Discovery and Preclinical Evaluation of BMS-711939, an Oxybenzylglycine Based PPARα Selective Agonist

Article abstract of DOI:10.1021/acsmedchemlett.6b00033

BMS-711939 (3) is a potent and selective peroxisome proliferator-activated receptor (PPAR) α agonist, with an EC₅₀ of 4 nM for human PPARα and >1000-fold selectivity vs human PPAR (EC₅₀ = 4.5 μM) and PPAR (EC₅₀ > 100 μM) i

Full text of DOI:10.1021/acsmedchemlett.6b00033

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Letter
Discovery and Preclinical Evaluation of BMS-711939,
an Oxybenzyl-glycine Based PPAR# Selective Agonist
Yan Shi, Jun Li, Lawrence J Kennedy, Shiwei Tao, Andres S. Hernandez, Zhi Lai, Sean Chen, Henry Wong,
Juliang Zhu, Ashok Trehan, Ngiap-Kie Lim, Huiping Zhang, Bang-Chi Chen, Kenneth T Locke, Kevin M
O'Malley, Litao Zhang, Raiajit Srivastava, Bowman Miao, Daniel S. Meyers, Hossain Monshizadegan, Debra
Search, Denise Grimm, Rongan Zhang, Thomas Harrity, Lori K Kunselman, Michael Cap, Jodi Muckelbauer,
Chiehying Chang, Stanley R. Krystek, YiXin Li, Vinayak Hosagrahara, Lisa Zhang, Pathanjali Kadiyala,
Carrie Xu, Michael A Blanar, Robert Zahler, Ranjan Mukherjee, Peter T.W. Cheng, and Joseph A Tino
ACS Med. Chem. Lett., Just Accepted Manuscript • DOI: 10.1021/acsmedchemlett.6b00033 • Publication Date (Web): 04 Apr 2016
Downloaded from http://pubs.acs.org on April 7, 2016
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Zhang, Rongan; Bristol-Myers Squibb Pharmaceutical Research and
Development
Harrity, Thomas; Bristol-Myers Squibb Pharmaceutical Research and
Development
Kunselman, Lori; Bristol-Myers Squibb Pharmaceutical Research and
Development
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Cap, Michael; Bristol-Myers Squibb Pharmaceutical Research and
Development
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Muckelbauer, Jodi; Bristol-Myers Squibb Pharmaceutical Research and
Development
Chang, Chiehying; Bristol-Myers Squibb Pharmaceutical Research and
Development
Krystek, Stanley; Bristol-Myers Squibb, Computer-Assisted Drug Design
Li, YiXin; Bristol-Myers Squibb Pharmaceutical Research and Development
Hosagrahara, Vinayak; Bristol-Myers Squibb Pharmaceutical Research and
Development
Zhang, Lisa; Bristol-Myers Squibb Pharmaceutical Research and
Development
Kadiyala, Pathanjali; Bristol-Myers Squibb Pharmaceutical Research and
Development
Xu, Carrie; Bristol-Myers Squibb Pharmaceutical Research and
Development
Blanar, Michael; Bristol-Myers Squibb Pharmaceutical Research and
Development
Zahler, Robert; Bristol-Myers Squibb Pharmaceutical Research and
Development
Mukherjee, Ranjan; Bristol-Myers Squibb Pharmaceutical Research and
Development
Cheng, Peter; Bristol-Myers Squibb Pharmaceutical Research Institute,
Metabolic Diseases Chemistry
Tino, Joseph; Bristol-Myers Squibb Pharmaceutical Research and
Development
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Discovery and Preclinical Evaluation of BMSꢀ711939, an Oxybenzylꢀ
glycine Based PPARα Selective Agonist
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Yan Shi,* Jun Li, Lawrence J. Kennedy, Shiwei Tao, Andrés S. Hernández, Zhi Lai, Sean Chen,
Henry Wong, Juliang Zhu, Ashok Trehan, Ngiap-Kie Lim, Huiping Zhang, Bang-Chi Chen, Ken-
neth T. Locke, Kevin M. O'Malley, Litao Zhang, Raiajit Srivastava, Bowman Miao, Daniel S. Mey-
ers, Hossain Monshizadegan, Debra Search, Denise Grimm, Rongan Zhang, Thomas Harrity,
Lori K. Kunselman, Michael Cap, Jodi Muckelbauer, Chiehying Chang, Stanley R. Krystek, Yi-Xin
Li, Vinayak Hosagrahara, Lisa Zhang, Pathanjali Kadiyala, Carrie Xu, Michael A. Blanar, Robert
Zahler, Ranjan Mukherjee, Peter T. W. Cheng, Joseph A. Tino
Research and Development, Bristol-Myers Squibb Company, 350 Carter Road, Hopewell, NJ 08540, U.S.A.
