Design and synthesis of selective, dual fatty acid binding protein 4 and 5 inhibitors

Article abstract of DOI:10.1016/j.bmcl.2016.08.071

Dual inhibition of fatty acid binding proteins 4 and 5 (FABP4 and FABP5) is expected to provide beneficial effects on a number of metabolic parameters such as insulin sensitivity and blood glucose levels and should protect against atherosclerosis. Starting from a FABP4 selective focused screening hit, biostructure information was used to modulate the selectivity profile in the desired way and to design potent dual FABP4/5 inhibitors with good selectivity against FABP3. With very good pharmacokinetic properties and no major safety alerts, compound 12 was identified as a suitable tool compound for further in vivo investigations.

Full text of DOI:10.1016/j.bmcl.2016.08.071

Bioorganic & Medicinal Chemistry Letters 26 (2016) 5092–5097
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Design and synthesis of selective, dual fatty acid binding protein
4 and 5 inhibitors
a
a
a
a
Holger Kühne a, , Ulrike Obst-Sander , Bernd Kuhn , Aurelia Conte , Simona M. Ceccarelli ,
Werner Neidhart a, Markus G. Rudolph a, Giorgio Ottaviani a, Rodolfo Gasser a, Sung-Sau So b, Shirley Li b,
Xiaolei Zhang b, Lin Gao b, Michael Myers b
⇑
a Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, 4070 Basel, Switzerland
b Hoffmann-La Roche Inc., 340 Kingsland Street, Nutley, NJ 07110, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Dual inhibition of fatty acid binding proteins 4 and 5 (FABP4 and FABP5) is expected to provide beneficial
effects on a number of metabolic parameters such as insulin sensitivity and blood glucose levels and
should protect against atherosclerosis. Starting from a FABP4 selective focused screening hit, biostructure
information was used to modulate the selectivity profile in the desired way and to design potent dual
FABP4/5 inhibitors with good selectivity against FABP3. With very good pharmacokinetic properties
and no major safety alerts, compound 12 was identified as a suitable tool compound for further
in vivo investigations.
Received 18 July 2016
Revised 18 August 2016
Accepted 20 August 2016
Available online 22 August 2016
Keywords:
FABP4
FABP5
Ó 2016 Published by Elsevier Ltd.
Structure-based design
Quinoline derivatives
Fatty acid binding proteins 4 and 5 (FABP4 and FABP5) are
members of a family of small, soluble proteins which contribute
to the trafficking of fatty acids within the cytosolic compartments
of cells. The proteins have no catalytic function but transport
hydrophobic fatty acids within the aqueous environment of the
cytosol to the various destinations enabling fatty acid oxidation,
membrane homeostasis or nuclear signaling. In addition, they are
likely involved in signaling processes which are so far poorly
understood.1–4
FABP4 is highly expressed in adipose tissue, macrophages and
endothelial cells. FABP5 is also expressed in macrophages and
endothelial cells, as well as in skin and several other tissues.3,5
We became interested in FABP4 and FABP5 as targets for inhibi-
tion after the discovery that genetic deletion of FABP4 and FABP5
in mice improves insulin sensitivity, lowers glucose, and protects
against atherosclerosis.4 In a clamp study in ob/ob mice, a specific
FABP4 inhibitor (BMS309403) showed a reduction of hepatic glu-
cose production, increased glucose uptake in muscle and adipose
tissue, and reduction in hepatic steatosis, but no change in body
weight and energy consumption. Additionally, this compound
showed a decrease in atherosclerotic plaque formation in ApoE
KO mice.6
In humans, plasma levels of FABP4 are increased in patients
with metabolic syndrome and atherosclerosis.7 In addition, there
is growing evidence for involvement of FABP4 in angiogenesis8
and growth of certain tumors.9 Increased levels of FABP5 have been
found in human breast cancers and experimental results suggested
that FABP5 is critical for mammary tumor development.10
The FABP family comprises nine isoforms, which differ in their
sequence and tissue distribution, but have remarkably similar
structures.4 Our goal was to provide a dual FABP4/5 inhibitor selec-
tive against other FABP isoforms with good physicochemical and
pharmacokinetic properties suitable as a tool for testing in models
of metabolic diseases, angiogenesis or tumor growth. As selectivity
filter, we chose activity against the structurally closely related
FABP3 and the less similar FABP1.
