Discovery of potent and stable conformationally constrained analogues of the MCH R1 antagonist SB-568849

Article abstract of DOI:10.1016/j.bmcl.2006.06.061

A strategy of systematically targeting more rigid analogues of the known MCH R1 receptor antagonist, SB-568849, serendipitously uncovered a binding mode accessible to N-aryl-phthalimide ligands. Optimisation to improve the stability of this compound class led to the discovery of novel N-aryl-quinazolinones, benzotriazinones and thienopyrimidinones as selective ligands with good affinity for human melanin-concentrating hormone receptor 1.

Full text of DOI:10.1016/j.bmcl.2006.06.061

Bioorganic & Medicinal Chemistry Letters 16 (2006) 4872–4878
Discovery of potent and stable conformationally constrained
analogues of the MCH R1 antagonist SB-568849
David R. Witty,* John Bateson, Guillaume J. Hervieu, Kamal Al-Barazanji,
Phillip Jeffrey, Dieter Hamprecht, Andrea Haynes, Christopher N. Johnson,
Alison I. Muir, Peter J. O’Hanlon, Geoffrey Stemp, Alex J. Stevens,
Kevin Thewlis and Kim Y. Winborn
GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, UK
Received 2 May 2006; revised 15 June 2006; accepted 17 June 2006
Available online 12 July 2006
Abstract—A strategy of systematically targeting more rigid analogues of the known MCH R1 receptor antagonist, SB-568849, ser-
endipitously uncovered a binding mode accessible to N-aryl-phthalimide ligands. Optimisation to improve the stability of this com-
pound class led to the discovery of novel N-aryl-quinazolinones, benzotriazinones and thienopyrimidinones as selective ligands with
good affinity for human melanin-concentrating hormone receptor 1.
Ó 2006 Elsevier Ltd. All rights reserved.
Interest in the 7-transmembrane G-protein coupled
receptor MCH R1, a cognate receptor for melanin-
concentrating hormone,1,2 has grown since the discovery
of its association with the regulation of feeding activities
in rodents.3 Intracerebroventricular (icv) dosing of
MCH elicits a feeding response in wild-type rodents,
while MCH knock-out mice are characterized by a lean
and hypophagic phenotype.4 Mice in which the MCH
R1 receptor has been deleted, show a reduced suscepti-
bility to diet induced obesity, and do not respond to
icv dosing of MCH with feeding behaviours.5,6 It is con-
jectured that brain penetrant antagonists of this receptor
may have applications in the treatment of human
obesity.7,8
paper, we disclose an investigation of conformational
constraints, undertaken with the aim of further improv-
ing both potency and developability properties.7,9
Our strategy was to subject three regions of compound 1
to systematic conformational constraint: the basic side
chain A, the biphenyl group B and the carbonyl moiety
C (Fig. 2).
Target compounds 8a–e,g, 11a, 13b–d, 15b–d, 20–24,
35a–d, 36b–d, 39 and 42 (Tables 1 and 2) were prepared
by the methods described in Schemes 1–5. Anilides 8a–e
containing O-linked constrained amines were prepared
by one of two routes (Scheme 1). Hydroxyl-pyrrolidines
3a–c were reacted with 4-nitro-2-methoxyphenol 2p in
the presence of tributylphosphine and azodicarbonyl-
dipiperidine (ADDP) in a Mitsunobu reaction to afford
4a–c. Examples 3d and 3e were treated with 4-chloroni-
trobenzene 2q in DMF with sodium hydride to form 4d
and 4e by nucleophilic aromatic substitution.10 Amines
6a–e were formed by hydrogenation of 4a–e and were
coupled to either 4-cyclohexyl-benzoyl chloride 7m,
(e.g., 8a–d) or 4-biphenyl-carbonyl chloride 7n (e.g.,
8e), under conditions of base catalysis. The correspond-
ing piperazines (8f and 8g) were formed in an analogous
manner from known piperazine 5 by protection of the
basic nitrogen using Boc anhydride to give 4f, followed
by hydrogenation of the nitro group and coupling to 4-
cyclohexyl-benzoyl chloride to form protected analogue
In the preceding paper we described the discovery of a
class of phenyl carboxanilide antagonists of MCH R1,
for example, 1a and 1b which, through a lead optimisa-
tion programme, led to the more soluble and metaboli-
cally stable analogue SB-568849 (Fig. 1) incorporating a
smaller basic moiety and an N-methyl amide.8 In this
Keywords: MCH; MCH R1; Biphenylcarboxamide; Antagonist;
Melanin-concentrating hormone; Obesity; Feeding; Stress; Anxiety;
Quinazolinone; Benzotriazinone; Thienopyrimidinone; Cyclisation;
Bicyclic heterocycle.
