Thienopyrimidinone bis-aminopyrrolidine ureas as potent melanin-concentrating hormone receptor-1 (MCH-R1) antagonists

Article abstract of DOI:10.1016/j.bmcl.2007.02.012

A series of thienopyrimidinone bis-aminopyrrolidine ureas were designed, synthesized, and evaluated for their ability to bind melanin-concentrating hormone receptor-1. These compounds exhibit potent binding affinity (K_i = 3 nM) and good in vitro metabolic stability.

Full text of DOI:10.1016/j.bmcl.2007.02.012

Bioorganic & Medicinal Chemistry Letters 17 (2007) 2535–2539
Thienopyrimidinone bis-aminopyrrolidine ureas as potent melanin-
concentrating hormone receptor-1 (MCH-R1) antagonists
Mingzhu Zhang, Junko Tamiya,* Linh Nguyen, Martin W. Rowbottom, Brian Dyck,
Troy D. Vickers, Jonathan Grey, David A. Schwarz, Christopher E. Heise,
Jason Haelewyn, Monica S. Mistry and Val S. Goodfellow
Department of Medicinal Chemistry, Pharmacology and Molecular Biology, Neurocrine Biosciences Inc.,
12790 El Camino Real, San Diego, CA 92130, USA
Received 5 January 2007; revised 5 February 2007; accepted 6 February 2007
Available online 8 February 2007
Abstract—A series of thienopyrimidinone bis-aminopyrrolidine ureas were designed, synthesized, and evaluated for their ability to
bind melanin-concentrating hormone receptor-1. These compounds exhibit potent binding affinity (Ki = 3 nM) and good in vitro
metabolic stability.
Ó 2007 Elsevier Ltd. All rights reserved.
Melanin-concentrating hormone (MCH) is a 19-member
cyclic peptide strongly associated with feeding behavior
in mammals.1 Although MCH is expressed throughout
the brain, concentrations are higher in the hypothala-
mus, a region linked with control of feeding.2 Elevated
levels of MCH peptide have been observed in both
fasting ob/ob and wild-type mice3 and central adminis-
tration of MCH induces hyperphagia and diet-induced
obesity (DIO)ꢀ.4/ꢀ,5 Knockout mice which lack the MCH
which lack the MCH-R1 receptor (mchr1 ꢀ/ꢀ) are lean
and hyperphagic, indicating alterations occur in metab-
olism as well as in feeding.7 Recently, structurally di-
verse small molecule MCH-R1 antagonists have been
reported and several have shown oral efficacy in various
animal models.8 These data suggest that a potent oral
antagonist of MCH-R1 would be clinically useful as
an anti-obesity agent.
pound 1 displayed potent binding (Ki = 7 nM) and func-
tional activity (IC50 = 14 nM); however, the compound
was rapidly metabolized in an in vitro human liver
microsome (HLM) assay with an intrinsic clearance of
59 mL/min/kg.10 In addition, 1 was a moderately
potent inhibitor of CYP2D6 (IC50 = 4.9 lM). Scientists
at GlaxoSmithKline recently disclosed a series of con-
strained-amide MCH-R1 antagonists (e.g., 2)8o,11,12
with good pharmacokinetic characteristics (bioavailabil-
ity = 31%, t1/2 = 11 h). We hypothesized that constrain-
ing the amide in our APU system in a similar manner
might improve the metabolic stability and modifications
near the basic nitrogen might alter inhibition of
CYP2D6.13 In this letter, we report the synthesis and
SAR of APU compounds with a thienopyrimidinone
ring (3) and the effect these changes have on metabolic
stability and CYP2D6 inhibition.
peptide (mch
) are lean and hypophagic,6 while mice
The synthesis of the thienopyrimidinone APU series is
shown in Scheme 1. 3-Amino-5-(4-chloro-phenyl)-thio-
phene-2-carboxylic acid methyl ester 7 was treated with
N,N-dimethylformamide dimethyl acetal followed by
reaction with Boc-protected (S)-3-aminopyrrolidine to
form the thienopyrimidinone 8. Subsequent deprotec-
tion followed by coupling with p-nitrophenyl carbamate
derivative 6 gave urea 10. Finally, removal of the Boc
protecting group gave amine 11 and reductive alkylation
or acylation provided an efficient method to compounds
12 with a variety of substituents.
Our group has previously reported a novel aminopyrr-
olidine urea (APU) core that has produced potent
MCH-R1 antagonists, exemplified by 1 (Fig. 1).9 Com-
Keywords: MCH; Melanin-concentrating hormone; Obesity.
*
Corresponding author. Tel.: +1 858 617 7787; fax: +1 858 617
7619; e-mail: jtamiya@neurocrine.com
Biofocus DPI, 9640 Town Centre Drive, San Diego, CA 92121,
USA.
0960-894X/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2007.02.012

