A thienopyridazinone-based melanin-concentrating hormone receptor 1 antagonist with potent in vivo anorectic properties

Article abstract of DOI:10.1021/jm051263c

Melanin-concentrating hormone receptor antagonists containing thieno- and a benzopyridazinone cores were designed and tested as potential anorectic agents. These ligands showed high affinity for the receptor, potent functional activity in vitro, and good oral bioavailability in rats. The thiophene analogue exhibited low iv clearance, long half-life, and high brain penetration. In obese rats, the thienopyridazinone demonstrated a dose-dependent reduction in feeding and body weight with doses between 1 and 10 mg kg^-1.

Full text of DOI:10.1021/jm051263c

© Copyright 2006 by the American Chemical Society
Volume 49, Number 13
June 29, 2006
Letters
Chart 1. Published and Proposed MCH1R Ligands
A Thienopyridazinone-Based
Melanin-Concentrating Hormone Receptor 1
Antagonist with Potent in Vivo Anorectic
Properties
Brian Dyck,* Stacy Markison, Liren Zhao, Junko Tamiya,
Jonathan Grey, Martin W. Rowbottom, Mingzhu Zhang,
Troy Vickers, Katie Sorensen, Christi Norton, Jenny Wen,
Christopher E. Heise, John Saunders, Paul Conlon,
Ajay Madan, David Schwarz, and Val S. Goodfellow
Neurocrine Biosciences Inc., 12790 El Camino Real,
San Diego, California 92130
ReceiVed December 19, 2005
efficacy for MCH1R antagonists in preclinical models of obesity
in rodents and dogs, and at least two compounds have advanced
into human clinical trials.7-9 Some evidence is also emerging
that suggests a role for such antagonists in the treatment of
anxiety and depression.7a,10,11 We have discovered a novel
MCH1R antagonist that demonstrates some of the most potent
in vivo efficacy reported to date in a rat model of diet-induced
obesity (DIO).
Abstract: Melanin-concentrating hormone receptor antagonists con-
taining thieno- and a benzopyridazinone cores were designed and tested
as potential anorectic agents. These ligands showed high affinity for
the receptor, potent functional activity in vitro, and good oral bio-
availabilty in rats. The thiophene analogue exhibited low iv clearance,
long half-life, and high brain penetration. In obese rats, the thieno-
pyridazinone demonstrated a dose-dependent reduction in feeding and
body weight with doses between 1 and 10 mg kg-1
.
Chart 1 shows several reported MCH1R antagonists, which
topologically have similar features. Among these, the recently
disclosed aminopyrrolidine-substituted pyridine 3 was shown
to have an excellent in vitro profile but suffered from high
clearance in rats.7h It also showed strong interaction with the
hERG channel (Ki ) 0.2 µM, dofetilide binding). To improve
the metabolic stability of this compound class, we replaced the
potentially labile carboxamide group with heterocyclic ring
systems. SARs from previous series convinced us of the
necessity of retaining a carbonyl group in this vicinity, possibly
as a result of the interaction of this group with Gln212 of
transmembrane 5 in the native receptor.12 As such, we pursued
the pyridazinone derivatives 4 because they retain most of the
features of 3 essential for high-affinity binding while removing
the acyclic carboxamide group present in the latter.
Obesity has reached epidemic proportions in the developed
world, and the impact of this disease on the health care and
economies of affected countries is difficult to overestimate.1
Many potential biological targets for treating obesity have
recently emerged, including the cannabinoid receptor 1, for
which the inverse agonist rimonabant is currently under review
by the FDA.2 The discovery of other anorectics, preferably
working through disparate mechanisms, remains a high priority.
The melanin-concentrating hormone receptor 1 (MCH1R) has
recently been the focus of considerable scrutiny as such a target.
Acute or chronic treatment of rats with melanin-concentrating
hormone (MCH) produces increased feeding or body weight,
respectively.3,4 Mice lacking the gene coding for the MCH
precursor are lean and hypophagic, and those lacking the
receptor are lean but slightly hyperphagic in order to compensate
for higher energy expenditure.5,6 Several groups have reported
The chemistry used to make the benzopyridazinones is based
on a procedure reported by Cherkez and co-workers and is
shown in Scheme 1.13 Bromophthalimide 5 was reduced with
zinc under acidic conditions to afford hydroxylactam 6, which
cyclized to the benzopyradizinone 7 upon treatment with
* To whom correspondence should be addressed. Telephone: 858-617-
7778. Fax: 858-617-7619. Email: bdyck@neurocrine.com.
10.1021/jm051263c CCC: $33.50 © 2006 American Chemical Society
Published on Web 05/28/2006