*
Corresponding author. Tel.: +44 0 1279 627620; fax: +44 0 1279
622790; e-mail: david.witty@gsk.com
Dr. Guillaume Hervieu sadly died before publication of this work.
0960-894X/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2006.06.061

D. R. Witty et al. / Bioorg. Med. Chem. Lett. 16 (2006) 4872–4878
4873
O
O
O
N(iPr)2
O
N(Et)2
N
H
OMe
N
OMe
Me
R
1a R = Ph
1b R = Cyclohexyl pKi = 7.6
pKi = 7.5
SB-568849 pKi = 7.7
F3C
Figure 1. MCH R1 antagonists.
coupling agent EDC, or by prior conversion of the acids
to the corresponding acid chloride, followed by amide
coupling under conditions of base catalysis (Scheme 2).
A
O
O
NiPr2
B
N
OMe
H
C
Isoindolone, 21, was isolated as a mixture of regioisom-
ers as prepared in a four-step process outlined in Scheme
3. Condensation of bromophthalic anhydride (16) with
aniline 12 in the presence of EDC resin gave phthalimide
18. A palladium-catalysed Suzuki reaction of this mate-
rial with benzeneboronic acid afforded the intermediate
phenyl-phthalimide (20). Reduction of just one of the
carbonyl groups proceeded without regioselectivity to
give isoindolone 21 as an ꢀ1:1 isomer mixture. Hetero-
atom-linked analogues (22 and 23) were prepared by
coupling phenol and aniline to bromophthalimide 18
under conditions of palladium catalysis, albeit in low
yield, while the thioether analogue 24 was prepared in
a two-step process from fluorophthalic anhydride (17).
This was coupled to 12 in the same manner as
Figure 2. Regions for conformational constraint.
8f, using the process described, for example, 8a–e.11
Removal of the Boc group of 8f with hydrochloric acid
was followed by alkylation using a resin bound cyano-
borohydride as reductant in the presence of acetalde-
hyde, affording 8g.
Constrained biphenyl compounds, 11a, 13b–d and
15b–d, were prepared by coupling the appropriate
biphenyl-carboxylic acids (10a–d) to the diisopropyl-
aniline (9), the pyrrolidinyl-aniline (12) or the N-meth-
yl-aniline (14).8 This was achieved either using the
R
X
H-R
(i)
22-73%
+
O2N
OMe
Boc
O2N
OMe
3a-3e
4a-4e
2p X = OH
2q X = Cl
N
NH
N
N
(ii)
80%
O2N
OMe
O2N
OMe
5
4f
R
COCl
(iv)
32-100%
(iii)
95-100%
4a-4f
+
H2N
OMe
R
Y
6a-6f
7m Y = Ph; 7n Y = cyclohexyl
Me
NMe
NMe
N
R
O
NNMe2
O
O
OMe
N
O
b
O
H
a
c
d
Y
8a-8d Y = cyclohexyl
Boc
Et
8e
8f
Y = Ph
Y = cyclohexyl
N
N
N
(v)
60%
8g
Y = cyclohexyl
N
N
O
e
f
g
Scheme 1. Reagents and conditions: (i) either 2p, Bu3P, ADDP, THF or 2q NaH, DMF, 80 °C; (ii) Boc2O, CH2Cl2; (iii) H2 10% Pd/C, EtOH; (iv)
Et3N or DIEA resin, CH2Cl2; (v) 4 M HCl in 1,4-dioxane, 70 °C, 5 min, evaporate, then acetaldehyde, Amberlyst cyanoborohydride resin, AcOH,
EtOH.