A number of FABP inhibitors have been described in the litera-
ture. The pyrazole BMS309403 (1)6,11 has been used extensively as
a tool for FABP4 inhibition, both in vitro and in vivo.12,13 Other
structurally diverse compounds include indoles from Biovitrum
(2),14 thiophenes from the University of Minnesota (3),15 as well
as non-carboxylic acids from Biovitrum (4),16 and Merck (5).12
We tested a selection of published FABP inhibitors in our FABP
binding assays measuring the displacement of a fluorescently
labeled fatty acid.17 However, we could not identify dual acting
FABP4/5 inhibitors of reasonable selectivity against other FABP iso-
forms. Moreover, most compounds had no activity against FABP5
(Fig. 1).
⇑
Corresponding author. Tel.: +41 616889176.
E-mail address: holger.kuehne@roche.com (H. Kühne).
http://dx.doi.org/10.1016/j.bmcl.2016.08.071
0960-894X/Ó 2016 Published by Elsevier Ltd.

H. Kühne et al. / Bioorg. Med. Chem. Lett. 26 (2016) 5092–5097
5093
O
HO2C
S
O
O
N N
O
HO
N
N
H
NH2
S
HO
O
MeO2C
BMS309403 (1)
2
3
N
CF3
N
N
H
N
N
HO2C
Cl
N
N
HO
N
S
O
O
O
Cl
4
5
focused screening hit (6)
Figure 1. Structure of some published FABP4 inhibitors and focused screening hit quinoline 6.
To identify novel chemical starting points for our program we
conducted a focused screen against FABP4 and profiled the hits
additionally against the FABP3 and 5 isoforms. The screening set
consisted of about 1200 molecules from the Roche compound
library which were selected based on 2D18,19 and 3D similarity20
to published FABP inhibitors. Although a number of structurally
diverse candidates were found, most of the compounds were
devoid of FABP5 activity. We decided to select hits for optimization
based on their physicochemical and eADME properties and tried to
design-in the desired dual FABP4/5 activity and selectivity against
other FABP isoforms, especially FABP3. The quinoline carboxylic
acid 6 appeared to be a good starting point (Table 1).
Despite the fact that compound 6 did not have the desired dual
FABP4/5 selectivity profile, it turned out to be a very attractive
starting point due to its favorable eADME properties such as high
solubility, good permeability, low clearance in both human and
mouse microsomes and low potential for drug–drug interactions.
Considering the mostly lipophilic nature of the FABP4 binding
pocket, compound 6 has a surprisingly low logD, which in combi-
nation with the low molecular weight offered good opportunities
for further optimization. In addition, a crystal structure from the
complex of 6 with FABP4 was obtained early in the program
revealing its binding mode (Fig. 2). The ligand occupies a buried
hydrophobic pocket with limited solvent access. The carboxylate
group is engaged in a direct hydrogen bond with the guanidinium
group of Arg127 as well as in two water-mediated hydrogen bonds
Figure 2. Crystal structure of human FABP4 with compound 6 (PDB code: 5edb).
Protein residues are colored in green and the ligand in cyan. Water molecules are
shown as red spheres. Favorable protein–ligand interactions23 are shown as dashed
lines (red: hydrogen bond, orange: p–p, blue: dispersion).
ligand binding site. To identify these regions, we overlaid the crys-
tal structure from Figure 2 with co-crystal structures of all three
isoforms with the common ligand palmitic acid. From this analysis,
several amino acids could be identified that are in close proximity
to bound compound 6 and differ between FABP4, 5 and 3. As illus-
trated in Figure 3, four potential selectivity regions S1–S4 were
identified, suggesting small differences in pocket size and shape
between the three isoforms. Regions S1, S3 and S4 were most
attractive as they could be readily reached with different sub-
stituents from the 4-phenyl quinoline scaffold of 6.
