Design, synthesis and evaluation of MCH receptor 1 antagonists - Part III: Discovery of pre-clinical development candidate BI 186908

Article abstract of DOI:10.1016/j.bmcl.2015.05.065

Abstract Although overweight and obesity are highly prevalent conditions, options to treat them are still very limited. As part of our search for safe and effective MCH-R1 antagonists for the treatment of obesity, two series of pyridones and pyridazinones

Full text of DOI:10.1016/j.bmcl.2015.05.065

Accepted Manuscript
Design, synthesis and evaluation of MCH Receptor 1 antagonists – Part III:
Discovery of pre-clinical development candidate BI 186908
Thorsten Oost, Armin Heckel, Jörg T. Kley, Thorsten Lehmann, Stephan
Müller, Gerald J. Roth, Klaus Rudolf, Kirsten Arndt, Ralph Budzinski, Martin
Lenter, Ralf R.H. Lotz, Gerd-Michael Maier, Michael Markert, Leo Thomas,
Dirk Stenkamp
PII:
S0960-894X(15)00539-9
DOI:
http://dx.doi.org/10.1016/j.bmcl.2015.05.065
BMCL 22755
Reference:
Bioorganic & Medicinal Chemistry Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
10 April 2015
22 May 2015
24 May 2015
Please cite this article as: Oost, T., Heckel, A., Kley, J.T., Lehmann, T., Müller, S., Roth, G.J., Rudolf, K., Arndt,
K., Budzinski, R., Lenter, M., Lotz, R.R.H., Maier, G-M., Markert, M., Thomas, L., Stenkamp, D., Design, synthesis
and evaluation of MCH Receptor 1 antagonists – Part III: Discovery of pre-clinical development candidate BI
186908, Bioorganic & Medicinal Chemistry Letters (2015), doi: http://dx.doi.org/10.1016/j.bmcl.2015.05.065
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Design, synthesis and evaluation of MCH
Receptor 1 antagonists – Part III: Discovery
of pre-clinical development candidate
BI 186908
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Thorsten Oost, Armin Heckel, Jörg T. Kley, Thorsten Lehmann, Stephan G. Müller, Gerald J. Roth, Klaus
Rudolf, Kirsten Arndt, Ralph Budzinski, Martin Lenter, Ralf R. H. Lotz, Gerd-Michael Maier, Michael Markert,
Leo Thomas, and Dirk Stenkamp
Boehringer Ingelheim Pharma GmbH & Co. KG, Research Germany, Birkendorfer Str. 65, 88397 Biberach an
der Riss, Germany
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Bioorganic & Medicinal Chemistry Letters
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Design, synthesis and evaluation of MCH Receptor 1 antagonists – Part III:
Discovery of pre-clinical development candidate BI 186908
Thorsten Oosta,∗, Armin Heckela, Jörg T. Kleya, Thorsten Lehmanna, Stephan Müllera, Gerald J. Rotha,
Klaus Rudolfa, Kirsten Arndtb, Ralph Budzinskib, Martin Lenterb, Ralf R. H. Lotzc, Gerd-Michael Maierc,
Michael Markertc, Leo Thomasb, and Dirk Stenkampa
a Boehringer Ingelheim Pharma GmbH & Co. KG, Department of Medicinal Chemistry
bBoehringer Ingelheim Pharma GmbH & Co. KG, Department of Cardiometabolic Research
cBoehringer Ingelheim Pharma GmbH & Co. KG, Department of Drug Discovery Support
Research Germany, Birkendorfer Str. 65, 88397 Biberach an der Riss, Germany
ARTICLE INFO
ABSTRACT
Article history:
Received
Although overweight and obesity are highly prevalent conditions, options to treat them are still
very limited. As part of our search for safe and effective MCH-R1 antagonists for the treatment
of obesity, two series of pyridones and pyridazinones were evaluated. Optimization was aimed
at improving DMPK properties by increasing metabolic stability and improving the safety
profile by reducing inhibition of the hERG channel and reducing the potential to induce
phospholipidosis. Steric shielding of a labile keto moiety with an ortho-methyl group and fine-
tuning of the polarity in several parts of the molecule resulted in BI 186908 (11g), a potent and
selective MCH-R1 antagonist with favorable DMPK and CMC properties. Chronic
administration of BI 186908 resulted in significant body weight reduction comparable to
sibutramine in a 4 week diet-induced obesity model in rats. Based on its favorable safety profile,
BI 186908 was advanced to pre-clinical development.
