Structure-guided evolution of a 2-phenyl-4-carboxyquinoline chemotype into PPARα selective agonists: New leads for oculovascular conditions

Article abstract of DOI:10.1016/j.bmcl.2018.03.010

Small molecule agonism of PPARα represents a promising new avenue for the development of non-invasive treatments for oculovascular diseases like diabetic retinopathy and age-related macular degeneration. Herein we report initial structure–activity relatio

Full text of DOI:10.1016/j.bmcl.2018.03.010

Bioorganic & Medicinal Chemistry Letters xxx (2018) xxx–xxx
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Structure-guided evolution of a 2-phenyl-4-carboxyquinoline
chemotype into PPAR
a selective agonists: New leads for
oculovascular conditions
Xiao-Zheng Dou a,c, Dinesh Nath a,c, Younghwa Shin b, Jian-Xing Ma b, Adam S. Duerfeldt a,
⇑
a Department of Chemistry & Biochemistry, Stephenson Life Sciences Research Center, University of Oklahoma, Norman, OK, United States
b Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Small molecule agonism of PPAR
sive treatments for oculovascular diseases like diabetic retinopathy and age-related macular degenera-
tion. Herein we report initial structure–activity relationships for the newly identified quinoline-based
a
represents a promising new avenue for the development of non-inva-
Received 2 February 2018
Revised 1 March 2018
Accepted 2 March 2018
Available online xxxx
PPARa agonist, Y-0452. Preliminary computational studies led to the hypothesis that carboxylic acid
transposition and deconstruction of the Y-0452 quinoline system would enhance ligand–protein interac-
tions and better complement the nature of the binding pocket. A focused subset of analogs was designed,
Keywords:
synthesized, and assessed for PPAR
other PPAR agonists, incorporation of the fibrate ‘‘head-group” decreases PPAR
provides pan-PPAR agonists and 2) computational models reveal a relatively unexploited amphiphilic
pocket in PPAR that provides new opportunities for the development of novel agonists. As an example,
compound 10 exhibits more potent PPAR
agonism (EC50 = ꢀ6 mM) than Y-0452 (EC50 = ꢀ50 mM) and
manifests >20-fold selectivity for PPAR over the PPAR and PPARd isoforms. More detailed biochemical
a
agonism. Two key observations arose from this work 1) contrary to
PPAR
a
a
a
selectivity and instead
Age-related macular degeneration
Diabetic retinopathy
PPAR selectivity
Structure-based design
a
a
a
c
analysis of 10 confirms typical downstream responses of PPAR
a
agonism including PPAR
a upregulation,
induction of target genes, and inhibition of cell migration.
Ó 2018 Elsevier Ltd. All rights reserved.
Despite a number of treatment options (e.g., laser photocoagu-
lation, blood-glucose regulation, corticosteroids and anti-vascular
endothelial growth factor (VEGF) injections), the ability to address
the complex nature of diabetic retinopathy (DR) and related oculo-
vascular diseases (e.g., wet age-related macular degeneration)
remains a significant challenge.1–3 Anti-VEGF has emerged as the
primary treatment option, but suffers from the requirement of fre-
quent intraocular injections, high cost, and the need for specialized
facilities. Additionally, although effective for most, ꢀ40–50% of
patients are refractory to intravitreal injection of anti-VEGF and
corticosteroids.3,4 This implies that auxiliary pathways and factors
that remain unaddressed with current interventions are involved
in disease causation and progression. A critical need exists to
develop new treatment options that are non-invasive and comple-
mentary to current approaches.
factors that consists of three members, PPARa, PPARc and
PPARd.5,6 Although PPAR isoforms share significant sequence
homologies, they exhibit diverse functions, have different tissue
distributions, and can be selectively targeted.7–10 Within this fam-
ily, PPAR
PPAR regulates the expression of genes involved in hyperlipi-
demia, diabetes, and inflammatory disorders and agonism of
PPAR
provides pharmacological benefits for these conditions.10,11
Only recently, however, have the roles of PPAR in regulating
inflammation, apoptosis, and neovascularization (NV) in diabetic
a has garnered the most attention as a therapeutic target.