We first focused our attention on region S4 because our analysis
suggested a smaller binding pocket for FABP3 due to the presence
of three Leu side chains which are bulkier compared to the set of
Ile, Val, Cys residues in FABP4 and 5. Moreover, the quinoline 2-
position was ideally suited to target this region. Increasing the size
of the quinoline 2-substituent from methyl to isopropyl (com-
pound 7) to provoke a steric clash with FABP3 already changed
the activity profile in the desired way. Not only did this modifica-
tion lead to a drop of the FABP3 inhibition constant from 0.093 to
with Tyr129. A large number of apolar p–p and dispersion interac-
tions are made between the remainder of the inhibitor and the
many lipophilic side chains pointing into the binding cavity.
One structure-based approach to modulate the selectivity pro-
file of a small molecule is to exploit sequence differences in the
Table 1
Properties of screening hit 6
hFABP4: Ki (
hFABP5: Ki (
hFABP3: Ki (
lM)
lM)
lM)
0.105
>23.2
0.093
logD (pH 7.4)
À0.44
Solubility (
l
g/ml)a
>355
Permeability (10À6 cm/s)b
0.23
CYP450 (3A4/2D6/2C9): IC50
CLint h/m (
(lM)
>50/>50/>50
<10/<10
l
l/min/mg of protein)c
a
b
c
LYSA21
.
PAMPA22
From incubation with human and mouse liver microsomes.
.
0.39
lM, it also afforded the first compound in this series with
measurable FABP5 activity. The concomitant strong gain in binding

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H. Kühne et al. / Bioorg. Med. Chem. Lett. 26 (2016) 5092–5097
Next we probed selectivity region S1 with small substituents in
the quinoline 8-position. This region contains Leu in FABP3 and
FABP5, and a smaller Val residue in FABP4. Replacing the hydrogen
in 8-position of compound 8 by –Cl (9) or –Me (10) led to a ꢀ5-fold
affinity increase in FABP5 and to a >25-fold gain for FABP3. Ki val-
ues for FABP4 changed only slightly within a factor of 2. Due to the
strong affinity enhancement for FABP3, compounds 9 and 10 are no
longer selective against this isoform. A subsequently determined
crystal structure of 9 in complex with FABP3 could rationalize
the improved binding to this isoform (Fig. 4b). The additional –Cl
substituent nicely fills a small cavity in the FABP3 binding site
which is formed by the side chains of Tyr20, Leu24, and Arg79,
and makes three short non-bonded contacts with distances
<4.0 Å to each of these amino acids. Further increasing the size of
this substituent, e.g. by an ethyl substituent, led again to an affinity
decrease for FABP3, and to a smaller extent also for FABP5 (data not
shown).
In line with the sequence conservation in this part of the bind-
ing site (S1), the SAR at the 8-position is qualitatively similar for
FABP3 and FABP5. The much steeper SAR for FABP3 suggests that
this isoform might be more rigid in selectivity region S1 compared
to FABP5.
Finally, we explored selectivity region S3 by addition of meta-
substituents to the quinoline 4-phenyl moiety. We discovered that
this position is suitable to obtain very selective FABP4 ligands such
as compound 11. The binding mode of compound 11 in FABP4
(Fig. 4c) shows several favorable dispersion interactions of the iso-
propyl-substituent at R3 with carbon atoms of the protein. The
crystal structure suggests that only the smaller Ser54 residue in
FABP4 is able to accommodate an isopropyl group at this position
while the bulkier Thr present in FABP3 and FABP5 might cause a
steric clash with the ligand resulting in FABP4 selective com-
pounds (Table 2).