KEYWORDS: peroxisome proliferator-activated receptor (PPAR)
α selective agonist, high fat fed hamster model, hu-
man ApoA1 transgenic mice, pharmacokinetics.
ABSTRACT: BMS-711939 (3) is a potent and selective peroxisome proliferator-activated receptor (PPAR) α agonist, with
an EC50 of 4 nM for human PPARα and >1000-fold selectivity vs. human PPARγ (EC50 = 4.5 ꢀM) and PPARδ (EC50 > 100
ꢀM) in PPAR-GAL4 transactivation assays. Compound 3 also demonstrated excellent in vivo efficacy and safety profiles in
preclinical studies and thus was chosen for further preclinical evaluation. The synthesis, structure–activity relationship
(SAR) studies, and in vivo pharmacology of 3 in preclinical animal models as well as its ADME profile are described.
Peroxisome proliferator-activated receptors (PPARs)
vide an opportunity for the treatment of atherosclerosis
and dyslipidemia as well as non-alcoholic steatohepatitis
(NASH)11 with minimized side effects. In addition, we
considered that a more potent and selective PPARα ago-
nist with minimized disparity in interspecies PPAR activi-
ties (particularly rodent), will be useful for mechanism-
based safety evaluation in preclinical animal models.
are ligand-activated transcription factors in the nuclear
2
hormone receptor superfamily.1,
Three subtypes of
PPARs, namely PPARα, PPARγ and PPARδ, have been
identified in various species, including humans. PPARα is
highly expressed in the liver and regulates the expression
of genes encoding lipid and lipoprotein metabolism.3 Up-
on binding of PPARα ligand agonists, the resulting con-
formational change leads to the modulation of a number
of PPARα responsive genes, which in turn have plei-
otropic effects on plasma lipoprotein levels, atherosclero-
sis and inflammation. There are currently several synthet-
ic PPARα ligands, including the fibrate class of hypoli-
pidemic drugs in clinical use.4, 5 Although fibrates are lig-
ands of PPARs, their binding affinity to PPARα is relative-
ly weak.6, 7 This results in the relatively high doses (e.g.
200 mg of fenofibrate and 1.2 g of gemfibrozil) needed to
achieve clinical efficacy, and unwanted side effects may
occur at these high doses. Several potent PPARα selective
agonists have been progressed into various phases of clin-
ical development, including GW5907358 and LY518674.9
However, the development of most of these potent and
selective PPARα agonist clinical candidates have been
suspended. Recently, the PPARα-selective α,γ dual ago-
nist saroglitazar was approved in India for the treatment
of diabetic dyslipidemia.10 A potent and efficacious
PPARα agonist with an excellent safety profile may pro-
Figure 1. Fenofibric acid and BMS-687453
In continuation of our research in the field of PPARs to
develop novel therapeutic agents to treat metabolic dis-
orders,12 we have reported the discovery of the selective
PPARα agonist 213 (Figure 1), which exhibited a high de-
gree of selectivity towards PPARα over PPARγ (PPARα
EC50 = 10 nM, EC50 ratio: γ/α = 410), and demonstrated an
excellent pharmacological and safety profile in preclinical
studies. Inspection of the X-ray crystal structures of 2
bound to the PPARα ligand binding domain (LBD; Figure
2) suggested that the carboxylic acid of 2 forms the well-
recognized hydrogen-bonding network with neighboring
residues: His440, Tyr464, Tyr314 and Ser280. The 1,3-
oxybenzyl central core anchors the acid head group and
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action of 23a-c with methyl chloroformate gave the corre-
the 4-chlorophenyl oxazole moiety into their appropriate
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8
binding pockets. Since the central phenyl core and the
benzylic carbon are partially surrounded by hydrophobic
residues such as Leu321, Ile317 and Phe318, we envioned
that small hydrophobic substituents on this region may
be tolerated and SAR investigations could be productively
conducted within this portion of the molecule to further
optimize the binding affinity/potency and/or reduce the
human/rodent species difference in PPARα activity. In
this paper, we describe the SAR findings from this effort,
which resulted in the discovery of 3 (BMS-711939). We
also disclose the pharmacokinetic and in vivo efficacy pro-
filing of 3, which progressed into preclinical toxicology
studies.
sponding methyl carbamates 24a-c in 90-99% yield. Base-
mediated alkylation of phenols 24a-c with 4-
(chloromethyl)-2-(4-chlorophenyl)-5-methyloxazole 25a
at 80oC provided the methyl esters 26a-c in 86-99% yield.