3754 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 13
Scheme 1. Synthesis of Benzopyridazinones 8a
Letters
Scheme 3. Synthesis of MCH1R Ligands 18-22a
a Reagents and conditions: (i) Zn, CuSO4, aqueous NaOH (95%); (ii)
N2H4, water, 95 °C (34%); (iii) arylboronic acid, Pd(dppf)2, K2CO3, DMF,
H2O, 80 °C (22-78%).
Scheme 2. Synthesis of Fused Pyridazinones 12-15a
a Reagents and conditions: (i) 3-(alkylamino)pyrrolidine, TsOH, 110 °C
(28-88%); (ii) 8 or 12-15, CuI, trans-1,2-diaminocyclohexane, Cs2CO3,
dioxane, 110 °C (11-85%).
Table 1. In Vitro MCH1R Affinities (nM) and HLM Clearances (mL
min-1 kg-1) for 18-22a
compd
X
R1
NR2N3
Ki ( SDa CLb
a Reagents and conditions: (i) DHP, TsOH, THF, reflux (87%); (ii) KOH,
methanol (83%); (iii) KOH, water, reflux (75%); (iv) Tf2O, TEA, DCM;
(v) arylacetylene, TBAI, CuI, Pd, DCM (82%); (vi) KOH, dioxane, reflux
(12) or CH3NH2, ACN, reflux; then NaHMDS, DMA, ethylene glycol, 130
°C (13) or Na2S, DMF, 70 °C (14) or Se, NaBH4, ethanol (15); (vii) HCl,
water, 50 °C (17-100%).
(R)-18a C2H2
4-Cl
4-Cl
4-Cl
4-Cl
4-Cl
4-Cl
4-Cl
4-CF3
4-CF3
N(CH3)2
N(CH3)2
NHCH3
NHCH3
NHCH2CH3 1.9 ( 0.1 9.2
pyrrolidinyl
morpholinyl 56%c
1.1 ( 0.6 21
1.1 ( 0.2 12
1.2 ( 0.6 8.9
1.5 ( 0.1 12
(S)-18a
(S)-18b
C2H2
C2H2
(R)-18b C2H2
(S)-18c
(S)-18d
(R)-18e
(R)-18f
(S)-18f
(S)-18g
(S)-19a
(S)-20a
(S)-21a
(R)-21b
(S)-21c
(R)-21c
(S)-21d
(R)-21d
(R)-21e
(R)-21f
(S)-22a
C2H2
C2H2
C2H2
C2H2
C2H2
C2H2
O
1.6 ( 0.2 16
40
NHCH3
NHCH3
10 ( 2
6.0
hydrazine. Suzuki reaction allowed the introduction of various
aryl substituents providing the left-hand component of the
benzopyridazinones 4 (X ) CHdCH).
8.4 ( 0.1 26
4-CH3O-2-CH3 NHCH3
4-CF3
11 ( 2
21 ( 9
14 ( 3
8.8
28
48
N(CH3)2
N(CH3)2
N(CH3)2
NHCH3
NHCH3
NHCH3
NHCH3
NHCH3
NHCH3
NHCH3
N(CH3)2
NCH3 4-CF3
The other fused analogues were prepared from the dichloro-
pyridazinone 9 (Scheme 2). Protection as the THP derivative,
selective methanolysis of the more active carbon-chlorine bond,
and alkaline hydrolysis afforded 10.14,15 This compound was
converted to the triflate to enable a Sonogashira coupling with
arylacetylenes, thus providing 11.16 This versatile intermediate
provided a series of heterocyclopyridazinones by varying the
conditions used in the cyclization. Alkynyl-substituted chloro-
pyridazinones have previously been described in the synthesis
of furan, pyrrole, and thiophene-fused derivatives, and by using
in situ generated sodium selenide, we have extended this
chemistry to the selenophene.16,17 Acid hydrolysis of the THP
protecting group provided 12-15, the left-hand side components
of the heterocyclo-fused analogues of 4.
The right-hand side components of target compounds 4 were
prepared from 2,5-dibromopyridine (16). Displacement of the
more active 2-bromine atom with 3-aminopyrrolidines afforded
the bromopyridines 17. These compounds efficiently coupled
with pyridazinones 8 and 12-15 in the presence of copper and
trans-1,2-diaminocyclohexane to provide final compounds 18-
22.18 Some key in vitro properties for representative pyridazi-
nones 18-22 are presented in Table 1. The benzopyridazinones
18 are potent binders of MCH1R in vitro. Typically small groups
are well tolerated on the exocyclic nitrogen atom of the
pyrrolidine ring, with various combinations of hydrogen, methyl,
ethyl, and cyclic analogues all giving comparable binding
constants (18a-d). Oxygen-containing groups (18e) provided
S
S
S
S
S
S
S
S
Se
4-CF3
4-Cl
4-F
4.4 ( 0.3 18
1.9 ( 0.3 8.4
2.0 ( 0.5 12
2.5 ( 0.5 8.2
3.1 ( 1.8 NDd
3.3 ( 1.8 8.5
1.3 ( 0.5 720
2.6 ( 0.8 155
4-F
4-CF3
4-CF3
4-CH3O
4-CH3CH2
4-CF3
28%c
27
a Averaged from a minimum of two replicates. b Intrinsic human clear-
ance determined in HLM.19 Estimated standard error of less than 10% based
on a reference compound used as a standard. c Percentage inhibition at 10
µM. d Not determined.
less potent analogues, and there appeared to be little stereo-
chemical preference exhibited by the receptor (18a,b,f). Al-
though the nature of the substituent in this part of the molecule
does not have a dramatic influence over binding potency,
minimization of the size of this group does have a positive
influence over the metabolic clearance of the molecule as
predicted in human liver microsomes (HLM), and the methyl-
amino substituent of 18b appears to be optimal for this purpose.
Other substitutions on the terminal phenyl ring produced
analogues with reduced binding affinity and/or increased
clearance in HLM (18f,g).
In the analogues with a five-membered heterocycle fused to
the pyridazinone, the most potent example was the thiophene
(S)-21a (Ki ) 4.4 nM), followed by the pyrrole (S)-20a (Ki )