For the most selective dual FABP4/5 inhibitor 8, bioisosteric
replacements of the carboxylic acid group were investigated
(Table 3). Tetrazole (12), oxadiazolone (13), and oxadiazolthione
(14) derivatives all retain good binding affinities to FABP4. With
all replacements the affinity to FABP5 could be improved and
selectivity against FABP3 was maintained. Despite a favorable
selectivity profile, the oxadiazole derivatives 13 and 14 were less
attractive, as these carboxylic acid replacements render the com-
pounds considerably more lipophilic and less soluble. A crystal
structure of 12 in FABP5 was determined revealing interesting
intermolecular interactions of the tetrazole head group (Fig. 5).
Figure 3. (a) 1-D sequence view of amino acid differences of human FABP3, 4, and 5
in close contact (65.5 Å) to bound compound 6 as identified from an overlay of the
co-crystal structures: FABP4-compound 6 (PDB code: 5edb), FABP3-palmitic acid
(2hmb), FABP4-palmitic acid (2hnx), and FABP5-palmitic acid (1b56). Selectivity
regions are (hFABP4 numbering): S1 (V24), S2 (T30, V33, A34, A37, F58), S3 (S54),
and S4 (I105, V116, C118). Numbering for hFABP3 is as for hFABP4; for hFABP5
numbers are shifted by +2. (b) 3-D structure view of (a). Only protein residues from
the fatty acid-bound structures are shown.
to FABP4 suggests that the S4 pocket was not optimally filled with
the original methyl substituent. Further increasing the size of the
quinoline 2-substituent to piperidinyl led to compound 8, which
keeps its activity on FABP4 and 5, but has >20-fold reduced FABP3
affinity compared to 7. An overlay of the complex crystal structure
of 8 in FABP4 with 6 in FABP3 indicates strong repulsive interac-
tions of the piperidinyl substituent in FABP3, which likely explains
the >100-fold weaker FABP3 activity of 8 versus 6 (Fig. 4a).
a)
b)
c)
Figure 4. (a) Overlay of co-crystal structures of human FABP4 with compound 8 (protein: green, ligand: cyan, PDB code: 5edc) with human FABP3 bound to compound 6
(protein: orange, ligand: magenta, PDB code: 5hz9). Protein residues of selectivity region S4 are highlighted as sticks. Electron density is rather weak for the piperidinyl group
in 5edc. Two conformations for the sidechain of Cys118 and for the ligand piperidinyl were used to model the electron density of this complex. (b) Crystal structure of human
FABP3 with compound 9 (PDB code: 5hz8). Protein residues are colored in orange and those residues with short contacts <4.0 Å (dashed blue lines) to the 8-chlorine
substituent of the ligand (magenta) are highlighted as sticks. (c) Crystal structure of human FABP4 with compound 11 (PDB code: 5hz6). Protein residues are colored in green
and those residues with short contacts <4.0 Å (dashed blue lines) to the isopropyl substituent at R3 of the ligand (cyan) are highlighted as sticks.

H. Kühne et al. / Bioorg. Med. Chem. Lett. 26 (2016) 5092–5097
5095
Table 2
Exploration of selectivity
R2
R1
N
HO2C
Cl
R3
R1
N
N
N
R2/R3
No.
H/H
7
H/H
8
Cl/H
9
CH3/H
10
H/iPr
11
hFABP4: Ki (
hFABP5: Ki (
hFABP3: Ki (
l
l
l
M)
M)
M)
0.012
1.2
0.39
0.022
0.50
10.2
0.82
>435
6.99
0.016
0.12
0.40
1.67
395
0.013
0.10
0.10
2.14
>465
0.016
4.3
22.4
1.67
>455
6.47
logD (pH 7.4)
À0.11
Solubility (
l
g/ml)
>370
Permeability (10À6 cm/s)
1.96
2.98
1.78
CYP450 (3A4/2D6/2C9): IC50
CLint h/m (ll/min/mg)
(lM)
>50/>50/>50
<10/<10
>50/>50/>50
<10/<10
>50/>50/21
<10/<10
16/42/12
<10/<10
>50/>50/9.7
17/<10
Table 3
Carboxylic acid bioisosteres
N
N
R
Cl
Ph
N
N
N
HN
O
N
N
HN
R
NH
O
O
13
S
14
No.