Revised
Accepted
Available online
Keywords:
Melanin-concentrating hormone (MCH)
MCH-R1 antagonists
Pyridazinone chemistry
Phospholipidosis
©2014 Elsevier Ltd. All rights reserved.
hERG inhibition
Obesity is a major risk factor in the modern world and
associated with many serious diseases of the metabolic syndrome
such as type 2 diabetes, dyslipidemia, coronary heart disease, and
stroke. Consequently, the pharmaceutical industry has made
major efforts over the last decades to develop new effective and
safe treatments of obesity; nevertheless, current treatment options
are still limited. A number of approaches have targeted central
mechanisms regulating food consumption and energy
homeostasis. The melanin-concentrating hormone (MCH), a
cyclic 19-amino acid polypeptide, has been a focus of obesity
research since the turn of the millennium. Despite many efforts of
the pharmaceutical industry to develop MCH-R1 antagonists as
potential anti-obesity agents, only few compounds have been
advanced to the clinical stage1. Safety concerns such as hERG
inhibition, potentially leading to cardiac liabilities, or
phospholipidosis2 were among the prominent reasons for the
discontinuation of research programs in the past3,4. Thus, in order
to assess the full therapeutic potential of the MCH-R1 antagonist
therapeutic concept, potent and safe antagonists with adequate
DMPK properties are required.
Our group has previously reported on a novel series of potent
and selective pyridazines 25 that was originally derived from the
alkyne class 1 (Figure 1)6. Based on two-dimensional structural
considerations, we reasoned that a molecular topology similar to
the pyridazine class 2 could be obtained by replacing the central
4-atom linker with a 2-atom linker and attaching the right-hand-
side phenyl via a 2-atom linker to an aryl or heteroaryl group.
Based on the lesson from the pyridazine series that polarity
reduces the risk for potent inhibition of the hERG channel and
phospholipidosis, we aimed to incorporate polar heteroaryl
groups. This strategy ultimately led to the pyridone series 3 and
pyridazinone series 4 of MCH-R1 antagonists. This letter
describes the synthesis and optimization towards pre-clinical
development candidate BI 186908 (11g) and its pharmacological
profile.
< FIGURE 1>
<SCHEME 1>
The synthesis of MCH-R1 antagonists described herein is
outlined in Scheme 1. Pyridone prototype 7 bearing a central
ethylene linker was synthesized starting from 5 in an alkylation,
———
∗ Corresponding author. Tel.: +49-7351-540; fax: +49-7351-54-5181; e-mail: thorsten.oost@boehringer-ingelheim.com

bromination, amination sequence. Pyridone series 10 and
pyridazinone series 11 bearing a central oxoethylene linker
(−C(=O)−CH2−) were synthesized in similar fashion from the
corresponding benzyl alcohols 9 (sequence B). The latter ones
were prepared from the corresponding substituted acetophenones
In vitro selectivity profiling of pyridone analogs 10a and 10b
revealed favorable selectivity (>200-fold, data not shown) for
MCH-R1 vs. M1 and 5HT2a, two receptors which had been
critical in the optimization of the alkyne and pyridazine class5,6;
however, both compounds exhibited significant blockage of the
hERG channel at 10 µM and first effects at ≤100 µM in a
phospholipidosis assay9. Following the strategy that had proven
successful in the pyridazine class5, we decided to increase the
polarity / reduce the logP by employing pyridinyl groups on the
right-hand side. Table 2 summarizes the structure-activity
relationships that were established in the pyridone class by means
of several key compounds. Replacing the right-hand side phenyl
with a 5-chloro-pyridin-2-yl or 5-bromo-pyridin-2-yl group
furnished MCH-R1 antagonists with slightly reduced logP and
acceptable potency and rat microsomal stability; in these cases,
the installation of the methyl group ortho to the metabolically
labile ketone moiety also led to improved stability in human
hepatocytes (10d vs. 10c and 10f vs. 10e) underlining the
generalizability of the steric shielding strategy. The more polar 5-
fluoro-pyridin-2-yl and 5-methoxy-pyridin-2-yl analogs 10g and
10h were hampered by a drop in potency. While there was a
slight reduction in hERG affinity, first effect concentrations in
the phospolipidosis assay remained below 100 µM for two
representative compounds.