Letters
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 13 3755
Table 2. In Vitro and in Vivo Properties of Selected
Pyridazinone-Based MCH1R Antagonists
compd
(S)-18b
(R)-21d
MCH1R Ki (nM)a
1.2 ( 0.6
8.5 ( 4
3.3 ( 1.8
7.7 ( 3
GTPγS IC50 (nM)a,b
c
Vd (L kg-1
)
14 ( 3
4.1 (1
CL (mL min-1 kg-1
)
17 ( 4
4.3 ( 0.6
8.4 ( 7
11 ( 1
24 ( 20
0.50 ( 0.40
0.19 ( 0.05
1.2 ( 0.2
1.4 ( 0.3
3.1 ( 0.6
c
AUC-po (µg h mL-1
)
2.2 ( 0.3
9.4 ( 0.3
22 ( 3
c,d
t
1/2 (h)c
F (%)c
c,e
C
C
C
max (µg mL-1
)
0.14 ( 0.02
0.094 ( 0.021
1.7 ( 0.8
7.8 ( 3
brain, 1 h (µg g-1
brain, 4 h (µg g-1
)
)
c,f
c,f
B/P (1 h)c
B/P (4 h)c
23 ( 7
a Averaged from a minimum of two replicates. b Functional assay
measuring GTPγS accumulation. c Determined in rats by administration of
10 mg kg-1, po, and 2.5 mg kg-1, iv. d Area under the curve for oral
administration. e Maximum plasma concentration after oral dosing. f Brain
concentration after oral dosing.
14 nM), the furan (S)-19a (Ki ) 21 nM), and the selenophene
(S)-22a (28% inhibition). In the thiophenyl derivatives, a variety
of 4-substituents on the phenyl ring produced comparably potent
compounds, but the chloro (21b), the fluoro (21c), and the
trifluoromethyl groups (21d) provided the most metabolically
stable compounds in vitro.
Because of their excellent in vitro properties, the pharmaco-
kinetics of the benzopyridazinone (S)-18b and the thieno-
pyridazinone (R)-21d were evaluated in rats. Compound (S)-
18b showed good bioavailability (F) and half-life (t1/2) when
administered orally. However, the compound demonstrated a
high volume of distribution (Vd), indicating extensive partition-
ing into tissues. The compound also showed extremely high
brain penetration reaching more than 20-fold plasma levels after
4 h. On the other hand, the thienopyridazinone (R)-21d
demonstrated comparable oral bioavailability to its benzo
counterpart but had much more reasonable Vd, clearance (CL),
and brain-to-plasma ratio (B/P) values. The excellent in vitro
and pharmacokinetic profiles of the thienopyridazinone (R)-21d
(NBI-845) prompted its evaluation in a preclinical model of
obesity. Male Sprague-Dawley rats were made obese by
allowing ad libitum access to a medium-high-fat diet (Research
Diets, product D12266B) for 12 weeks after weaning. When
rats were approximately 550 g, they were divided into four
groups, balanced for body weight, then habituated to handling
and oral dosing. Baseline food intake and body weight were
measured over 8 days. Treatment, once daily oral dosing (during
the hour prior to dark onset), was initiated and continued for
14 days. Results indicated that (R)-21d dose-dependently
reduced both feeding (p < 0.001) and body weight change (p
< 0.001). Food intake was significantly reduced by the 3 and
10 mg kg-1 doses (all p < 0.001). All doses of (R)-21d reduced
body weight relative to vehicle (0.25% methylcellulose) treated
controls. Differences in weight loss were statistically significant
from controls on all days for the 3 and 10 mg kg-1 groups and
days 2-14 for the 1 mg kg-1 group (all p < 0.001).