12 (RO6806051)
hFABP4: Ki (
hFABP5: Ki (
hFABP3: Ki (
lM)
lM)
lM)
0.011
0.086
2.3
0.020
0.167
9.7
0.007
0.133
4.1
logD (pH 7.4)
2.12
>420
3.4
3.53
<1
0.06
>50/38/11
2.87
108
1.44
Solubility (
l
g/ml)
Permeability (10À6 cm/s)
CYP450 (3A4/2D6/2C9):
>50/33/13
15/47/3.5
IC50
CLint h/m (
(
l
M)
Figure 5. Crystal structure of human FABP5 with compound 12 (PDB code: 5hz5).
Protein residues are colored in green and the ligand in salmon. Water molecules are
shown as red spheres. Protein residues in contact with the tetrazole head group are
highlighted as sticks. Electron density is weak for the piperidinyl group. Two
conformations for the sidechain of Cys120 and for the ligand piperidinyl were
required to model the electron density. Intermolecular interactions of the ligand
tetrazole are shown as dashed lines (red: hydrogen bond, blue: dispersion).
ll/min/mg)
<10/<10
19/40
<10/18
While all four nitrogen lone pairs of the tetrazole are engaged in
either direct (Arg129, Tyr131) or water mediated hydrogen bonds,
an additional dispersion interaction between the Cc of Thr56 and
bioavailability, low clearance, moderate volume of distribution
and a half-life of more than 5 h after oral application (Table 4).
Detailed synthetic pathways to new quinoline derivatives 7–14
are depicted in Schemes 1–5, respectively.17 Compounds 6 and 7
were obtained by condensation reaction of amino-benzophenone
15a with the appropriate b-ketoester and subsequent ester cleav-
age (Scheme 1).
Synthesis of compounds 8, 9 and 10 (Scheme 2) started with
amide formation between amino-benzophenone derivatives 15a-
c and methyl 3-chloro-3-oxopropanoate followed by cyclization
to quinolone derivatives 17a–c with NaOMe. Treatment of 17a–c
with POCl3 afforded 2-chloro-quinoline derivatives 18a–c. Com-
pound 8 was prepared from 18a by reaction with piperidine and
subsequent ester cleavage. Due to the strong steric hindrance of
the apolar side of the head group can be detected. We hypothesize
that the additional gains in binding affinity for FABP5 and FABP3
for the carboxylate replacements might be due to this additional
dispersion interaction which is not possible with the analogous
Ser in FABP4.
As a potent dual FABP4/5 inhibitor with good selectivity and an
appealing eADME profile, tetrazole derivative 12 (RO6806051) was
profiled in more detail. When 12 was tested against a panel of 72
receptors, channels, transporters and 25 enzymes, it showed no
significant interaction with any of the targets at a concentration
of 10
lM. In addition, compound 12 exhibited no interaction with
the hERG channel (IC20 > 10
l
M) and tested negative in the Ames
and micronucleus test. In vivo pharmacokinetic studies in mouse
revealed a very attractive profile with nearly complete oral

5096
H. Kühne et al. / Bioorg. Med. Chem. Lett. 26 (2016) 5092–5097
Ph
Ph
Ph
N
Table 4
a
b,c
Cl
Cl
CN
O
Cl
CN
N
Pharmacokinetic properties of 12 in mouse
O
Parameter
Value
NH2
N
H
iv dose (3.3 mg/kg)
CL (ml/min/kg)
Vss (l/kg)
5.8
3.3
15a
21
22
po dose (8.4 mg/kg)
Bioavailability F (%)
t1/2 (h)
N
Ph
N
N
99
5.8
<0.26
N
d
Cl
N
PPB (% unbound)
H
N
12
Ph
Ph
N
Ph
N
Cl
Cl
CO2Et
R
Cl
CO2H
R
a
b
Scheme 4. Reagents and conditions: (a) ethyl 2-cyanoacetate, CeCl3–7H2O (cat.),
200 °C (microwave), 0.5 h, 32%; (b) POCl3, reflux, 1 h, 76%; (c) piperidine, TEA, DMF,
120 °C (microwave), 0.3 h, 85%; (d) azidotrimethyltin, xylene, 120 °C, 48 h, 49%.