Basic hydrolysis of 26a-c provided 3-5 in 90-93% yield.
Compound 6 was synthesized in a similar fashion from
intermediate 27.14 Compounds 7-13 were synthesized from
intermediate 24a and oxazoles 25b-h15 using the same
synthetic sequence as described for 3-5.
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Compounds 14-20 were synthesized through a slightly
different sequence as shown in Scheme 2. Alkylation of 2-
fluoro-5-hydroxybenzaldehyde 21a with 4-(chloromethyl)
oxazole 25a provided aldehyde 28 in 95% yield. Reductive
amination of 28 with 22 afforded the secondary amine 29
in 90% yield. Reaction of 29 with different chloroformates
and subsequent hydrolysis of the resulting esters provided
compounds 14-20 in 80-93% yield.
O
Me
O
O
HO
a
O
N
Cl
H
O
+
Cl
N
H
Cl
F
F
21a
25a
28
O
CO2H
CO2Me
Me
R
Me
c, d, e
O
O
b
O
N
HN
Cl
Cl
O
O
N
N
F
F
14: R = Et
15: R = n-Pr
29
16: R = F(CH2)3
17: R = n-Bu
18: R = i-Bu
19: R = 4-MePh
20: R = 4-MeOPh
Figure 2. X-ray crystal structure of 2 bound in PPARα LBD
with 2.7Å resolution. Residues within 4.5 Å of benzylglycine
are shown with thick sticks. Hydrogen bonds are shown as
black dashed lines. The PDB deposition number is 3KDT.
Scheme 2. The synthesis of 14-20. Reagents and conditions:
(a) K2CO3, MeCN, 80°C. (b) 22, Et3N, MeOH, NaBH4, 0°C to
rt. (c) ROCOCl, aq. NaHCO3, THF. (d) LiOH, THF-H2O, rt.
(e) 1N aq. HCl.
O
HO
4
HO
b
a
H
N
CO2Me
Our initial effort to further optimize 2 focused on struc-
tural modifications of the central core and the benzylic
position of the benzylglycine. The SAR results are shown
in Table 1. Introducing a fluorine atom at the 2-position of
central core resulted in a very potent and selective
PPARα/γ agonist 3 (EC50 γ/α ratio = 1128), with PPARα
EC50 = 4 nM and PPARγ EC50 = 4.51 ꢀM in the transactiva-
tion assays.13 This compound is ~2.5-fold more potent
than 2 (EC50 = 10 nM) at PPARα, and is slightly less potent
at PPARγ than 2 (PPARγ EC50 = 4.1 ꢀM). These functional
data correspond well to their PPARα and PPARγ binding
affinities (Table 1).16 On the other hand, the opposite ef-
fects were observed when introducing a fluorine atom at
the 3-position of central phenyl core; compound 4 (EC50
γ/α ratio = 157) is less potent at PPARα (EC50 = 18 nM) and
more potent at PPARγ (EC50 = 2.82 ꢀM) than 2. Interest-
ingly, the 4-fluoro-substituted analog 5 is less active than
2 at both PPARα and PPARγ with a γ/α EC50 ratio of 98.