a
a
a
retinae been revealed, establishing a new avenue for PPAR
a
agonists as therapeutics for oculovascular diseases.12,13
Two independent large clinical studies (FIELD and ACCORD)
demonstrate that fenofibrate (Fig. 1), a widely used drug in the
clinic for the treatment of hyperlipidemia, has robust protective
effects against diabetic macular edema (DME) and retinal NV in
type 2 diabetic patients.14,15 Fenofibrate represents the first orally
available and safe drug with proven clinical efficacy on retinal NV
and DME in humans with DR. This finding has excited clinicians,
researchers and pharmaceutical companies who are interested in
new drug treatments for oculovascular diseases. The protective
Peroxisome proliferator-activated receptors (PPARs) are a fam-
ily of nuclear hormone-activated receptors and transcription
⇑
Corresponding author.
E-mail address: adam.duerfeldt@ou.edu (A.S. Duerfeldt).
Authors contributed equally.
c
https://doi.org/10.1016/j.bmcl.2018.03.010
0960-894X/Ó 2018 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Dou X.-Z., et al. Bioorg. Med. Chem. Lett. (2018), https://doi.org/10.1016/j.bmcl.2018.03.010

2
X.-Z. Dou et al. / Bioorganic & Medicinal Chemistry Letters xxx (2018) xxx–xxx
that the results reproduced the bound conformation of the ligand.
As shown in Fig. 2A, the overlay of co-crystallized (cyan) and
docked (orange) GW409544 shows excellent congruence (RMSD
= 0.34 Å). Maintaining the same constraints and parameters, Y-
0452 was docked into hPPARa and the results were analyzed for
strategies to improve or introduce key interactions. Previous stud-
ies have demonstrated the significance of hydrogen bond interac-
tions between hPPAR
a Ser280, Tyr314, His440, and Tyr464 and
the carboxylate motif of ligands.18,25–31 Interactions with all four
of these residues is believed to be responsible for triggering full
agonism of hPPARa 27
.
Poorer agonists tend to only interact with
some of these hydrogen-bonding partners. As can be seen in Fig.
2B, while the quinoline core of Y-0452 provides a -system for
p
additional beneficial ligand-protein interactions via edge-to-face
stacking with His440, the position of the carboxylate group on Y-
0452 is predicted to only allow for two of the four possible hydro-
gen bonds (Tyr464 and His440).
We hypothesized that deconstruction of the quinoline core
would 1) provide a more synthetically tractable scaffold amenable
to facile assessment of carboxylate location and 2) relieve the
rigidity encompassed within the aromatic 2-phenyl-carboxyquino-
line chemotype. Although conformational constraint is a common
technique used in medicinal chemistry to reduce entropic penal-
ties through conformational bias, we hypothesized that, in this
case, the rigidity of Y-0452 may be disadvantageous when the frag-
ment is ‘‘grown” to fit the ‘‘U-shaped” binding pocket. We antici-
pated, however, that over simplification of an already modest hit
may lead to inactive compounds, simply due to a reduction in sur-
face area, thus limiting beneficial ligand-protein interactions.
Indeed, simple N-benzylated variants of i (Fig. 2C) resulted in inac-
tive derivatives (data not included). Docking of the simple N-ben-
zylated analogs, however, revealed a 180° rotation of the molecules
in the binding pocket, which positioned the substituted benzyl
group in the same pocket as the oxazole of GW409544. Taking this
into account and recognizing the value in the molecular orienta-
tion, we utilized structure-guided design to develop 9–14 and
21–24 that filled the hydrophobic binding pocket more efficiently.
This focused set of analogs allowed us to test our hypothesis that
quinoline deconstruction and transposition of the carboxylic acid
Fig. 1. PPARa agonists referenced in this manuscript.
effects of fenofibrate on retinal NV and DME are unrelated to its
lipid-lowering activity, but rather result from its agonism of
PPARa 12,16
To date, fenofibrate is the only PPARa agonist known
.
to cross the blood-ocular barrier and provide protective effects
against DME and NV. Fenofibrate however, suffers from low ocular
distribution, low affinity for PPARa, lack of selectivity between
PPAR isoforms, and dose-limiting toxicities, all of which will limit
its use as a DR therapy.16–21 The clinical results paired with recent
biochemical confirmation,12,22–24 however, demonstrate that small
molecule PPARa agonists with improved potency and enhanced
ocular distribution have high promise to become non-invasive
treatment options for oculovascular conditions.