8
by α-bromination and subsequent alkylation of the
corresponding right-hand side pyrid(azin)one intermediates 15
and 18. The acetophenone precursor 13 bearing an ortho-methyl
substituent was prepared from (4-bromo-3-methyl-phenyl)-
methanol (12) by bromine-iodine exchange, Heck reaction with
butyl vinyl ether and acidic hydrolysis of the vinyl ether
intermediate. Right-hand side pyridones 15 were prepared by
regio-selective alkylation of 2,4-dihyroxypyridine. The
corresponding pyridazinone precursors 18 were typically
prepared by Mitsunobu reaction of THP-protected 5-hydroxy-
pyridazin-3-one 20 (accessible from commercially available
building block 19) with the corresponding substituted aryl or
heteroaryl methanol precursors 16 followed by acidic removal of
the THP protecting group. The above reactions proceeded in
good-to-acceptable yields and full experimental details have been
reported elsewhere8.
< TABLE 1>
<TABLE 3>
In support of the original design hypothesis (Figure 1),
pyridone prototype 7 bearing a central ethylene linker was found
to be a single-digit nanomolar antagonist of the MCH-R1
(Table 1). Similar to the previously disclosed pyridazine and
alkyne class, a large variety of left-hand side benzylic amine
moieties are tolerated with tertiary amines typically exhibiting
less undesirable P-gp efflux than secondary amines (data not
shown)5,6. As in vivo pharmacological profiling in this project
was performed in rats, we routinely tested metabolic stability of
Encouraged by the promising metabolic stability achieved in
the pyridone series, we applied the learnings to the pyridazinone
series (Table 3). We were pleased to find that prototypes 11a and
11b retained potency in the 10 nM range, and we also confirmed
the beneficial effect of the ortho-methyl group on human
hepatocyte stability in this series. Still, compound 11b displayed
potent hERG inhibition and exhibited first effects below 100 µM
in the phospholipidosis assay. The corresponding 5-halogen-
pyridine-2-yl analogs 11c-11f retained acceptable potency and –
in the case of the ortho-methyl analogs 11d and 11f – exhibited
acceptable rat microsomal as well as human hepatocyte stability,
but did not exhibit any advantages with respect to hERG
inhibition or phospholipidosis-inducing potential. In contrast to
the pyridone series, it was the most polar 5-methoxy-pyridine-2-
yl analog 11g in the pyridazinone series that eventually provided
the desired balance of potency (MCH-R1 IC50 = 22 nM, ~3-fold
improvement over pyridone analog 10h), acceptable metabolic
stability in rat liver microsomes as well as human hepatocytes,
and favorable in vitro safety properties (M1, 5HT2a, hERG IC50
>10 µM, no phospholipidosis at 100 µM). Encouraged by this
attractive initial profile, we initiated in-depth pharmacological
and DMPK studies for 11g (BI 186908).
potent MCH-R1 antagonists in
a rat microsome assay;
unfortunately, 7 as well as other close analogs bearing tertiary
amines exhibited only very poor stability in this assay (data not
shown). Metabolic instability of structurally similar pyridone
derivatives bearing an ethylene linker was also reported by
others7.