When a (S)-methyl group is placed at the α-position of
the benzylglycine of 2, the resulting 6 (EC50 γ/α ratio =
332) has similar potency at PPARα but is more potent at
PPARγ than 2. These results indicate that a subtle substi-
tution change on the central phenyl core or at the ben-
zylic position can result in changes in both the PPARα
and PPARγ agonist activities and thus the PPARγ/α selec-
H2N
CO2Me
H
2
F
3
F
22
21a, 2-F
21b, 3-F
21c, 4-F
23a, 2-F
23b, 3-F
23c, 4-F
Me
O
N
HO
N
CO2Me
Cl
c
O
N
CO2Me
O
O
F
O
O
F
26a, 2-F
26b, 3-F
26c, 4-F
24a, 2-F
24b, 3-F
24c, 4-F
Me
O
O
d, e
Cl
1
R
O
5
N
Cl
N
CO2H
N
O
O
25a, R = Cl 25e, R = CF3
25b, R = Me 25f, R = OCF3
F
3
3, 2-F
4, 3-F
5, 4-F
25c, R = F
25d, R = H 25h, R = SO2Me
25g, R = t-Bu
Me
O
O
N
Cl
HO
c, d, e
N
CO2Me
N
CO2H
O
O
O
O
27
6
Scheme 1. The synthesis of 3-6. Reagents and conditions:
(a) Et3N, MeOH, NaBH4, 0°C to rt. (b) methyl chloroformate,
aq. NaHCO3, THF. (c) 25a, K2CO3, MeCN, 80°C. (d) LiOH,
THF-H2O, rt. (e) 1N aq. HCl.
The syntheses of 3-6 are described in Scheme 1. Reduc-
tive amination of fluoro-substituted hydroxybenzalde-
hydes 21a-c with glycine methyl ester hydrochloride 22
afforded the secondary amines 23a-c in 85-95% yield. Re-
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tivety. The 2-fluorophenyl glycine analog 3 has the most ingly, a bulky aliphatic substituent such as t-butyl (12)
1
2
3
4
5
6
7
8
potent PPARα agonist activity and is also the most selec-
tive PPARα agonist among the three isomeric monofluor-
inated analogs.
significantly improved PPARγ potency while maintaining
PPARα activity, thus resulting in a significant reduction
in PPARα selectivity versus 3. These results suggested that
polarity and steric effects play important roles in deter-
mining PPARα/γ functional activities and selectivity in
this portion of the molecule. This SAR study of the “left-
hand” phenyl ring substituents showed that the 4-Cl-
phenyl moiety was optimal, providing potent PPARα ac-
tivity and the highest level of PPARα selectivity.
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The corresponding SAR study of the “right-hand” side
Cp
d
αEC50
(nM)
γEC50
(nM)
γ/α
Ratio
R1
R2
Table 1. Transactivation EC50 and binding IC50 of 2-6a
3
7
4-Cl
4-Me
4-F
Me
Me
Me
Me
Me
Me
4.0
2.8
14.5
59
4511
2182
1128
787
691
146
566
556
8
10010
8607
2062
2384
9
4-H
10
11
4-CF3
4-CF3O
3.6
4.3
Cp
d
αEC50
(nM)
γEC50
(nM)
γ/α EC5
0 ratio
αIC50
(nM)
γIC50
(nM)
4-
C(CH3)3
R
12
Me
2.7
414
154
>4800
0
13
14
15
16
17
18
19
20
4-MeSO2
4-Cl
Me
Et
>2500 >25000
NA
1085
594
413
2
H
10
4096
410
260
4.0
3.4
10.6
2.8
2.3
4273
2013
4383
1235
1504
1255
1087
>9840
0
4-Cl
n-Pr
3
4
5
6
2-F
3-F
4-F
-
4.0
18
4511
2819
9168
2857
1128
157
98
97
1341
1563
671
4-Cl
F(CH2)3
n-Bu
>15000
>15000
>15000
4-Cl
435
666
224
160
94
8.6
4-Cl
i-Bu
332
4-Cl
4-MePh
4-MeOPh
5.6
6.8
a Compounds were tested for agonist activity on hPPAR-
GAL4 HEK transactivation assay. Transactivation efficacy
was defined as percentage of maximum activity as compared
with an appropriate standard set at 100% (100 ꢀM fenofibric
acid for PPARα, 1.0 ꢀM rosiglitazone for PPARγ). Full PPARα
intrinsic activity (>50% relative to 100 ꢀM fenofibric acid)
was observed for all tested compounds (n = 1-3).