Recently,
a
new PPAR
a
agonist, 7-chloro-8-methyl-2-
phenylquinoline-4-carboxylic acid (Y-0452, Fig. 1), was reported.23
Y-0452 displays protective effects in vivo against DR and exhibits
anti-inflammatory, anti-angiogenic and neuroprotective effects
without signs of toxicity in the retinas of mice and diabetic rats.23
Y-0452 is structurally distinct from fenofibrate, making it an
attractive lead; however, Y-0452 exhibits only weak on-target
would provide improved PPARa agonists.
Derivatives 9–14 were synthesized as shown in Scheme 1. Com-
mercially available 4-hydroxybenzaldehyde was coupled with var-
ious benzyl bromides 3–8 to afford benzaldehydes 3a-8a.
Treatment of 3a-8a with 3-aminobenzoic acid produced the
respective imines in situ, which were then reduced upon the addi-
tion of sodium triacetoxyborohydride to provide 9–14 in an unop-
timized 40–82% yield.
activity in biochemical PPAR
ifests a low level of agonism compared to known PPAR
a
assays (EC50 ꢁ 25–50 mM), and man-
a
agonists.23
Additionally, the highly-functionalized quinoline core of Y-0452
represents significant synthetic challenges regarding comprehen-
sive structure-activity relationship (SAR) studies. These aspects
inspired us to investigate the SAR of Y-0452 through molecular
simplification with a goal of enhancing synthetic tractability, tar-
In addition to the benzoic acid derivatives 9–14, we wanted to
incorporate the classical fibrate ‘‘head-group” with an aim to
get engagement, selectivity, and level of PPARa agonism. Towards
this initiative, we utilized structure-based approaches to design a
series of derivatives, which were then synthesized and evaluated
improve potency and instill selectivity for PPAR
forms.31 The preparation of these analogs is depicted in Scheme 2.
Commercially available 3-nitrophenol was coupled with ethyl
a over other iso-
for PPARa agonism. The results from these studies are reported
a-
herein.
bromoisobutyrate to afford 15, which was then reduced to the cor-
responding aniline (16) under catalytic hydrogenation conditions
(H2 and Pd/C in ethanol). Treatment of 16 with 3a, 4a, 6a, or 8a fol-
lowed by reduction with sodium triacetoxyborohydride yielded
17–20, respectively. Hydrolysis of the pendant ester gave the
desired products 21–24 in an unoptimized 46–88% yield.
To gain insight into the potential binding modes of Y-0452 to
PPAR , we conducted docking studies with the Schrödinger Drug
a
Discovery Suite. For these initial computational studies we selected
PDB 1K7L, a co-crystal structure of GW409544 (Fig. 1) bound to
human PPAR
higher selectivity for hPPAR
a (hPPARa
).25 Although GW409544 exhibits 10-fold
c
(EC50 = 0.28 nM) over hPPARa
With the focused subset of Y-0452 analogs in-hand, our efforts
(EC50 = 2.3 nM)25 this structure was selected on the basis that
detailed structural analyses of this chemotype and its interactions
with different hPPAR isoforms are available for comparison and the
data have been well-vetted in subsequent studies.25
shifted to the evaluation of these derivatives for PPAR
a agonism.