We hypothesized that oxidation of the benzylic position in the
central linker may contribute to the observed metabolic
instability; thus, we designed and synthesized analog 10a which
−C(=O)−CH
features an oxoethylene (
2−) instead of the ethylene
linker. 10a retained potent binding to MCH-R1 and exhibited
somewhat improved stability in rat liver microsomes. However,
in a human hepatocyte assay, 10a was found to be unstable.
Analysis of metabolites after incubation with human hepatocytes
revealed that the ketone moiety is rapidly reduced to the
corresponding alcohol (data not shown). In order to block the
carbonyl group from attack by reductases we prepared compound
10b which features a sterically demanding methyl group in
ortho-position potentially preventing the attack. Gratifyingly,
10b not only retained acceptable potency and metabolic stability
in the rat microsome assay but also exhibited strongly improved
metabolic stability / reduced clearance in the human hepatocyte
assay, supporting our original design hypothesis and defining
10b as lead for further evaluation.
<TABLE 4>
BI 186908 (11g) was shown to bind with comparably high
affinity to the recombinant human, cynomolgus monkey, dog and
rat MCH-R1 (Table 4). A broad radioligand binding affinity
screen on 164 receptors revealed a favorable selectivity profile;
substantial binding was detected only to the histamine H3
receptor at concentrations which were regarded as noncritical; the
hERG channel was blocked with an IC50 of 16 µM in a patch
clamp assay.
<TABLE 2>

BI 186908 (11g) was shown to have low metabolic stability in
hepatocytes from rats and dogs and moderate stability in
hepatocytes from monkeys and humans (Table 4). A good
correlation was found between in vitro metabolic stability and in
vivo clearance in the animal species investigated. The low
bioavailability observed in dog is most likely caused by first pass
elimination (in accordance with the high plasma clearance) and
not by poor absorption. Plasma protein binding is comparable
across species with a slightly lower value observed in dogs.
There is no indication that transporters significantly influence
absorption or brain penetration (efflux in the Caco-2 model 1.0;
concentrations in cerebrospinal fluid were comparable to
unbound plasma concentrations). BI 186908 (11g) causes a
moderate inhibition of CYP 3A4 and exhibits a moderate CYP
induction potential (only at 30 µM, PXR screening assay). BI
186908 (11g) tested negative in the AMES screening assay, and
the phospholipidogenic potential was considered to be low as no
effects were observed at 100 µM in the screening assay. The
crystalline hydrochloride salt of BI 186908 (11g) exhibted
favorable aqueous solubility (Table 4).
parameters employing property-based design yielded BI 186908
(11g), a potent and selective antagonist of the MCH-R1 with
favorable DMPK, CMC and pharmacological properties. Based
on its favorable safety profile, BI 186908 was advanced to pre-
clinical development.
Acknowledgements
We thank Fabian Aich, Kathi Beller, Vanessa Hiller, Siegfried
Kolb, Nicole Maier and Stefanie Rausenberger for their skillful
syntheses of the MCH-R1 antagonists described in this
manuscript.
References and notes
1. Johannson, A. Expert Opin. Ther. Pat. 2011, 21,905.
2. Reasor, M. J.; Hastings, K. L.; Ulrich, R. G. Expert Opin. Drug.
Saf. 2006, 5, 567.
3. Méndez-Andino, J. L.; Wos, J. A. Drug Disc. Today 2007, 12,
972.
4. Högberg, T.; Frimurer, T. M.; Sasmal, P. K. Bioorg. Med. Chem.
Lett. 2012, 22, 6039.
5. Roth, G. J.; Heckel, A.; Kley, J. T.; Lehmann, T.; Müller, S. G.;
Oost, T.; Rudolf, K.; Arndt, K.; Budzinski, R.; Lenter, M.; Lotz,
R. R. H.; Schindler, M.; Thomas, L.; Stenkamp, D.; preceding
paper.