4-Cl
carbamate showed that simple alkyl carbamates (14-20)
generally provide excellent PPARα potency and selectivity
(EC50 γ/α ratio > 400-fold), with the ethyl carbamate 14
having almost the same PPARα potency and selectivity
(PPARα EC50= 4 nM, γ/α ratio = 1085) as 3. Interestingly,
replacing the terminal methyl group of the n-propyl car-
bamate 15 with a fluoromethyl (16) resulted in a >2-fold
decrease in potency at both PPARα and γ, but retained
the high γ/α selectivity ratio. The aryl carbamates (19 &
20) were also potent PPARα agonists, but with slightly
lower γ/α selectivity compared to the simple alkyl carba-
mates. The overall SAR in this carbamate region is similar
to that previously observed with 2, with the methyl car-
bamate being optimal.13
With lead compound 3 in hand, we systematically in-
vestigated the SAR of the “left-hand” phenyl ring substit-
uents and the “right-hand” carbamate substituents, as
shown in Table 2. In general, all the 2-fluoro-phenyl cen-
tral core based compounds show enhanced PPARα ago-
nist activity and PPARα/γ selectivity versus their corre-
sponding unsubstituted phenyl analogs.13 On the “left-
hand” phenyl ring (of the oxazole), while the compound
without a para substituent (9, PPARα EC50= 59 nM, γ/α
ratio = 146) is ~15-fold less potent and far less selective
than 3, the para-fluoro compound 8 is only about 3.5-fold
less potent than 3 at PPARα and maintains high selectivi-
ty (PPARα EC50= 15 nM, γ/α ratio = 691). Compounds with
a non-polar substituent (7, 10-12) at the para position
generally have similar PPARα potencies to 3. On the other
hand, the relatively bulky polar methylsulfonyl substitu-
ent (13) obliterates both PPARα and γ activities. Interest-
Table 2. In vitro activity of 2-fluoro substituted ben-
zylglycine 3, 7-20a
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serum HDL cholesterol by 88% and lowered triglycerides
1
2
3
4
5
6
7
8
9
a See notes for Table 1.
by 33% after 10 days of dosing. By comparison, compound
3 (at a dose of 50 mg/kg/day) raised HDL cholesterol by
109% and lowered triglycerides by 59% respectively. These
data clearly demonstrated that 3 robustly elevated HDLc
and lowered triglycerides in the human ApoA1 transgenic
mouse model.
The PPARα potency and selectivity of 3 were further
confirmed by testing it in co-transfection assays in HepG2
cells using full length human PPARα and PPARγ recep-
tors.13 In these assays, compound 3 showed excellent
PPARα potency (EC50 = 5 nM) with > 320-fold selectivity
vs. PPARγ (EC50 > 1.61 ꢀM). These results correlated well
with the data observed from the primary GAL-4 HEK
transactivation based screening assays as shown in Table
1. Compound 3 also is a full PPARα agonist in the rodent
assays, and is > 2.5-fold more potent than 2 in rodent
PPARα functional assays, with EC50s of 178 nM, 144 nM
and 123 nM for hamster, mouse and rat, respectively.17
Importantly, compound 3 showed negligible activity (EC50
for transactivation >25 ꢀM and efficacies <15% of stand-
ard) against a panel of human nuclear hormone receptors,
including PPARδ, LXR, GR and RXR.
In a 21-day head-to-head comparison study in a high fat
fed hamster model,21 both 2 and 3 dose dependently low-
ered triglycerides and LDL levels. As shown in Table 5,
after three weeks of dosing, compound 3 lowered fasting
plasma LDLc by 61% at the 3 mg/kg/day dose and 87% at
the 10 mg/kg/day dose respectively; it also reduced plas-
ma triglycerides by 50%, 74% and 85% at the 1, 3 and 10
mg/kg/day doses, respectively. In comparison, compound
2 lowered fasting plasma LDLc by 46% at the 3 mg/kg/day
dose and 60% at the 10 mg/kg/day dose respectively; it
reduced plasma triglycerides by 40%, 45% and 77% at the
1, 3 and 10 mg/kg/day doses, respectively. For liver triglyc-
erides and cholesterol, compound 3 lowered liver choles-
terol by 57% at the 3 mg/kg/day dose and 68% at the 10
mg/kg/day dose respectively; it also reduced liver triglyc-
erides by 19%, 40% and 48% at the 1, 3 and 10 mg/kg/day
doses, respectively. By comparison, compound 2 only im-
pacted the hepatic lipids at the 10 mg/kg dose level (41%
for liver cholesterol and 23% for liver triglycerides). Over-
all, compound 3 significantly lowered plasma triglycerides
and LDLc in a chronic dyslipidemic hamster model, and
compares favorably to 2 in terms of both potency and
overall efficacy in lipid lowering in this model.