4874
D. R. Witty et al. / Bioorg. Med. Chem. Lett. 16 (2006) 4872–4878
R'
R'
(i)
R"
R"CO2H
+
O
O
30-80%
X
O
10a-10d
R
N
OMe
9,12,14
OMe
R"
N
R
Y
H
11,13,15
X
C=O
CH2
CH2CH2 bond
bond
Y
bond
bond
9 R = H, R' = NiPr2
12 R = H, R' =
R = H, R' = NiPr2
a
11a
6%
b
c
d
N
13b-13d R = H, R' = N
14-84%
92-95%
O
14 R = Me, R' = NiPr2
15b-15d R = Me,R' = NiPr2
Scheme 2. Reagents and conditions: (i) either 10a–d, EDC, DMF, HOBT or 1—10a–d, SOCl2, CH2Cl2, reflux, 3 h, evaporate then 2. Compounds
9/12/14, Et3N, CH2Cl2.
O
O
O
X
X
N
12
(ii)
O
N
OMe
18
45%
Quantitative
O
16 X = Br
17 X = F
O
18 X = Br
19 X = F
O
O
O
Ph
Ph
N
N
N
OMe
21
N
OMe
(iii)
35%
O
20
O
(iv)
O
O
18
18
19
22
23
24
15%
(v)
R
N
22 R = PhO
N
OMe
23 R = PhNH
24 R = PhS
5%
(vi)
O
68%
Scheme 3. Reagents and conditions: (i) EDC resin, CH2Cl2, 12 h; (ii) Pd(PPh3)4, toluene, Cs2CO3, PhB(OH)2; (iii) 1—NaBH4, EtOH then
2—DIBAL-H, MDC; (iv) PhOH, Pd(PPh3)4, toluene, Cs2CO3; (v) PhNH2, BINAP, toluene, Cs2CO3; (vi) PhSH, NaH, DMF.
compound 16, then imide 19 subjected to a nucleophilic
aromatic substitution of fluoride by thiophenol to afford
24.
This material reacted with sodium phenoxide in
DMF to give the 4-phenoxyl-substituted analogue
(29c). The fourth substitution pattern was established
by conversion of the dinitrobenzoic acid 31 to the
phenyl ester. This was treated with sodium phenoxide
to give predominant displacement of the 4-nitro group
such that hydrolysis of the ester gave acid 33. This was
converted to the nitroamide 29d using the same proto-
col as for 29a and 29b. Nitroamides 29a–d were then
converted to the corresponding ortho-amino amides
(34a–d) by hydrogenation over a palladium catalyst.
Ring closures to the quinazolinones (35a–d) were effect-
ed with trimethyl orthoformate, while the correspond-
ing benzotriazinones (36b–d) were prepared by
treatment of the amino amides with butyl nitrite in
the presence of TFA.
Quinazolinones (35a–d) and benzotriazinone-linked
compounds (36b–d) were prepared by the methods out-
lined in Scheme 4. For the aryl-substituted heterocyclic
precursors (29a and 29b), the parent substitution pat-
tern was established using a vicarious nucleophilic sub-
stitution (VNS) reaction on 4-chloro-40-nitrobiphenyl
(25) and 3-nitrobiphenyl (26). Reaction of the nitro-
aromatics with the chloroform anion, generated using
potassium tert-butoxide in THF/DMF, in both cases,
gave a dichloromethyl moiety ortho to the nitro group.
In the case of 25, the 40-chloro substituent blocked an
alternative VNS reaction in the distal ring. The CHCl2
group was hydrolysed in the presence of wet silver tri-
flate to form aldehydes which were oxidised to the cor-
responding acids (27 and 28) using sodium perborate in
acetic acid. These were converted to their acid chlo-
rides using oxalyl chloride and a trace of DMF in
dichloromethane, then coupled to aniline 12 to afford
nitroamides 29a and 29b, respectively. Analogous
aryloxy compound 29c was prepared from 5-chloro-
2-nitrobenzoic acid (30) by conversion to the acid chlo-
ride, as described previously, then coupling to amine 12
under conditions of base catalysis to form amide 32.