Figure 1. Effects on food intake (A) and body weight change (B)
with once daily oral dosing of (R)-21d over 14 days in rats with DIO.
All values are the mean ( SEM; n ) 7-10 per group.
suggest that the likelihood of this is minimal. The compound
was also tested and was not shown to significantly inhibit the
cytochrome P450 enzymes 2D6 and 3A4 (<10% at 5 µM). A
key safety concern of antiobesity and other chronic medications
is cardiotoxicity, and untoward cardiovascular effects have been
recently observed for some MCH1R antagonists.7i Compound
(R)-21d was tested in a patch clamp assay for hERG affinity,
and the compound was found to have an IC50 of 1.8 µM.
However, during 14 days of dosing at 1 mg kg-1, the maximum
daily plasma concentration observed in rats ranged from 0.28
µM ((0.08 µM) on day 1 to 0.79 µM ((0.31 µM) on day 14,
indicating that efficacy was achieved at doses below those that
would be expected to block the hERG channel. Preliminary
toxicological studies in rats also showed no effects that would
explain the observed weight loss, and when combined with the
selectivity screen discussed above, these data provide strong
support that the effect is MCH1R-mediated.
Modification of the benzamide group of 3 to a bicyclic
derivative was an effective strategy for minimizing the clearance
of these compounds and optimizing the terminal half-life.
However, in the case of the fused benzene ring analogues 18,
the improved pharmacokinetics were also associated with some
untoward partitioning of the compound into tissues and very
high brain penetration. Replacement of the internal phenyl ring
with a thiophene moiety produced a ligand with much more
suitable pharmacokinetics. In addition, the molecule demon-
strated dose-dependent weight loss in a rat DIO model.
Compound (R)-21d provides an interesting research tool in the
ongoing study of MCH1R antagonists in feeding and other
behavioral models. Detailed in vivo studies of this compound
will be reported elsewhere.
Compound (R)-21d was evaluated in a selectivity screen of
more than 75 receptors and channels including MCH2R but
showed only modest cross-reactivity with select muscarinic
receptors (M1R Ki ) 260 nM; M3R Ki ) 160 nM). Although
M3R knockout mice are hypophagic and lean, the M3R
antagonist darifenacin has not been reported to produce anti-
obesity effects in clinical trials.20,21 Although we cannot entirely
discount a role for this receptor in the anorectic effects of (R)-
21d in rats, the clinical data mentioned above and the 50-fold
selectivity this compound exhibits for MCH1R over M3R
Acknowledgment. The authors thank Robert Petroski for
hERG patch clamp experiments, Paul Crowe and Mark Santos
for muscarinic receptor binding, and Mike Hedrick for P450
IC50 determinations.

3756 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 13
Letters
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Supporting Information Available: Experimental protocols
and characterization data. This material is available free of charge
via the Internet at http://pubs.acs.org.
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