung W, Jung HJ, Nam EH, et al. Bioorg Med Chem Lett. 2018;28:3155.
9. Choung W, Jung HJ, Yang D, et al. Bioorg Med Chem Lett. 2019;29:631.
10. Meanwell NA. J Med Chem. 2011;54:2529.
This research was supported by the Bio & Medical Technology
Development Program (2014M3A9D9033717 & 2014M3A9D9070788)
and the Pioneer Research Center Program (NRF-2014M3C1A3051476)
from the National Research Foundation (NRF), Republic of Korea
funded by the Ministry of Science, ICT & Future Planning of Republic of
Korea.
11. Benson SC, Pershadsingh HA, Ho CI, et al. Hypertension. 2004;43:993.
12. Omote Y, Deguchi K, Kurata T, et al. Curr Neurovascular Res. 2015;12:91.
13. For experimental details, see “Supporting Information”.
14. Takazawa T, Yamauchi T, Tsuchida A, et al. J Biol Chem. 2009;284(44):30049.
15. Kudoh A, Satoh H, Hirai H, Watanabe T. Life Sci. 2011;88:1055.
16. Kletzien RF, Clarke SD, Ulrich RG. Mol Pharmacol. 1992;41(2):393.
17. Schwartz MW, Baskin DG. J Clin Investig. 2013;123:2344.
18. Seven-week-old male db/db mice were obtained from Central Lab Animal Co. (Seoul,
Korea) and were acclimated to the laboratory condition for 1 week. To investigate
the anti-diabetic effect so BR102375K (potassium salt), the mice were assigned into
three groups (n = 9/group) by blood glucose level and weight Mice were treated
once or twice daily by gavage with BR102357K (75 mg/kg/day), poiglitazone
(30 mg/kg/day) or vehicle (0.5 CMC in 1% Tween 80) for 2 weeks. Blood samples
were collected from tail vein and blood glucose levels were measured by Accu-Check
(Roche) once each week. Body weight and food intake were also measured once each
week. To confirm anti-diabetic effects of BR102357, oral glucose tolerance test was
carried out after 12 h fasting. A glucose solution (1 g/kg of body weight) was ad-
ministered by orally gavage. At the time points indicated, blood glucose levels were
measured with an Accu-Check (Roche) before (0 min) and after (30, 60, 90, and
120 min) the glucose gavage.
Appendix A. Supplementary data
Supplementary data to this article can be found online at https://
doi.org/10.1016/j.bmcl.2019.06.027.
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