Preliminary evaluation utilized a commercially available PPAR
a
luciferase cell reporter assay (Indigo Biosciences). The cell-line
employed is engineered to constitutively express high-levels of
To validate our docking approach, constraints, and parameters,
GW409544 was extracted, exposed to MM2 energy-minimization,
hPPARa. Upon interaction with an agonist, hPPARa translocates
to the nucleus, binds to the PPAR response element (PPRE), and
and re-docked into the hPPARa ligand binding domain to ensure
upregulates gene transcription, including the inserted luciferase
Please cite this article in press as: Dou X.-Z., et al. Bioorg. Med. Chem. Lett. (2018), https://doi.org/10.1016/j.bmcl.2018.03.010

X.-Z. Dou et al. / Bioorganic & Medicinal Chemistry Letters xxx (2018) xxx–xxx
3
Fig. 2. A) Overlay of GW409544 extract (cyan) with GW409544 docked (orange). B) Y-0452 docked. Binding pocket cavity depicted by pale cyan surface, PDB: 1K7L. C)
Molecular deconstruction approach for Y-0452 to provide the targeted analogs.
Scheme 1. Synthesis of benzoic acid derivatives 9–14. Reagents and conditions: (a) benzyl bromide (i.e., 3–8), K2CO3, DMF, 80 °C, 12 h; (b) 3-aminobenzoic acid, toluene, 155
°C, 2 h; sodium triacetoxyborohydride, AcOH, THF, 0 °C to 25 °C, 12 h.
Scheme 2. Synthesis of 21–24. Reagents and conditions: (a) ethyl
a-bromoisobutyrate, K2CO3, DMF, 80 °C, 12 h; (b) H2, Pd/C, ethanol, 12 h; (c) aldehyde (i.e., 3a, 4a, 6a, or 8a),
toluene, 155 °C, 2 h; sodium triacetoxyborohydride, AcOH, THF, 0 °C to 25 °C, 12 h; (d) LiOHÁH2O, THF/MeOH/H2O, 12 h.
gene. Luciferase activity is detected indirectly through quantifica-
tion of oxyluciferin production. Initially, 9–14 and 21–24 were
evaluated at 5 mM and 50 mM to provide an idea of agonism-level
at two 10-fold increments. As shown in Fig. 3, a number of com-
appreciable activity at 5 mM, whereas the benzoic acid analogs 9–
14 all exhibit significant PPAR agonism at this lower concentra-
tion. Compounds 10 and 22 were selected for more detailed eval-
uation, and a more expansive 10-point dose-response assessment
was conducted to obtain EC50 values (Table 1): 10 (5.6 mM), and
22 (25.3 mM).
a
pounds exhibited levels of hPPARa agonism on par with or sur-
passing the positive control, GW590735 (5 mM and 10 mM), at
one or both of the concentrations evaluated. Direct comparison
of 9/21, 10/22, 12/23, 14/24 reveals that incorporation of the
To further confirm that this 4-benzyloxy-benzylamino chemo-
type acts as a PPAR
ous biochemical assays. As expected for a PPAR
induced the expression of PPAR in a dose-dependent manner
(Fig. 4A and B), as demonstrated by Western blot analysis using a
a
agonist, we evaluated compound 10 in vari-
fenofibrate ‘‘head-group” enhances the level of PPAR
a
agonism at
a
agonist, 10
50 mM. This data also indicates, however, that incorporation of
the fibrate ‘‘head-group” decreases potency, as 21–24 fail to elicit
a
Please cite this article in press as: Dou X.-Z., et al. Bioorg. Med. Chem. Lett. (2018), https://doi.org/10.1016/j.bmcl.2018.03.010

4
X.-Z. Dou et al. / Bioorganic & Medicinal Chemistry Letters xxx (2018) xxx–xxx
Fig. 3. Initial evaluation results of 9–14 and 21–24 for hPPARa agonism. Results presented from a single experiment as fold-induction versus the DMSO control S.E. (n = 3).
GW590735 was evaluated at 5 and 10 mM due to observed cytotoxicity at higher concentrations.
PPARa
target genes (Fig. 4C),32 including acyl-CoA dehydrogenase
Table 1
Human PPAR agonism of select analogs. Data are represented as the EC50 (mM) for the
agonism of the corresponding luciferase reporter cell-lines (Indigo Biosciences).