<FIGURE 2>
6. Müller, S. G.; Heckel, A.; Kley, J. T.; Lehmann, T.; Lustenberger,
P.; Oost, T.; Roth, G. J.; Rudolf, K.; Arndt, K.; Lenter, M.; Lotz,
R. R. H.; Maier, G.-M.; Markert, M.; Schindler, M.; Thomas, L.;
Stenkamp, D.; preceding paper.
Pharmacological efficacy of BI 186908 (11g) was assessed in
a 4-week study in diet-induced obese female Wistar rats made
obese by feeding a simplified cafeteria diet (high-fat chow,
chocolate and peanuts) for four months (baseline body weight
440-450 g). In this study, a twice daily oral dosing regimen of 3,
6 and 10 mg/kg BI 186908 (11g) was chosen in comparison to
the marketed oral anorexiant sibutramine (5 mg/kg once daily).
The dose chosen for sibutramine is the maximally tolerated dose
in rat. Whereas sibutramine showed a rapid onset of efficacy, all
other treatments resulted in a more gradual weight loss which
was sustained after 4 weeks of dosing (Figure 2). Placebo-
corrected body weight reduction was 7.7% (3 mg/kg bid BI
186908), 10.1% (6 mg/kg bid BI 186908), 10.2% (10 mg/kg bid
BI 186908), and 10.9% (5 mg/kg qd sibutramine). This can be
attributed exclusively to a decrease in body fat content. The
content of water and protein was unchanged. All treatments were
well tolerated. The efficacious human dose was conservatively
estimated (data not shown) based on the exposure observed in the
fully efficacious 6 mg/kg bid dosing regimen (AUC0-24h ~ 2,600
nM·h).
7. Ando, M.; Sekino, E.; Haga, Y.; Moriya, M.; Ito, M.; Ito, J.;
Iwaasa, H.; Ishihara, A.; Kanatani, A.; Ohtake, N. Bioorg. Med.
Chem. Lett. 2009, 19, 5186.
8. Oost, T.; Lotz, R.; Stenkamp, D. WO13131935, 2013; Stenkamp,
D. et al.WO09103478, 2009; Stenkamp, D. et al. WO08022979,
2008; MCH-R1 binding assay: Membranes from CHO/Galpha16
cells stably transfected with human MCH-R1 are re-suspended
using a syringe (needle 0.6 x 25 mm) and diluted in test buffer (50
mM HEPES, 10 mM MgCl2, 2 mM EGTA, pH 7.00; 0.1 % bovine
serum albumin (protease-free), 0.021 % bacitracin, 1 µg/ml
aprotinin, 1 µg/ml leupeptin and 1 µM phosphoramidone) to a
concentration of 5 to 15 µg/ml. 200 µL of this membrane fraction
(contains 1 to 3 µg of protein) are incubated for 60 minutes at
ambient temperature with 100 pM of 125I-tyrosyl melanin
concentrating hormone (125I-MCH commercially obtainable from
NEN) and increasing concentrations of the test compound in a
final volume of 250 µL. After the incubation the reaction is
filtered using a cell harvester through 0.5% PEI treated fibreglass
filters (GF/B, Unifilter Packard). The membrane-bound
radioactivity retained on the filter is then determined after the
addition of scintillator substance (Packard Microscint 20) in a
measuring device (TopCount of Packard). The non-specific
binding is defined as bound radioactivity in the presence of 1 µM
MCH during the incubation period. The analysis of the
concentration binding curve is carried out on the assumption of
one receptor binding site. IC50 values are the mean of at least two
separately performed experiments. Standard: Non-labelled MCH
competes with labelled 125I-MCH for the receptor binding with an
IC50 value of 0.06 - 0.15 nM. The KD value of the radioligand is
0.16 nM; HPLC-based logP determinations according to:
Donovan, S. F.; Pescatore, M. C. J. Chromatogr. A 2002, 952, 47.
9. Phospholipidosis assay according to: (a) Xia, Z.; Appelkvist, E.-
L.; DePierre, J. W.; Nässberger, L. Biochem. Pharm. 1997, 53,
1521. (b) Casartelli, A.; Bonato, M.; Cristofori, P.; Crivellente, F.;
Dal Negro, G.; Masotto, I.; Mutinelli, C.; Valko, K.; Bonfante, V.