Thienopyrimidines 39 and 42 were prepared from
commercial
aminothiophenes
as described in
Scheme 5. 3-Amino-4-phenylthiophene-1-carboxylic
acid methyl ester (37) was treated with di-2-pyridyl
thionocarbonate in dichloromethane to form the 3-iso-
thiocyanate. This was reacted with compound 12 to
form thiourea 38. Treatment of the thiourea with
methyl iodide and base resulted in alkylation on sulfur
to give the imidothiocarbamate, which, on warming,
cyclised to the desired substituted heterocycle with a

D. R. Witty et al. / Bioorg. Med. Chem. Lett. 16 (2006) 4872–4878
4875
O
X
CO2H
X
Y
(ii)
N
O
(i)
X
Y
32-84%
5-42%
OMe
N
Y
NO2
NO2
H
25 X = Ph(4-Cl), Y = H
26 X = H, Y = Ph
27 X = Ph(4-Cl), Y = H
28 X = H, Y = Ph
NO2
29a, 29b, 29d
33 X = H, Y = OPh
(viii)
N
N
47%
O
O
31 X = H, Y = NO2
O
O
X
CO2H
Cl
X
Y
O
O
(iii)
N
H
N
H
(iv)
Me
Me
100%
78%
Y
NO2
NO2
NO2
32
29c
30 X = Cl, Y = H
N
N
O
O
O
O
N
(vi)
20%-80%
X
X
Y
(v)
OMe
34a-34d
(vii)
N
OMe
35a-35d
N
29a-29d
H
CH
Y
NH2
quantitative
~50%
X
Y
O
N
O
a Ph(4-Cl)
b H
c PhO
d H
H
Ph
H
PhO
X
Y
OMe
N
N
N
36b-36d
Scheme 4. Reagents and conditions: (i) 1—CHCl3, KOtBu, THF, DMF; 2—AgOTf, aq MeCN reflux; 3—NaBO3, AcOH 60 °C 16 h; (ii) 1—
(COCl)2, CH2Cl2, DMF; 2—12, DIEA resin, MDC; (iii) 1—(COCl)2, CH2Cl2, DMF; 2—12, DIEA resin, MDC; (iv) PhONa, DMF; (v) H2, Pd/C,
EtOH; (vi) HC(OMe)3, 100 °C, 24 h; (vii) BuONO, TFA then DBU; (viii) 1—(COCl)2, CH2Cl2, DMF; 2—PhOH, DIEA resin 1 h; 3—NaH, DMF;
4—aq NaOH, EtOH then aq HCl.
N
N
S
CO2Me
S
O
CO2Me
Ph
O
(i)
(ii)
O
N
S
42%
56%
Ph
S
N
O
NH2
O
N
N
H
Ph
H
Me
Me
37
38
39
O
O
N
O
N
N
CONH2
Ph
H
(iii)
(iv)
~5%
N
N
O
Ph
Ph
S
87%
N
Me
S
S
NH2
40
41
42
Scheme 5. Reagents and conditions: (i) 1—S@C(OPy)2, CH2Cl2 0 °C then 2—12, CH2Cl2, rt; (ii) 1—MeI, K2CO3, THF; 2—toluene reflux;
3—Raney-Ni, methanol, rt; (iii) NaNO2, aq HCl 1,4-dioxane (iv) 1—12, p-xylene, reflux; 2—HC(OEt)3, 100 °C, 24 h.
2-methylthio substituent. Synthesis was completed by
desulfurisation to compound 39 with Raney-nickel in
methanol. The isomeric compound was prepared from
2-amino-4-phenyl-thiophene-3-carboxamide (40) which
was cyclised to the thienotriazinone (41) by treatment
with aqueous nitrous acid. The carbonyl was
sufficiently activated to react directly with compound
12 at high temperature to give an amino amide, which
Compounds modified in each of the regions A–C were
assessed for receptor affinity in a binding assay.12
A—Basic side-chain constraint. In earlier studies, effec-
tive basic side chains were found to include 2-N-di
alkylamino-ethoxy and 2-N-pyrrolidine-ethoxy groups.8
Fusion of this basic side chain was therefore investigated
by linking specific cyclic 2-aminoethoxy groups onto the
core aniline template, retaining the tertiary amine by
N-alkylation, to give amides 8a–e and 8g (Table 1).
was
closed
triethylorthoformate.