O
NH2
15a
16a (R = Me)
16b (R = iPr)
6 (R = Me)
7 (R = iPr)
Ph
Ph
Scheme 1. Reagents and conditions: (a) for R = Me: ethyl 3-oxobutanoate, TMSCl,
DMF, 100 °C (sealed tube). o.n., 60%; for R = iPr: ethyl 4-methyl-3-oxo-pentanoate,
Yt(OTf)3, EtOH, rt, o.n., 28%; (b) for R = Me: NaOH, EtOH, reflux, o.n. 56%; for R = iPr:
KOH, MeOH/H2O/THF, 65 °C, 50 h, 77%.
Cl
CO2Me
O
Cl
CO2H
O
a
b
N
H
N
H
17a
23
Ph
Ph
Ph
N
Ph
O
N
CO2Me
O
CO2Me
Cl
Cl
Cl
Cl
a,b
c
Ph
O
O
Cl
NH2
H
N
c
N
Cl
H
N
H
Fmoc
NH2
N
H
N
R
R
R
N
Cl
17a (R = H)
17b (R = Cl)
17c (R = Me)
18a (R = H)
18b (R = Cl)
18c (R = Me)
15a (R = H)
15b (R = Cl)
15c (R = Me)
24
25
X
Ph
O
N
NH
Cl
Ph
N
d or e
N
Cl
CO2H
N
d,e or f
N
R
13 (X = O)
14 (X = S)
8 (R = H)
9 (R = Cl)
10 (R = Me)
Scheme 5. Reagents and conditions: (a) LiOH, EtOH, 50 °C, 72 h, 95%; (b) (i) POCl3,
120 °C, o.n., (ii) Fmoc-hydrazine, DCM, rt, 4 h. 60%; (c) piperidine, TEA, DMF, 120 °C,
3 h, 82%; (d) CDI, TEA, THF, rt, 2 h, 87%; (e) CS2, KOH, EtOH, reflux, o.n., 74%.
Scheme 2. Reagents and conditions: (a) methy 3-chloro-3-oxopropanoate, DCM,
0 °C to rt, 3 h, 93–95%; (b) NaOMe, MeOH, rt, 1 h. 90–99%; (c) POCl3, reflux, o.n., 84–
92%; (d) for R = H: piperidine, TEA, DMF, 130 °C (microwave), 0.3 h, 74%; (e) LiI,
pyridine, reflux, o.n., 99%; (f) for R = Cl, Me: piperidine, pyridine, reflux (sealed
tube); 48 h, 50–99%.
tive 20 which can be further elaborated into compound 11 by
Suzuki coupling with (3-isopropylphenyl)boronic acid and subse-
quent ester cleavage (Scheme 3).
The synthesis of tetrazole derivative 12 started by condensation
reaction of 15a and ethyl 2-cyanoacetate to obtain quinolone 21.
Chlorination of 21 with POCl3 followed by reaction with piperidine
provided intermediate 22 which was converted into 12 by reaction
with azidotrimethyltin (Scheme 4).