Dosing was done in triplicate as a single experiment. n.d. = not determined. Values in
parentheses indicate the ratio of agonism compared to GW590735.
medium chain (Acadm), carnitine palmitoyltransferase 1A (Cpt1a),
fatty acid binding protein 3 (Fabp3), and solute carrier family 25
member 20 (Slc25a20). Compound 10 was also evaluated in an
in vitro wound healing assay utilizing human retinal capillary
Compound
EC50
(lM)
endothelial cells (HRCEC). PPARa
agonism reduces cell migration12
hPPAR
a
hPPARd
hPPARc
and 10, indeed, inhibits wound closure in a dose-dependent fash-
10
22
26
28
5.6 (1.5)
25.3 (1.7)
5.1 (1.1)
2.1 (1.4)
0.012
n.d.
n.d.
52.4 (0.3)
>100
38.6
>100
8.9
n.d.
n.d.
>100
18.3
>100
5.6
n.d.
0.083
n.d.
ion (Fig. 4D).
Convinced that 4-benzyloxy-benzylamino derivatives exhibit
characteristic PPAR
tings, the selectivity of 10 for PPAR
PPAR was assessed. Luciferase assays were conducted on isogenic
cell-lines engineered to overexpress either PPARd or PPAR with
a
agonistic activity in several biological set-
a
agonism over PPARd and
GW590735
Rosiglitazone
GW0742
Y-0452
c
0.002
n.d.
c
n.d.
expression of the requisite luciferase reporter gene dependent
upon exogenous activation of each isoform. As shown in Table 1,
compound 10 exhibits ꢂ20-fold selectivity for hPPAR
hPPARd and hPPAR , whereas 22 displays pan-agonism. This is
interesting, as the fibrate ‘‘head-group” has been described as a
a over
cell line derived from C57BL/6N mouse photoreceptors (661 W).
Likewise, RT-PCR studies on the same cell-line confirm PPAR
agonism, as treatment with 10 induces the expression of various
c
a
Fig. 4. Biochemical analysis of 10. A) Western blot analysis of mouse 661 W cells after 24 h treatment with 10. B) Densitometry quantification of PPARa production from
Western blot analysis. C) RT-PCR analysis of mouse 661 W cells after 24 h (n = 6) treatment with 10. D) HRCEC wound healing assay results for both 10 h and 24 h incubation
time points. Experiments were performed three times in triplicate unless otherwise noted. All values shown are expressed as mean S.D. Differences between groups were
tested for statistical significance using the Student’s t-test. *P < 0.05, **P < 0.01, ***P < 0.001.
Please cite this article in press as: Dou X.-Z., et al. Bioorg. Med. Chem. Lett. (2018), https://doi.org/10.1016/j.bmcl.2018.03.010

X.-Z. Dou et al. / Bioorganic & Medicinal Chemistry Letters xxx (2018) xxx–xxx
5
GW590735ÁhPPAR
(see Supporting information). GW590735 is a selective PPAR
over PPARc
a co-crystal structure, for docking assessment
a
agonist that exhibits ꢂ500-fold selectivity for PPAR
a
and PPARd.31 As shown in Fig. 5A and B, compound 10 is pre-
dicted to bind in an orientation similar to GW590735. Interest-
ingly, however, 10 lacks the gem-dimethyl ‘‘head-group” and
amide linker domain, both of which have been postulated to
be critical determinants in GW590735 selectivity and major
enhancers of potency.31 The acid, however, for 10 is predicted
to make four hydrogen bonds with Ser280, Tyr314, His440, and
Tyr464, consistent with our hypothesis that deconstruction of
the Y-0452 quinoline core and transposition of the carboxylic
acid would provide a significant improvement in PPAR
a ago-
nism. We were interested if this 4-benzyloxy-benzylamino
chemotype could be expanded to take advantage of an apparent
amphiphilic pocket that lies below GW590735 (Fig. 5A) and is
comprised of Met330, Tyr334, Glu282, Thr279, Met320, Val324,
Leu321, Ile317, and Met220. We postulated that functionaliza-
tion of the B-ring meta to the ether linkage (Schemes 2 and 3)
on 10 would provide an optimal trajectory for accessing this
amphiphilic pocket. To the best of our knowledge, few PPAR
a
agonists exploit this pocket and little SAR exists regarding the
effect of occupying this domain on the level of agonism and/or
isoform selectivity.