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Compound 3 did not show any significant activity in li-
ability profiling assays (e.g. in 5 human CYP isozymes,
PXR and hepatocyte toxicity assays).18 No in vitro liabili-
ties were noted in: 1) extensive screens for recep-
tor/enzyme binding inhibition; 2) assays for bacterial mu-
tagenicity or CHO cell clastogenicity and 3) an explorato-
ry Ames test at up to 5000 ꢀg per plate in TA98 and
TA100 strains. Cardiovascular safety evaluations were car-
ried out on 3: 1) no hERG and sodium channel activity was
observed at concentrations up to 30 ꢀM and 10 ꢀM, re-
spectively; and 2) no drug-related changes in hemody-
namic and electrocardiographic (ECG) effects were ob-
served at up to 20 mg/kg of 3 in a single-dose monkey
telemetry study.
In summary, the SAR investigation on the oxybenzyl-
glycine-based lead 2 led to the discovery of a series of 2-
flouro-substituted benzylglycine analogs as potent and
highly selective PPARα agonists. BMS-711939 (3) was
found to be a potent and highly selective PPARα agonist
(PPARα EC50 = 4 nM, EC50 γ/α ratio = 1128) that is highly
efficacious in elevating HDLc in human ApoA1 transgenic
mice and lowering LDLc in dyslipidemic hamsters in
chronic efficacy studies. It also robustly lowers triglycer-
ides in both of these animal models. In comparison to the
2, BMS-711939 is more potent at PPARα and more selec-
tive against PPARγ, and shows superior potency on lower-
ing LDLc and TG in hamsters. On the basis of its potency
and selectivity, its excellent in vitro liability profile, favor-
able pharmacokinetics and pharmacodynamic effects in
animal models, compound 3 was selected for further eval-
uation in preclinical animal toxicity studies.
Compound 3 also exhibited an excellent pharmacoki-
netic profile across all tested animal species. Table 3
shows the pharmacokinetic parameters of 3 in mouse, rat,
dog and monkey (cynomulgus). It exhibited low plasma
clearance in the mouse, rat, and monkey, and moderate
plasma clearance in the dog. The half-life of ranged from
1.8 h in mouse to 26.3 h in monkey. It also had excellent
absolute oral bioavailability ranging from 59% (dog) to
100% (rat). Additionally, it has excellent crystalline aque-
ous solubility (367 ꢀg/mL at pH 7.2).
Compound 3 has been profiled in multiple animal mod-
els of dyslipidemia.19 In a 10-day dose response study in
the human ApoA1 transgenic mouse,20 it robustly and
dose-dependently increased both ApoA1 and HDL choles-
terol, as shown in Table 4. In this study, the reference
compound fenofibrate (at a dose of 100 mg/kg) raised
Table 3. Pharmacokinetic profile of 3a
Dose
route
CLPl
(mL/min/kg)
VSS
(L/kg)
Cmax (ꢀM) AUCb (ꢀM⋅h)
Species
Mouse
Dose (mg/kg) tmax (h)
t1/2 (h) F%
IV
5
-
-
13
17
13.8
-
0.6
-
1.8
-
-
PO
10
0.25
22.7
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IV
4
8
-
-
9.4
32
15.3 ± 0.7
-
2.2 ± 0.5
-
3.3
-
-
Rat
Dog
1
2
3
4
5
6
7
PO
0.3 ± 0.1
14.9
100
IV
PO
IV
1
2
1
-
-
3.5
4.0
7.5
8.5
10.7 ± 2.4
2.1 ± 1.2
5.5
-
-
0.8 ± 0.3
-
1.5
-
-
-
59
-
5.9 ± 2.7
-
3.9 ± 1.5
-
26.3
-
Monkey
PO
2
0.9 ± 0.1
1.4
65
8
9
aFor each experimental study, n ≥ 3. bAUC0-8h reported here, not AUCINF.