Oxadiazole derivatives 13 and 14 were synthesized starting
from quinolone 17a (Scheme 5). Reaction of 17a with LiOH pro-
vided intermediate 23 which was reacted with POCl3 to convert
the carboxylic acid to the acid chloride and the quinolone into
the corresponding 2-chloro-quinoline at the same time. The crude
product of this chlorination reaction was immediately reacted with
Fmoc protected hydrazine to obtain hydrazide derivative 24. Treat-
ment of 24 with piperidine introduced the piperidinyl substituent
in the quinoline 2-position and simultaneously cleaved the Fmoc
protecting group. Final reaction of 25 with CDI or CS2 provided
the oxadiazole derivatives 13 or 14 respectively.
OTf
N
O
a,b
c,d
Cl
CO2Me
Cl
O
Cl
CO2H
N
H
O
N
20
11
19
Scheme 3. Reagents and conditions: (a) methyl 4-methyl-3-oxo-pentanoate, NaH,
DMA, 0–120 °C, 1 h, 42%; (b) NaH, PhN(Tf)2, DMF, rt, 2 h. 95%.
the ester group, cleavage is most effective with LiI in pyridine.
Compounds 9 and 10 were prepared from 18b and 18c in one step
with piperidine in pyridine in
nucleophilic substitution reaction and the ester cleavage
simultaneously.
a sealed tube, effecting the
In summary, we describe the structure-based design of a novel
class of selective, dual FABP4/5 inhibitors. Several selectivity pock-
ets could be identified by a structural bioinformatics analysis and
Starting from isatoic anhydride derivative 19, reaction with
methyl 4-methyl-3-oxo-pentanoate followed by reaction with N-
phenyl-bis(trifluoromethanesulfonimide) provided triflate deriva-

H. Kühne et al. / Bioorg. Med. Chem. Lett. 26 (2016) 5092–5097
5097
9. Nieman, K. M.; Kenny, H. A.; Penicka, C. V.; Ladanyi, A.; Buell-Gutbrod, R.;
Zillhardt, M. R.; Romero, I. L.; Carey, M. S.; Mills, G. B.; Hotamisligil, G. S.;
Yamada, D. S.; Peter, M. E.; Gwin, K.; Lengyel, E. Nat. Med. 2011, 17, 1498.
10. Levi, L.; Lobo, G.; Doud, M. K.; von Lintig, J.; Seachrist, D.; Tochtrop, G. P.; Noy,
N. Cancer Res. 2013, 73, 4770.
11. Sulsky, R.; Magnin, D. R.; Huang, Y.; Simpkins, L.; Taunk, P.; Patel, M.; Zhu, Y.;
Stouch, T. R.; Bassolino-Klimas, D.; Parker, R.; Harrity, T.; Stoffel, R.; Taylor, D.
S.; Lavoie, T. B.; Kish, K.; Jacobson, B. L.; Sheriff, S.; Adam, L. P.; Ewing, W. R.;
Robl, J. A. Bioorg. Med. Chem. Lett. 2007, 17, 3511.
three of them were targeted with specific substitution on the
quinoline core. This allowed us to change the selectivity profile
from a dual FABP3/4 screening hit to a dual FABP4/5 inhibitor with
optimized activity. The most advanced derivative 12 (RO6806051)
has a very good selectivity profile, favorable physico-chemical
properties and no major safety alert. The attractive pharmacoki-
netic profile in mouse makes 12 a suitable tool compound for fur-
ther in vivo pharmacological investigations.
12. Lan, H.; Cheng, C. C.; Kowalski, T. J.; Pang, L.; Shan, L.; Chuang, C.; Jackson, J.;
Rojas-Triana, A.; Bober, L.; Liu, L.; Voigt, J.; Orth, P.; Yang, X.; Shipps, G. W., Jr.;
Hedrick, J. A. J. Lipid Res. 2011, 52, 646.