Cell Biol. Tox. 2003, 19, 161.
Cardiovascular effects of BI 186908 (11g) were assessed in
the conscious cynomolgus monkey after oral administration of 3,
10 and 30 mg/kg (corresponding to 2.4, 8 and 24-fold estimated
human Cmax, respectively). In summary, BI 186908 exhibited a
favorable cardiovascular safety profile (data not shown); no
effects on systolic and diastolic blood pressure, left ventricular
pressure, or myocardial contractility were observed at any dose.
For the 30 mg/kg dose, there was a significant slight decrease in
heart rate, a trend towards increase in the PR interval and a trend
towards reduction in body temperature. When corrected for heart
rate and body temperature, there was no significant increase in
the QTc-interval.10
10. Markert, M.; Shen, R.; Trautmann, T.; Guth, B. J. Pharmacol.
Toxicol. 2011, 64, 25.
In conclusion, optimization of metabolic stability employing
steric shielding of a labile keto moiety and in vitro safety

R
A
A
1 (A = CH or N)
R1R2
R1R2
R1R2
N
N
N
O
R
A
N
N
2 (A = NH or O)
R
O
A
N
3 (A=CH)
4 (A=N)
O
Figure 1. Molecular tailoring of the pyridone series 3 and pyridazinone series 4.

Table 1. Discovery of pyridone lead with improved human metabolic stabilitya
O
R
A
N
O
N
MCH-R1
Rat Microsomes
Human Hepatocytes
hERG Patch Clamp
Phospholipidosis
A
R
logP
IC50 [nM]
T1/2 [min]
Clint [µL/(min*106 cells)]
Blockage @ 10 µM
First effect conc. [µM]
7
CH2
CO
CO
H
H
3.2
3.0
3.3
7
5
NT
24
4
NT
100
100
50
10a
10b
13
17
23
24
63%
67%
CH3
a For the description of assay methods, see reference 8; NT: not tested.
Table 2. Optimization of pyridone series towards improved metabolic stabilitya
R2
O
R1
O
N
N
O
N
MCH-R1
IC50 [nM]
Rat Microsomes
T1/2 [min]
Human Hepatocytes
hERG Patch Clamp
Blockage @ 10 µM
Phospholipidosis
R1
R2
logP
Clint [µL/(min*106 cells)]
First effect conc. [µM]
10c
10d
10e
10f
H
Cl
Cl
2.3
2.7
2.5
2.8
NT
NT
41
33
28
17
70
57
>45
44
69
14
NT
41%
NT
NT
50
CH3
H
Br
32
66
NT
50
CH3
CH3
CH3
Br
45
21
42%
NT
10g
10h
F
NT
NT
NT
NT
NT
NT
OCH3
NT
a For the description of assay methods, see reference 8; NT: not tested.
Table 3. Optimization of pyridazinone series towards improved metabolic stability and in vitro safety parametersa
R2
O
R1
O
N
N
A
O
N
MCH-R1
Rat Microsomes
T1/2 [min]
Human Hepatocytes
hERG Patch Clamp
Blockage @ 10 µM
Phospholipidosis
R1
R2
A
logP
IC50 [nM]
Clint [µL/(min*106 cells)]
First effect conc. [µM]
11a
11b
11c
11d
11e
11f
H
CH3
H
H
H
CH
CH
N
3.6
3.8
2.9
3.1
3.1
3.4
2.3
10
8.7
25
24
22
16
22
6
15
14
>45
7
17
4.8
NT
NT
58
NT
88%
39%
NT
NT
50
Cl
50
CH3
H
Cl
N
50
Br
N
NT
NT
50
CH3
CH3
Br
N
29
>45
12
85%
17%
11g
OCH3
N
3.3
200
a For the description of assay methods, see reference 8; NT: not tested.