Table 4: Effect of 3 and fenofibrate on plasma parameters in human ApoA1 transgenic micea
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Liver TG mg/dL ±
SEM (% change)
Liver chol mg/dL ±
SEM (% change)
Plasma LDLc mg/dL ±
Plasma TG mg/dL ±
SEM (% change)
Entry
SEM (% change)
High Fat Vehi-
cle
24.1 ± 1.5
16.9 ± 1.2
91.7 ± 8.1
173.5 ± 17
3, 10 mg/kg
3 mg/kg
12.5 ± 1.2 (-48%*)
14.5 ± 0.8 (-39.8%*)
19.6 ± 0.9 (-18.7%*)
18.5 ± 1.2 (-23%*)
19.9 ± 3.0 (-17%)
5.5 ± 0.5 (-67.5%*)
7.3 ± 0.7 (-56.8%*)
14.7 ± 1.9 (-13%)
12.2 ± 4.6 (-87%*)
35.7 ± 4.5 (-61%*)
69.3 ± 11 (-24%)
36.3 ± 5.7 (-60%*)
49.9 ± 8.4 (-46%*)
89.3 ± 9.4
25.2 ± 2.6 (-85%*)
44.7 ± 4.3 (-74%*)
85.7 ± 18 (-50%*)
39.7 ± 3.6 (-77%*)
95.2 ± 13 (-45%*)
103.2 ± 11 (-40%*)
1 mg/kg
2, 10 mg/kg
3 mg/kg
10.0 ± 1.0 (-40.8%*)
14.3 ± 2.4 (-15.4%)
20.7 ± 2.1 (+22%)
1 mg/kg
22.6 ± 1.1 (-6%)
ap < 0.05 compared to vehicle-treated group (n = 10). Data represent the mean ± SEM (n=10).
Table 5: Effect of compounds 2 and 3 on lipid parameters in high fat-fed hamstersa
Liver TG mg/dL ±
SEM (% change)
Liver chol mg/dL ±
SEM (% change)
Plasma LDLc mg/dL ±
Plasma TG mg/dL ±
SEM (% change)
Entry
SEM (% change)
High Fat Vehi-
cle
24.1 ± 1.5
16.9 ± 1.2
91.7 ± 8.1
173.5 ± 17
3, 10 mg/kg
3 mg/kg
12.5 ± 1.2 (-48%*)
14.5 ± 0.8 (-39.8%*)
19.6 ± 0.9 (-18.7%*)
18.5 ± 1.2 (-23%*)
19.9 ± 3.0 (-17%)
5.5 ± 0.5 (-67.5%*)
7.3 ± 0.7 (-56.8%*)
14.7 ± 1.9 (-13%)
12.2 ± 4.6 (-87%*)
35.7 ± 4.5 (-61%*)
69.3 ± 11 (-24%)
36.3 ± 5.7 (-60%*)
49.9 ± 8.4 (-46%*)
89.3 ± 9.4
25.2 ± 2.6 (-85%*)
44.7 ± 4.3 (-74%*)
85.7 ± 18 (-50%*)
39.7 ± 3.6 (-77%*)
95.2 ± 13 (-45%*)
103.2 ± 11 (-40%*)
1 mg/kg
2, 10 mg/kg
3 mg/kg
10.0 ± 1.0 (-40.8%*)
14.3 ± 2.4 (-15.4%)
20.7 ± 2.1 (+22%)
1 mg/kg
22.6 ± 1.1 (-6%)
ap
<0.05 versus vehicle control. Data represent the mean ± SEM (n=8).
ASSOCIATED CONTENT
Supporting Information
ACKNOWLEDGMENT
We thank Dr. Jeff Robl for careful proofreading of this manu-
script. The Discovery Toxicology department at Bristol-
Myers Squibb is acknowledged for the preclinical safety eval-
uation of BMS-711939.
The Supporting Information is available free of charge on the
ACS Publications website at DOI: XXX.
Synthetic methods, characterization of key compounds,
and biology assay protocols (PDF).
ABBREVIATIONS
Peroxisome Proliferator Activated Receptor (PPAR); ligand
binding domain (LBD); low-density lipoprotein-cholesterol
(LDLc); high-density lipoproteincholesterol (HDLc); triglyc-
erides (TG); Cytochromes P450 (CYP); Human Ether-à-go-
go-Related Gene (hERG); Liver X Receptor (LXR); Glucocor-
AUTHOR INFORMATION
Corresponding Author
* Tel: 1-609-466-5076. E-mail: yan.shibms.com
Notes
The authors declare no competing financial interest.
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ACS Medicinal Chemistry Letters
cose and Lipid-Lowering Activities. J. Med. Chem. 2005, 48,
ticoid Receptor (GR); Pregnane X Receptor (PXR); Retinoid
1
2
3
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5
6
7
8
2248-2250.
X Receptor RXR.