Acknowledgments
13. Lee, M. Y. K.; Li, H.; Xiao, Y.; Zhou, Z.; Xu, A.; Vanhoutte, P. M. Br. J. Pharmacol.
2011, 162, 1564.
14. Barf, T.; Lehmann, F.; Hammer, K.; Haile, S.; Axen, E.; Medina, C.; Uppenberg, J.;
Svensson, S.; Rondahl, L.; Lundbäck, T. Bioorg. Med. Chem. Lett. 2009, 19, 1745.
15. Hertzel, A. V.; Hellberg, K.; Reynolds, J. M.; Kruse, A. C.; Juhlmann, B. E.; Smith,
A. J.; Sanders, M. A.; Ohlendorf, D. H.; Suttles, J.; Bernlohr, D. A. J. Med. Chem.
2009, 52, 6024.
The authors gratefully acknowledge contributions by Eva Anna
Krafft, Quentin Strebel, Marianne Rueher, Patrick Boissin, Noemi
Raschetti, Jitka Weber, Andreas Ehler, Dave Solis and Jeff Tilley.
16. Ringom, R.; Axen, E.; Uppenberg, J.; Lundbäck, T.; Rondahl, L.; Barf, T. Bioorg.
Med. Chem. Lett. 2004, 14, 4449.
References and notes
17. Ceccarelli, S. M.; Conte, A.; Kuehne, H.; Kuhn, B.; Neidhart, W.; Obst Sander, U.;
Rudolph, M. WO 2,013,064,465; Chem. Abstr. 2013, 158, 679208.
18. Hassan, M.; Brown, R. D.; Varma-O’brien, S.; Rogers, D. Mol. Divers. 2006, 10,
283.
19. Stahl, M.; Mauser, H.; Tsui, M.; Taylor, N. R. J. Med. Chem. 2005, 48, 4358.
20. Hawkins, P. C. D.; Skillman, A. G.; Nicholls, A. J. Med. Chem. 2007, 50, 74.
21. Aqueous solubility was measured by lyophilization solubility assay (LYSA).
Solubility was measured from lyophilized DMSO stock solutions
spectrophotometrically at pH 6.5 in a 50 mM phosphate buffer.
22. Parallel artificial membrane permeation assay (PAMPA). See: Kansy, M.;
Senner, F.; Gubernator, K. J. Med. Chem. 1998, 41, 1007.
1. Hotamisligil, G. S.; Bernlohr, D. A. Nat. Rev. Endocrinol. 2015, 11, 592.
2. Hardaway, A. L.; Podgorski, I. Future Med. Chem. 2013, 5, 1089.
3. Furuhashi, M.; Ishimura, S.; Ota, H.; Miura, T. Int. J. Inflammation 2011 642612.
4. Furuhashi, M.; Hotamisligil, G. S. Nat. Rev. Drug Disc. 2008, 7, 489.
5. Thumser, A. E.; Moore, J. B.; Plant, N. J. Curr. Opin. Clin. Nutr. Metab. Care 2014,
17, 124.
6. Furuhashi, M.; Tuncman, G.; Görgün, C. Z.; Makowski, L.; Atsumi, G.;
Vaillancourt, E.; Kono, K.; Babaev, V. R.; Fazio, S.; Linton, M. F.; Sulsky, R.;
Robl, J. A.; Parker, R. A.; Hotamisligil, G. S. Nature 2007, 447, 959.
7. For a review see: Kralisch, S.; Fasshauer, M. Diabetologia 2013, 56, 10.
8. Elmasri, H.; Ghelfi, E.; Yu, C.; Traphagen, S.; Cernadas, M.; Cao, H.; Shi, G.;
Plutzky, J.; Sahin, M.; Hotamisligil, G.; Cataltepe, S. Angiogenesis 2012, 15, 457.
23. Kuhn, B.; Fuchs, J. E.; Reutlinger, M.; Stahl, M.; Taylor, N. R. J. Chem. Inf. Model.
2011, 51, 3180.