Table 4. Properties of pre-clinical development candidate BI 186908 (11g)
O
O
O
N
N
N
N
O
In vitro pharmacology
In vitro safety properties
MCH-R1 IC50 / Ki
22 / 14 nM
CYP inhibition IC50
3A4/2C8/2C9/2C19/2D6
3A4: 18 µM, others > 50 µM
H3 receptor: 78% inhibition @ 10 µM;
others <50% inhibition @ 10 µM
Ricerca panel of 164 receptors
CYP 3A4: Time-dependent inhibn.
CYP induction PXR
85% CTRL (30 min @ 25 µM)
17% of rifampicin induction @ 10 µM
Negative
Rat / Dog / Cynomolgus IC50
ADME properties
18 / 23 / 18 nM
AMES screen
Cytotoxicity (U-937 cells)
IC50 = 506 µM
Hepatocyte Stability
Human / Rat / Dog / Cynomolgus
26 / 78 / 98 / 43 %Qh
93 / 90 / 80 / 90 %
Phospholipidosis
(Nile red uptake in U-937 cells)
No effect at 100 µM; first effect at 200
µM
Plasma protein binding
Human / Rat / Dog / Cynomolgus
hERG patch clamp IC50
Physicochemical properties
logP, logD, pKa
16 µM
Caco-2 Papp (a-b), 10 µM
52·10-6 cm/s
1.0
Caco-2 efflux ratio, 10 µM
2.3, 1.4, 8.3 / 2.8
> 1 mg/mL
Clearance Rat / Dog / Cynomolgus
Vss Rat / Dog / Cynomolgus
MRTdisp Rat / Dog / Cynomolgus
MRTtot Rat / Dog / Cynomolgus
Foral Rat / Dog / Cynomolgus
164 / 229 / 40 %Qh
3.3 / 2.9 / 1.3 L/kg
0.5 / 0.7 / 1.2 h
3.4 / 2.9 / 2.2 h
53 / 1.4 / 44 %
Aqueous solubility
(pH 2.2 / 4.5 / 6.8 / 7.4)

O
O
a
b,c
N
N
Cl
(A)
HO
O
HO
N
O
5
6
7
R2
O
O
R1
R1
R1
O
O
A
X
N
O
X
N
A
d,e
b,c
(B)
HO
HO
O
N
O
X = CH: Pyridone series 10
X = N: Pyridazinone series 11
A = CH or N
8
9
O
R1= H or Me
Br
f,g,h
R2= According to Tables 1-3
(C)
HO
HO
12
13
R2
R2
O
i
A
A
HN
Br
A
O
R2
R2
14
15
(D)
O
R2
O
k
l
N
N
N
A
O
HN
HO
A
O
O
16
17
18
OH
Cl
OH
m
N
N
N
N
O
O
O
O
19
20
Scheme 1. Reagents and conditions: (a) 4-Benzyloxy-1H-pyridin-2-one, K2CO3, DMF, 100°C; (b) PBr3, CH2Cl2, r.t.; (c)
NHMe2, DMF, 20-50°C; (d) Bu4NBr3, CH2Cl2/MeOH, r.t.; (e) Cs2CO3, DMF or DMSO, 15 or 18; (f) CuI, NaI, N,N’-
dimethylethylenediamine, dioxane, 120°C; (g) butyl vinyl ether, Pd(OAc)2, 1,3-bis(diphenylphosphino)propane, K2CO3, LiCl,
DMF/H2O, 90°C; (h) 1M aq. HCl, r.t.; (i) 2,4-dihydroxypyridine, K2CO3, acetonitrile, r.t.; (k) polymer-bound PPh3, diisopropyl
azodicarboxylate, CH2Cl2/THF, 0°Cꢀr.t.; (l) 12M aq. HCl in MeOH; (m) H2 (1700 hPa), 10% Pd/C, MeOH, Et3N, r.t.

Figure 2. Effect of administration of BI 186908 (11g) and sibutramine on body weight in dietary-induced obese Wistar rats. Results are means + SEM.
Significant differences from the control group are denoted by **p<0.01 and ***p<0.001.