To investigate the possible impact of occupying the amphiphilic
pocket, we synthesized two additional derivatives, 26 and 28
(Scheme 3). Briefly, commercially available 2,4-dihydroxyben-
zaldehyde was treated with 4-methoxybenzaldehyde in the pres-
ence of potassium carbonate in acetone to produce the di-p-
methoxybenzyl (PMB) functionalized resorcinol 25. This interme-
diate was coupled to either 3-aminobenzoic acid or 16 followed
by reduction of the resulting imine to provide analog 26 and the
methyl ester 27, respectively. Following saponification of 27, the
desired derivative 28 was obtained in 75% yield. Incorporation of
the 4-methoxybenzyl motif as the ‘‘third-arm” was rather arbitrary
at this point and was selected on belief that it 1) would be compat-
ible with the predicted binding environment and 2) could be easily
synthesized through dialkylation of an aldehyde already in our
chemical inventory.
Derivatives 26 and 28 were evaluated for hPPAR
a agonistic
activity and selectivity in the luciferase cell-lines. Analysis of the
data suggests that regarding the benzoic acid derivatives (compare
10 and 26), the additional 4-methoxybenzyl substituent does not
affect potency and maintains the selectivity, at least within the
range of doses evaluated. For derivatives containing the fibrate
‘‘head-group” (compare 22 and 28), however, the addition of the
third substituent on the B-ring resulted in a 10-fold improvement
in potency, but the pan-agonist profile was maintained. Both 26
and 28 were docked using our previously generated model and
as can be seen in Fig. 5C the additional 4-methoxybenzyl group
is, indeed, predicted to extend into the amphiphilic pocket. Exper-
imental validation is necessary to confirm the binding mode pre-
dicted by in silico methods, but thus far the SAR data seem to
support the models. Studies are ongoing to optimize each of the
Fig. 5. A) Co-crystallized (green) and docked (cyan) GW590735. B) Predicted
binding pose of 10. C) Predicted binding pose of 28. Binding pocket cavity depicted
by surface representation, PDB: 2P54.
critical feature for PPARa
selectivity,10 but with this 4-benzyloxy-
benzylamino chemotype it seems to be detrimental.
To better visualize the 4-benzyloxy-benzylamino derivatives
in the hPPARa binding pocket, we utilized PDB 2P54, the
Scheme 3. Synthesis of derivatives 26 and 27. Reagents and conditions: (a) 4-methoxybenzyl bromide, K2CO3, Acetone; (b) 3-aminobenzoic acid or 16, toluene, 155 °C, 2 h;
sodium triacetoxyborohydride, AcOH, THF, 0 °C to 25 °C, 12 h; (c) LiOHÁH2O, THF/MeOH/H2O, 12 h.
Please cite this article in press as: Dou X.-Z., et al. Bioorg. Med. Chem. Lett. (2018), https://doi.org/10.1016/j.bmcl.2018.03.010

6
X.-Z. Dou et al. / Bioorganic & Medicinal Chemistry Letters xxx (2018) xxx–xxx
three substituents on the B-ring and results will be reported in due
course.
References
1. Cai X, McGinnis JF. J Diabetes Res. 2016. Article ID 3789217.
2. Cheung N, Wong IY, Wong TY. Diabetes Care. 2014;37:900.
3. Simo R, Hernandez C. Prog Retin Eye Res. 2015;48:160.
4. Lois N, McCarter RV, O’Neill C, Medina RJ, Stitt AW. Front. Endocrinol.. 2014;5.
Article 44.
5. Berger J, Moller D. Annu. Rev. Med.. 2002;53:409.
6. Feige JN, Gelman L, Michalik L, Desvergne B, Wahli W. Prog Lipid Res.
2006;45:120.