to
form
compound
42
by

4876
D. R. Witty et al. / Bioorg. Med. Chem. Lett. 16 (2006) 4872–4878
Cyclisation from the nitrogen, whether onto the linker
position next to the oxygen (8a), or next to the nitrogen
(8b and 8c), slightly reduced receptor affinity, but little
discrimination: both R and S isomers (8b and 8c) gave
similar pKi values. The bridged piperidine (8e) substan-
tially retained affinity (pKi 7.3), and only the trans-fu-
conformation led to a significant (ꢀ10-fold) loss of affin-
ity for MCH R1 (Table 1). This trend was independent
of the basic side chain and whether or not the amide
nitrogen was methylated. Fused meta-substituted
examples, such as 15d (pKi 5.7), were especially poor,
confirming the previously observed preference for a
para-biphenyl scaffold.
sion of
a hexyl ring on the ethyl group (8d)
significantly reduced the pKi to 5.6. Replacement of
the aminoethoxy group with a piperazine gave, in 8g,
a compound which retained some receptor affinity (pKi
7.1). However, disappointingly, no fusion showed im-
proved potency relative to the parent template of 1b.
C—Carbonyl moiety constraint. Previous studies had
indicated that while an N-methyl substituent on the
amide nitrogen was advantageous, larger groups were
detrimental to potency.8 Therefore, a fusion from the
anilide nitrogen to the 2-position on the benzoyl ring
was of particular interest. Disappointingly, the first
compound with this feature, 21, prepared as a mixture
of regioisomers, also showed a reduction in affinity
(pKi 6.4, Table 2). Surprisingly, the synthetic intermedi-
ate, phthalimide 20, exhibited relatively higher receptor
binding (pKi 6.9). This discovery led to the preparation
of corresponding O-, N- and S-linked aryl-phthalimides:
22 (pKi 7.7), 23 (pKi 7.8) and 24 (pKi 7.5), respectively,
all of which demonstrated improved affinity for the
receptor. Unfortunately, stability studies indicated that
this class of N-aryl-phthalimides decomposed in aque-
ous phosphate buffer at ꢀpH 7, due to hydrolytic
phthalimide ring-opening.
B—Biphenyl group constraint. The constraints applied to
the biphenyl group were bridging substituents. In the
case of the para-biphenyl these comprised a methylene
(13b and 15b), a carbonyl (11a) or an ethyl group (13c
and 15c). For the meta-biphenyl, a para-oxygen linker
(13d and 15d) was introduced. Amides in which the
amide nitrogen was N-methylated (series 15) were as-
sessed in comparison with the NH analogues (series
13) as this modification had proved advantageous in un-
fused series.
Due to synthetic availability, examples were prepared
with two basic side-chain variants (diisopropyl and pyr-
rolidinyl groups). Compounds with these groups had
been shown to differ little in potency in the original un-
fused series.8 Although some affinity was retained, most
noticeably with the carbonyl-linked 11a (pKi 6.7), in all
cases, constraining the biphenyl rings to a near planar
We reasoned that the improved affinity could relate to
an additional hydrogen bonding, or polar interaction
with the lone pair on the second carbonyl group. A
series of alternative heterocycles was therefore
Table 1. MCH R1 affinities of aniline-benzamides
R"
O
O
NR2
O
OMe
N
H
X
Y
N
R'
Compound
R00
pKi
Compound
N(R)R
N(iPr)2
R0
H
X
Y
pKi
N(iPr)2
Me
1b
7.6
11a
C@O
Bond
6.7
O
N
8a
8b
8c
8d
8e
8g
7.2
7.1
7.4
5.6
7.3
7.1
13b
15b
13c
15c
13d
15d
1-Pyrrolidine
N(iPr)2
H
CH2
Bond
Bond
Bond
Bond
O
6.3
6.4
6.0
6.5
5.6
5.7
O
Me
H
CH2
N
Me
O
O
1-Pyrrolidine
N(iPr)2
CHCH2
CH2CH2
Bond