2536
M. Zhang et al. / Bioorg. Med. Chem. Lett. 17 (2007) 2535–2539
Cl
N
O
O
N
N
O
O
N
S
O
N
N
Cl
N
1
2
F3C
O
N
N
R
S
N
N
N
Ar
O
3
Figure 1. MCH-R1 antagonists.
NO2
O
b
N
R
N
Boc
HN
O
N
4: R = H
5: R = Boc
6
a
O
O
N
f
c, d
S
O
S
N
N
R
Cl
Cl
NH2
7
8: R = Boc
9: R = H
e
O
O
N
R
N
S
R
N
N
O
h
N
N
N
N
S
Cl
N
Cl
O
N
12
10: R = Boc
11: R = H
g
Scheme 1. Reagents and conditions: (a) (Boc)2O, DCM, 0 °C, 1 h, 99%; (b) 4-nitrophenyl chloroformate, TEA, THF, 0 °C to rt, 12 h, 97%; (c) N,N-
dimethylformamide dimethyl acetal, EtOH, 90 °C, 2 h; (d) (S)-3-amino-1-N-Boc-pyrrolidine, EtOH, 100 °C, 16 h, 74% over 2 steps; (e) TFA, DCM,
0 °C, 30 min, 89%; (f) 6, TEA, DMA, 80 °C, 24 h, 95%; (g) TFA, DCM, 0 °C, 30 min, 76%; (h) for 12a–m: aldehyde or ketone, NaBH(OAc)3, DCM,
MeOH, rt, 12 h, 20–70%; for 12n–o: acyl bromide, TEA, DMF, 60 °C, 24 h, 10–30%.
Data from both MCH binding and GTPcS functional
assays for the thienopyrimidinone APUs are shown in
Table 1. The thienopyrimidinone 12a is analogous to
compound 1 and showed comparable binding activity
(Ki = 6 nM). Intrinsic clearance (41 mL/min/kg) and
CYP2D6 inhibition (8.6 lM) were moderately improved
relative to 1, providing a promising starting point for
SAR studies. When the 3-phenylpropyl side chain was
removed (11), the binding affinity decreased 3-fold rela-
tive to 12a, although no decrease in functional activity
was observed. A methyl substituent (12b) retained most
of the binding affinity of 12a and had very low CYP2D6
inhibition (IC50 = 99 lM). Small cyclic aliphatics (12d–
g) gave potent MCH antagonists; however, these com-
pounds showed moderate CYP2D6 inhibition (12f,
IC50 = 3.4 lM). In contrast, ether derivatives (12j–
12m) were equally potent, but showed significantly less
CYP2D6 inhibition (12k, IC50 = 22.5 lM). Although
aliphatic ketone 12n was moderately potent
(Ki = 17 nM), aromatic ketone 12o had significantly re-
duced binding affinity (Ki = 80 nM). Based on the bind-
ing and CYP2D6 data, compounds 12b and 12k were
chosen for further optimization.
The other three stereoisomers of 12k were synthesized
(Table 2) to determine the effect of stereochemistry on
binding affinity. The two chiral centers in the molecule
could be independently controlled by using different chi-
ral aminopyrrolidines at steps d and f (Scheme 1). The
stereochemistry of the pyrrolidine closer to the thieno-
pyrimidinone had a greater effect on binding. The
(S,S) diastereomer 12k was the most potent isomer with
a Ki of 3 nM. Binding affinity decreased 7-fold for the
(S,R) diastereomer 13 (Ki = 21 nM) and 20-fold for the
(R,R) diastereomer 14 (Ki = 69 nM). The (R,S) diaste-
reomer 15 was the least potent with a 50-fold decrease

