W. Jiang et al. / Bioorg. Med. Chem. Lett. 16 (2006) 4674–4678
4677
Table 3. SAR of the N-alkyl or acyl group at the human MC4R
mice. After an intravenous injection at 5 mg/kg, 22p
exhibited a very low clearance (CL = 3.5 mL/min kg)
and low volume of distribution (Vd = 1.6 L/kg), result-
ing in a long half-life (t1/2 = 5.2 h) in this species. At 1-
and 4-h postdosing, the whole brain concentrations were
62 and 70 ng/g, which exhibited low brain/plasma ratio
of 0.02 and 0.03, respectively. After an oral dose of
10 mg/kg, 22p reached a maximal concentration of
1166 ng/mL at 6 h, and an area under the curve
(AUC) of 12,067 ng/mL h, which gave an absolute bio-
availability of 26.1%. The high plasma exposure might
reflect high plasma protein binding of this compound,
indicated by its low Vd value for a highly lipophilic mol-
ecule (measured logD was 4.0).14 In comparison, the
more lipophilic 23d (measured logD of 4.5) had a mod-
erate CL of 26.9 mL/min kg, a high Vd of 8.8 L/kg, and
a moderate t1/2 of 3.8 h. However, despite its high vol-
ume of distribution, the brain penetration of 23d was
still low, presumably caused by efflux mechanism at
the blood–brain barrier.15 23d had a moderate oral bio-
availability of 11.2%.
R1
X
R2
N
N
H
Cl
Cl
N
22-25
R1
O
Compound
X
R2
Ki (nM)
22a
22b
22c
22d
22e
22f
CF3 s-Bu
CF3 s-Bu
CF3 s-Bu
CF3 s-Bu
CF3 s-Bu
CF3 s-Bu
CF3 s-Bu
CF3 s-Bu
CF3 s-Bu
CF3 s-Bu
CF3 s-Bu
CF3 s-Bu
CF3 s-Bu
CF3 s-Bu
CF3 s-Bu
CF3 s-Bu
CF3 i-Bu
CF3 i-Bu
CF3 i-Bu
CF3 i-Bu
CF3 i-Bu
Et
92
2800
780
5900
>10,000
2600
56
CH2CH(Me)CH2CH3
CH2-2-tetrafuranyl
CH2C6H5
CH2C6H4F-2
CH2CH2Ph
22g
22h
22i
CH2CH2NH2
S-CH2CH(NH2)CH3
R-CH2-2-pyrrolidyl
S-CH2-2-pyrrolidyl
CH2CH2CH2NH2
SO2Me
89
110
64
22j
22k
22l
30
1800
2400
360
18
22m
22n
22o
22p
23a
23b
23c
23d
23e
24a
25a
25b
COOMe
COMe
In conclusion, a series of 3-arylpropionylpiperazines
were synthesized and studied as antagonists of the mel-
anocortin-4 receptor. The potency was increased when
the a-methyl of 11 was replaced by a larger s-butyl or
iso-butyl group. Further enhancements were observed
when either a glycine or b-alanine was incorporated
onto the benzylamine. Some compounds demonstrated
good potency, moderate selectivity, and reasonable oral
bioavailability.
COCH2NH2
COCH2CH2NH2
Me
13
1900
170
620
19
Et
CH2CH2Ome
COCH2NH2
COCH2CH2NH2
COCH2CH2NH2
25
a
F
F
F
EtOCH2
300
400
210
a
BnOCH2 CH2CH2NH2
a
BnOCH2 COCH2CH2NH2
a Racemic mixture.
References and notes
1. Cone, R. D. Nat. Neurosci. 2005, 8, 571.
2. Scarlett, J. M.; Marks, D. L. Expert Opin. Invest. Drugs
2005, 14, 1233.
3. Foster, A. C.; Chen, C.; Markison, S.; Marks, D. L.
IDrugs 2005, 8, 314.
Table 4. Selectivity profiles of S-16, 22p, and 23da
Compound
Ki (nM)
MC1R
MC3R
MC4R
MC5R
4. Chaki, S.; Okuyama, S. Peptides 2005, 26, 1952.
5. (a) Vos, T. J.; Caracoti, A.; Che, J. L.; Dai, M.; Farrer, C.
A.; Forsyth, N. E.; Drabic, S. V.; Horlick, R. A.; Lamppu,
D.; Yowe, D. L.; Balani, S.; Li, P.; Zeng, H.; Joseph, I. B.;
Rodriguez, L. E.; Maguire, M. P.; Patane, M. A.;
Claiborne, C. F. J. Med. Chem. 2004, 47, 1602; (b)
Nicholson, J. R.; Kohler, G.; Schaerer, F.; Senn, C.;
Weyermann, P.; Hofbauer, K. G. J. Pharmacol. Exp.
Ther. 2006, online ahead of print.
6. (a) Chaki, S.; Hirota, S.; Funakoshi, T.; Suzuki, Y.;
Suetake, S.; Okubo, T.; Ishii, T.; Nakazato, A.; Okuyama,
S. J. Pharmacol. Exp. Ther. 2003, 304, 818; (b) Chaki, S.;
Oshida, Y.; Ogawa, S. I.; Funakoshi, T.; Shimazaki, T.;
Okubo, T.; Nakazato, A.; Okuyama, S. Pharmacol.
Biochem. Behav. 2005, 82, 621.
7. Xi, N.; Hale, C.; Kelly, M. G.; Norman, M. H.; Stec, M.;
Xu, S.; Baumgartner, J. W.; Fotsch, C. Bioorg. Med.
Chem. Lett. 2004, 14, 377.
8. Vos, T. J.; Balani, S.; Blackburn, C.; Chau, R. W.; Danca,
M. D.; Drabic, S. V.; Farrer, C. A.; Patane, M. A.; Stroud,
S. G.; Yowe, D. L.; Claiborne, C. F. Bioorg. Med. Chem.
Lett. 2006, 16, 2302.
S-16
22p
23d
(21%)
(17%)
(18%)
1400
800
110
13
1200
170
1200
19
500
a Binding affinity at the human melanocortin receptors expressed in
HEK293 cells with [125I]NDP-MSH as radio-labeled ligand.
Table 5. Pharmacokinetic parameters of compounds 22p and 23d in
micea
Compound
22p
23d
iv dose (mg/kg)
CL (mL/min kg)
Vd (L/kg)
5
5
3.5
1.6
5.2
26.9
8.8
3.8
t1/2 (h)
AUC (ng/mL h)
Cbrain (ng/g) at 1, 4 h
Cbrain/Cplasma
po dose (mg/kg)
Cmax (ng/mL)
Tmax (h)
23,132
62, 70
3,071
43, 33
0.02, 0.03
0.08, 0.17
10
1,166
6
10
115
2
9. (a) Tucci, F. C.; White, N. S.; Markison, S.; Joppa, M.;
Tran, J. A.; Fleck, B. A.; Madan, A.; Dyck, B. P.; Parker, J.;
Pontillo, J.; Arellano, L. M.; Marinkovic, D.; Jiang, W.;
Chen, C. W.; Gogas, K. R.; Goodfellow, V. S.; Saunders, J.;
AUC (ng/mL h)
F (%)
12,067
687
26.1
11.2
a Average of three animals.