13. Li, J.; Kennedy, L. J.; Shi, Y.; Tao, S.; Ye, X.-Y.; Chen, S. Y.;
Wang, Y.; Hernández, A. S.; Wang, W.; Devasthale, P. V.;
Chen, S.; Lai, Z.; Zhang, H.; Wu, S.; Smirk, R. A.; Bolton, S.
A.; Ryono, D. E.; Zhang, H.; Lim, N.-K.; Chen, B.-C.; Locke,
K. T.; O’Malley, K. M.; Zhang, L.; Srivastava, R. A.; Miao, B.;
Meyers, D. S.; Monshizadegan, H.; Search, D.; Grimm, D.;
Zhang, R.; Harrity, T.; Kunselman, L. K.; Cap, M.; Kadiyala,
P.; Hosagrahara, V.; Zhang, L.; Xu, C.; Li, Y.-X.; Muckelbau-
er, J. K.; Chang, C.; An, Y.; Krystek, S. R.; Blanar, M. A.; Zah-
ler, R.; Mukherjee, R.; Cheng, P. T. W.; Tino, J. A. Discovery
of an Oxybenzylglycine Based Peroxisome Proliferator Acti-
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17. Compound 2 shows full PPARα agonist activity in rodents
with EC50s of 488 nM, 426 nM and 317 nM for hamster,
mouse and rat, respectively.
18. Compound 3 has following profile: Plasma Protein binding:
99.7% (h), 99.8% (m), 99.6% (r), 99% (c), 99.5% (d); CYP
(inhibition) 3A4, 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, all IC50s >
40 ꢀM. PXR EC60 > 50 ꢀM; HHA (2C19, 2C9, 2D6, 3A4, TC5)
all IC50 > 150 ꢀM; hERG (flux) IC50 > 80 ꢀM; (patch-clamp)
4.0% at 30 μM; Sodium Channel (EP, % block @ 10 ꢀM): 12%
@ 1 Hz and 14% @ 4 Hz; Purkinje fiber% change APD90 = -
5.4 @ 30 ꢀM.
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Blanar, M.; Cheng, P. T.; Tino, J. A.; Srivastava, R. A. Novel
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dyslipidemia with peroxisome proliferator activated recep-
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Figure 1. Fenofibric Acid and BMS-687453
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Figure 2. Xꢀray crystal structure of compound 2 bound in PPARα LBD with 2.7Å resolution. Residues within
4.5 Å of benzylglycine are shown with thick sticks. Hydrogen bonds are shown as black dashed lines. The
PDB deposition number is 3KDT.
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Scheme 1. The synthesis of 3-6. Reagents and conditions: (a) Et3N, MeOH, NaBH4, 0°C to rt. (b) methyl
chloroformate, aq. NaHCO3, THF. (c) 25a, K2CO3, MeCN, 80°C. (d) LiOH, THF-H2O, rt. (e) 1N aq. HCl.
156x147mm (300 x 300 DPI)
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Scheme 2. The synthesis of 14-20. Reagents and conditions: (a) K2CO3, MeCN, 80°C. (b) 22, Et3N, MeOH,
NaBH4, 0°C to rt. (c) ROCOCl, aq. NaHCO3, THF. (d) LiOH, THF-H2O, rt. (e) 1N aq. HCl.
170x93mm (300 x 300 DPI)
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Discovery and Preclinical Evaluation of BMSꢀ711939, an Oxybenzylꢀglycine Based PPARα
Selective Agonist
Yan Shi,* Jun Li, Lawrence J. Kennedy, Shiwei Tao, Andrés S. Hernández, Zhi Lai, Sean Chen, Henry Wong,
Juliang Zhu, Ashok Trehan, Ngiap-Kie Lim, Huiping Zhang, Bang-Chi Chen, Kenneth T. Locke, Kevin M.
O'Malley, Litao Zhang, Raiajit Srivastava, Bowman Miao, Daniel S. Meyers, Hossain Monshizadegan, Debra
Search, Denise Grimm, Rongan Zhang, Thomas Harrity, Lori K. Kunselman, Michael Cap, Jodi Muckelbauer,
Chiehying Chang, Stanley R. Krystek, Yi-Xin Li, Vinayak Hosagra-hara, Lisa Zhang, Pathanjali Kadiyala,
Carrie Xu, Michael A. Blanar, Robert Zahler, Ranjan Mukherjee, Peter T. W. Cheng, Joseph A. Tino
60x34mm (300 x 300 DPI)
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