M. Zhang et al. / Bioorg. Med. Chem. Lett. 17 (2007) 2535–2539
2537
Table 1. Binding affinities and functional activities for 11 and 12
Table 2. Effect of stereochemistry on MCH-R1 receptor binding
affinity
O
R
N
N
N
O
S
N
Cl
O
O
N
N
N
S
N
N
Cl
O
a
IC50 (nM)
Kia (nM)
b
N
Compound
R
H
a
11
17
29
Compound
a,b
Kia (nM)
12a
6
31
12
13
14
15
S,S
S,R
R,R
R,S
3
21
69
154
12b
12c
Me
iPr
10
5
20
23
a Values are averaged from at least two experiments. Observed values
typically fell within a 2-fold range of this mean.
12d
12e
12f
12g
12h
12i
1
9
4
13
10
10
53
15
10
acid methyl ester 17 was reacted with trifluoroacetic
anhydride and pyridine to give the protected amine 18.
Lithiation at the C-5 position of the thiophene was
achieved using LDA, followed by bromination with dib-
romoethane to give 19. Removal of the trifluoroacetyl
group, condensation with N,N-dimethylformamide
dimethyl acetal, and reaction with amine 16 gave the
versatile intermediate 21, which allowed modifications
to be introduced at both ends in the last stages of syn-
thesis. Removal of the Boc protecting group, then
reductive alkylation, followed by Suzuki couplings with
aryl boronic acid gave compounds 22 and 23.
2
3
50
4
O
12j
4
O
The binding affinities for the methyl and tetrahydropyr-
anyl derivatives are shown in Table 3. The tetrahydro-
pyranyl derivatives (12k and 23) generally had 2- to
3-fold higher binding affinity for MCH-R1 than the
methyl derivatives (12b and 22). The two series showed
similar SAR around the substitution on the phenyl
group. Small substitutents in the para position were
the most favorable with chloro (12b and 12k) and ethyl
(22b and 23b) giving the most potent compounds. The
electronic nature of the substituent did not appear to
have an effect on binding affinity since the 4-methyl
derivatives (22a and 23a) had the same binding affinity
as the 4-trifluoromethyl derivatives (22d and 23d). The
larger ethylenedioxy ring (22i and 23h) substantially
reduced affinity. Incorporation of a methyl group in
the ortho position also led to decreased potency (22a
vs 22c; 22f vs 22g), in contrast to our previous APU
series in which 2,4-disubstituted aryls were preferred.14
These data and the different stereochemical preferences
suggest that constraining the amide forces these mole-
cules to adopt a subtly different conformation in the
binding pocket.
12k
12l
3
23
11
11
44
O
7
O
12m
12n
7
O
O
17
O
12o
80
N.D.b
OCF3
a Values are averaged from at least two experiments. Observed values
typically fell within a 2-fold range of this mean.
b Not determined.
(Ki = 154 nM) compared to 12k. This stereochemical
preference is slightly different from the original APU
series where the most potent isomer is the (S,R)
diastereomer.9
The CYP2D6 inhibition and intrinsic clearance of the
4-chloro and 4-ethyl phenyl derivatives are shown in
Table 4. The methyl derivatives (12b and 22b) had virtu-
ally no inhibition of CYP2D6 and the tetrahydropyranyl
derivatives (12k and 23b) had weak inhibition. The
intrinsic clearance of the 4-ethyl phenyl derivatives
(22b and 23b) was very high, indicating the ethyl moiety
as a probable site of metabolism. In contrast, the 4-chlo-
ro phenyl derivatives (12b and 12k) had much lower
To further explore the SAR of the thienopyrimidinone
APU series, the aryl group was modified on 12b and
12k. Scheme 2 shows how the synthetic route was
altered to allow different phenyl groups to be introduced
late in the synthesis. 3-Amino-thiophene-2-carboxylic

