G. K. Mittapalli et al. / Bioorg. Med. Chem. Lett. 22 (2012) 3916–3920
3919
Table 3
SAR of the carbamate analogs
NH
NH
NH
a
b
HO
3
4
3
R
O
N
O
R2
HO
c
c
R2
R3
Y2 IC50
(lM)
a
32-33
34
Compound
51
52
53
54
55
56
57
58
59
60
61
62
63
64
65
H
H
H
H
H
H
H
H
H
H
H
H
OCH3
OC2H5
SO2N(CH3)2
SO2N(C2H5)2
SO2-Pyrrolidine
SO2CH3
2.68
1.58
0.061
0.012
0.049
0.141
0.059
0.057
0.043
0.22
NA
Scheme 2. Reagents and conditions: (a) TFA, CH2Cl2, rt, 6 h; (b) (CH3)3SiH, CH2Cl2,
3 days, rt; (c) aryl isothiocyanate, CH2Cl2, rt, 2–3 h.
R
NH.HCl
N
NH
b
a
SO2C2H5
SO2(CH3)2
SO2(C2H5)2
CON(C2H5)2
NHCOCH3
NHCOC2H5
NHSO2CH3
H
HO
HO
O
R4
R = CO2CH2Ph or CO2C2H5
R4
R
R
R
R
4 = cyclohexyl
38
39
40
41
NA
0.394
NA
R3
4 = pyridin-3-yl
4 = pyridin-2-yl
H
S
CON(C2H5)2
SO2N(C2H5)2
c
N
N
H
4 = thiophen-3-yl
H
NA
42 R4 = furan-3-yl
HO
a
R4
All compounds were inactive at NPY Y1 receptor; the highest concentration
tested in the assay was 10 lM (NA = not active).
43 R4 = 3,5-dimethylisoxazol-4-yl
44 R4 = 4(F)-phenyl
38 - 44
Scheme 3. Reagents and conditions: (a) (i) ethyl or benzylchloroformate, Et3N,
CH2Cl2, rt, 12 h; (ii) cyclohexylmagnesium bromide, THF, À78 °C, 1 h or heteroaryl
bromide, THF, n-BuLi, À78 °C, 30 min, then addition of ketones, À78 °C, 3 h; (b) H2,
10% Pd/C, MeOH, 3 h or K2CO3, MeOH, reflux, 24 h; (c) aryl isothiocyanate, CH2Cl2,
2–3 h, rt.
OH
R3
R3
R2
F
O
a
b, c
N
O
R2
R2
HO
R3
51-65
Scheme 5. Reagents and conditions: (a) 2-butyn-1-ol, KOtBu, DMSO, 125 °C
O
O
O
O
O
a
O
OH c
Cl
b
microwave, 15 min; (b) triphosgene, NaOH, CH2Cl2/H2O, 0 °C to rt, 3 h; (c)
a,a-
HN
HN
HN
i
diphenylpiperidino-4-methanol, Pr2EtN, CH2Cl2, rt, 6 h.
49
47
48
of in vivo PK and further lead optimization of the series of com-
pounds will be reported in due course.
O
S
d
e
O
HN
O
S O
N
N
NH
N
N
HN
HN
Acknowledgment
46
50
This work was supported by the National Institute of Health
Grant 1U01AA018665.
Scheme 4. Reagents and conditions: (a) NaN3, H2SO4, CHCl3, reflux, 12 h; (b)
NaBH4, MeOH, 0 °C to rt, 3 h; (c) SOCl2, CHCl3, reflux, 4 h; (d) piperazine, iPr2EtN,
DMF, 145 °C, microwave, 1 h; (e) 4-isothiocyanato-N,N-dimethylbenzenesulfona-
mide, CH2Cl2, rt, 3 h.
References and notes
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carboxamide analogs 61 and 62 completely lost the activity. The 3-
substituted analogs 64 and 65 displayed no activity, which sug-
gests that in both the carbamate and thiourea series the substitu-
tion at the 4-position of phenyl ring (A) is important for the
antagonist activity.
The carbamate analogs 51–65 were prepared by reacting the
a,a-diphenylpiperidino-4-methanol with aryl chloroformates, ob-
tained from the reaction of phenols with triphosgene, in the pres-
ence of iPr2EtN. The non-commercially available phenols were
prepared by conversion of the appropriate aryl fluoride into the
corresponding phenol with 2-butyn-1-ol and potassium tert-
butoxide in DMSO (Scheme 5).23
In summary, we systematically explored the SAR of the hit mol-
ecule SF-11 that led to the identification of selective and highly po-
tent small molecule NPY Y2 receptor antagonists 16 (CYM 9484;
IC50 = 19 nM) and 54 (CYM 9552; IC50 = 12 nM). The investigation
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Bloom, S. R. Brain Res. 2005, 1043, 139.
13. Rimondini, R.; Thorsell, A.; Heilig, M. Neurosci. Lett. 2005, 375, 129.
14. Andres, C. J.; Zimanyi, I. A.; Deshpande, M. S.; Iben, L. G.; Grant-Young, K.;
Mattson, G. K.; Zhai, W. Bioorg. Med. Chem. Lett. 2003, 13, 2883.
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