7. Michalik L, Wahli W. Curr Opin Biotechnol. 1999;10:564.
8. Issemann I, Green S. Nature. 1990;347:645.
9. Willson TM, Brown PJ, Sternbach DD, Henke BR. J Med Chem. 2000;43:527.
10. Pirat C, Farce A, Lebegue N, et al. J Med Chem. 2012;55:4027.
11. Fruchart JC. Cardiovasc Diabetol. 2013;12:82.
In conclusion, we have leveraged in silico methods to provide
structure-guided insight towards the evolution of a new PPAR
a
agonistic chemotype. The results confirm our hypothesis that
transposition of the carboxylic acid and deconstruction of the rigid
quinoline core of Y-0452 provides a more synthetically tractable
class of analogs that exhibit promising PPARa agonism levels and
selectivity over other isoforms. Two classes of PPAR agonists have
emerged from the initial SAR studies; benzoic acid derivatives that
exhibit >20-fold selectivity for PPARa and a second class that con-
tains the classical fibrate head-group and exhibits pan-PPAR ago-
nism. The preliminary results presented suggest that a relatively
unexploited amphiphilic pocket provides a promising avenue to
interrogate in future SAR studies. Co-crystallization studies are
underway to provide more detailed insight into the specific
12. Chen Y, Hu Y, Lin M, et al. Diabetes. 2013;62:261.
13. Hu Y, Chen Y, Ding L, et al. Proc Natl Acad Sci USA. 2013;110:15401.
14. Ginsberg HN, Elam MB, Lovato LC, et al. N Engl J Med. 2010;362:1563.
15. Keech AC, Mitchell P, Summanen PA, et al. Lancet. 2007;370:1687.
16. Noonan JE, Jenkins AJ, Ma JX, Keech AC, Wang JJ, Lamoureux EL. Diabetes.
2013;62:3968.
ligand-protein interactions driving PPARa potency and selectivity
17. Gross B, Staels B. Best Pract Res Clin Endocrinol Metab. 2007;21:687.
18. Li J, Kennedy LJ, Shi Y, et al. J Med Chem. 2010;53:2854.
19. Nentwich MM, Ulbig MW. World J. Diabetes. 2015;6:489.
20. Nissen SE, Nicholls SJ, Wolksi K, et al. J Am Med Assoc. 2007;297:1362.
21. Wong TY, Simo R, Mitchell P. Am J Ophthalmol. 2012;154:6.
22. Cheng R, Ding L, He X, Takahashi Y, Ma JX. Diabetes. 2016;3730.
23. Deng G, Moran EP, Cheng R, et al. Invest Ophthalmol Vis Sci. 2017;58:5030.
24. Moran E, Ding L, Wang Z, et al. Invest Opthalmol Vis Sci. 2014;55:4568.
25. Xu HE, Lambert MH, Montana VG, et al. Proc Natl Acad Sci USA. 2001;98:13919.
26. Bernardes A, Souza PCT, Muniz JRC, et al. J Mol Biol. 2013;425:2878.
27. Capelli D, Cerchia C, Montanari R, et al. Sci Rep. 2016;6:34792.
28. Gangwal RP, Damre MV, Das NR, Sharma SS, Sangamwar AT. Bioorg Med Chem
Lett. 2015;25:270.
within this 4-benzyloxy-benzylamino chemotype.
Acknowledgments
Research reported in this publication was supported by the
National Eye Institute of the National Institutes of Health under
award number R21EY028279 (A.S.D.). The content is solely the
responsibility of the authors and does not necessarily represent
the official views of the National Institutes of Health.
29. Mizuno CS, Ma G, Khan S, Patny A, Avery MA, Rimando AM. Bioorg Med Chem.
2008;16:3800.
30. Nomura M, Tanase T, Ide T, et al. J Med Chem. 2003;46:3581.
31. Sierra ML, Beneton V, Boullay AB, et al. J Med Chem. 2007;50:685.
32. McMullen PD, Bhattacharya S, Woods CG, et al. Chem Biol Interact. 2014;209:14.
A. Supplementary data
Supplementary data associated with this article can be found, in
the online version, at https://doi.org/10.1016/j.bmcl.2018.03.010.
Please cite this article in press as: Dou X.-Z., et al. Bioorg. Med. Chem. Lett. (2018), https://doi.org/10.1016/j.bmcl.2018.03.010