2538
M. Zhang et al. / Bioorg. Med. Chem. Lett. 17 (2007) 2535–2539
Boc
N
O
NO2
O
a
N
N
N
Boc
O
N
H2N
6
16
S
S
CO2Me
R
Br
CO2Me
R
c
e, f
N
N
H
H
17: R = H
18: R = COCF3
19: R = COCF3
20: R = H
b
d
O
O
O
Boc
R
R1
N
g, h, i
N
N
N
N
S
N
S
N
N
Br
O
N
N
21
22: R = Me
23: R = THP
Scheme 2. Reagents and conditions: (a) (S)-3-aminopyrrolidine, TEA, DMA, 70 °C, 15 h, 58%; (b) trifluoroacetic anhydride, pyridine, MeCN, 0 °C,
2 h, 99%; (c) i—LDA, THF, ꢀ78 °C, 1 h; ii—dibromoethane, ꢀ78 °C to rt, 1 h, 44%; (d) K2CO3, MeOH, H2O, rt, 30 min, 98%; (e) N,N-
dimethylformamide dimethyl acetal, EtOH, 90 °C, 1 h, 99%; (f) 16, EtOH, 90 °C, 15 h, 57%; (g) TFA, DCM, 0 °C, 30 min, 98%; (h) formaldehyde or
tetrahydro-4H-pyran-4-one, NaBH(OAc)3, DCM, MeOH, rt, 1 h, 97% for 22, 80% for 23; (i) ArB(OH)2, Pd(PPh3)4, Na2CO3, 1,4-dioxane, H2O,
100 °C, 4 h, 10–70%.
Table 3. Binding affinities for 12b, 12k, 22, and 23
Table 4. CYP2D6 inhibition and intrinsic clearance data
O
R
Compound
CYP2D6 (lM)
Clearance (mL/min/kg)
R'
N
N
N
S
N
12b
22b
12k
23b
99
16
42%a
23
200
24
O
N
22: R = Me
23: R = THP
57
85
a % inhibition at 120 lM.
Compound
R0
Kia (nM)
12b
22a
22b
22c
22d
22e
22f
22g
22h
22i
4-Cl
4-Me
10
15
5
In summary, we discovered a new class of potent and
functional MCH-R1 antagonists containing a thieno-
pyrimidinone bis-aminopyrrolidine urea. The substitu-
tion on the basic nitrogen altered the interaction with
CYP2D6 and very small (methyl) or hydrophilic
(THP) groups significantly reduced the inhibition of
CYP2D6. The series also showed improved intrinsic
clearance resulting in compounds that may have a satis-
factory in vivo profile.
4-C2H5
2,4-Me
4-CF3
4-CF3O
4-CH3O
49
17
39
21
46
26
143
3
2-CH3,4-CH3O
2-Cl,4-C2H5O
3,4-O(CH2)2O
4-Cl
12k
23a
23b
23c
23d
23e
23f
23g
23h
4-Me
4-C2H5
14
8
Acknowledgments
2,4-Me
4-CF3
4-CF3O
70
19
18
28
14
45
We thank John Harman, Chris Devore, and Shawn
Ayube for LC-MS support and John Saunders for help-
ful discussions in the discovery of these compounds.
2-CH3,4-CH3O
2-Cl,4-C2H5O
3,4-O(CH2)2O
a Values are averaged from at least two experiments. Observed values
typically fell within a 2-fold range of this mean.
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