N
Me
O
Me
H
Me2N
O
N
1-Pyrrolidine
N(iPr)2
H
Bond
O
N
NEt

D. R. Witty et al. / Bioorg. Med. Chem. Lett. 16 (2006) 4872–4878
Table 2. MCH R1 affinities of heterocycle-linked anilides
4877
O
O
X
R
N
N
Z
OMe
R
Y
Compound
N(R)R
N(iPr)2
X
Y
Z
pKi
21
Ph:H
H:Ph
–CH2–
6.4
1:1 Isomer mix
20
22
N(iPr)2
H
H
H
H
Ph
C@O
C@O
C@O
C@O
–N@CH–
–N@CH–
–N@CH–
–N@CH–
–N@N–
–N@N–
–N@N–
6.9
7.7
7.8
7.5
6.0
7.7
6.5
7.3
7.6
7.4
7.1
1-Pyrrolidine
1-Pyrrolidine
1-Pyrrolidine
1-Pyrrolidine
1-Pyrrolidine
1-Pyrrolidine
1-Pyrrolidine
1-Pyrrolidine
1-Pyrrolidine
1-Pyrrolidine
PhO
PhNH
PhS
H
23
24
35a
35b
35c
35d
36b
36c
36d
4-Cl-Ph–
H
Ph
H
PhO
H
PhO
Ph
H
PhO
H
H
PhO
O
O
O
N
N
O
N
N
S
N
O
O
Ph
;
Ph
Me
Me
S
N
42 pKi 6.1
39 pKi 7.7
investigated in which there was a hydrogen bond
accepting group at both sides. The terminal aryl group
(phenyl or 4-chlorophenyl for 35a) was linked either
directly or by an oxygen linker. Three phenyl-substi-
tuted ring systems showed particular promise:
7-quinazolinone, 7-benzotriazinone and 6-thienopyri-
midinone. The relative orientation of the carbonyl
group and aryl substituent was important—in the case
of the quinazolinone, a para-relationship was preferred
(35b, pKi 7.7; 35d, pKi 7.3). This was reversed for the
benzotriazinone examples (36c, pKi 7.4 and 36d, pKi
7.1). The most potent examples (35b and 36b, pKi
7.6) shared a common feature in the 7-phenyl group,
and both compounds demonstrated low intrinsic clear-
ance in human liver microsome preparations (CLi
<1.5 mL/min/g).13
around these molecules is consistent with a linear bind-
ing mode for the constitutive ring systems. Molecules
containing all three classes of heterobicycle have good
aqueous stability, and both the quinazolinone and
benzotriazinone compounds showed low in vitro suscep-
tibility to metabolism by liver microsomes.
Acknowledgments
The authors acknowledge the scientific and technical
contribution to this work by Catherine O’Toole, Martin
Jones and Gemma Bosch, and thank Kerry-Ann
Garwood for her help formatting this paper.
Supplementary data
This substitution pattern was therefore applied to
related heterocycles. The isomeric thienopyrimidines
39 and 42 showed a marked difference in receptor
affinity, suggesting a subtle preference for the substitu-
tion geometry of the thieno[3,2-d]pyrimidin-4(1H)-one
(39, pKi 7.7). Unlike the phthalimides, all three substi-
tuted heterocycles 35b, 36b and 39 proved stable to
phosphate buffer.
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.bmcl.
2006.06.061.
References and notes
1. Chambers, J.; Ames, R. S.; Bergsma, D.; Muir, A.;
Fitzgerald, L. R.; Hervieu, G.; Dytko, G. M.; Foley, J. J.;
Martin, J.; Liu, W.-S.; Park, J.; Ellis, C.; Ganguly, S.;
Konchar, S.; Cluderay, J.; Leslie, R.; Wilson, S.; Sarau, H.
M. Nature 1999, 400, 261.
2. Hill, J.; Duckworth, M.; Murdock, P.; Rennie, G.;
Sabido-David, C.; Ames, R. S.; Saito, Y.; Nothacker, H.
P.; Wang, Z.; Lin, S. H.; Leslie, F.; Civelli, O. Nature
1999, 400, 265.
The 4-phenyl-N-methyl benzamide moiety found in lead
MCH R1 antagonist 1a can be effectively replaced with
conformationally constrained amide isosteres: the
7-phenyl-4(3H)-quinazolinone, 7-phenyl-2,3-benzotria-
zin-4(1H)-one and 6-phenyl-thieno[3,2-d]pyrimidin-
4(1H)-one ring systems, leading to compounds with
comparable binding affinity such as 35b, 36b and 39.
The substitution pattern and consequent geometry

4878
D. R. Witty et al. / Bioorg. Med. Chem. Lett. 16 (2006) 4872–4878
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