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S. Berglund et al. / Bioorg. Med. Chem. Lett. 19 (2009) 4274–4279
O
PS-Cyanoborohydride
NH4+CH3CO2-
N+
F
F
+
N
N
O
O
N
MeOH
MW, 140oC, 5 min
(100%)
N
F
N
N
O
N
N
N
O
NH2
H
DIPEA
DCM
RT, 16 hr
(61.8%)
F
F
N
O
N
N
F
N
N
N
N
H
H
32
Scheme 2.
shown in Table 3. Nevertheless, 25, a (1-hydroxy-cyclohexylmeth-
yl)-urea derivative yielded the first MCH-R1 antagonist with
acceptable potency (IC50 < 50 nM) and no detectable hERG inhibi-
tion in this series. Intriguingly, simple N-methylation of 25 to pro-
ingly, the compound with the most solvent-accessible imidazole
ring in the series, 34, was found to be a very potent 3A4 inhibitor
(IC50 = 40 nM) while 29, a less flexible analog, only moderately
inhibited 3A4 (IC50 = 13.4 lM). Imidazole analogs (27–29 and
vide 24, converted a hERG inactive compound into a 2.16
l
M hERG
31–33) as well as 2-substitution (30) had a positive impact on
3A4 inhibition (14- to 110-fold reduction), while replacement of
imidazole with an alcoholic function yielded the best compromise
inhibitor. Whilst this finding supports modulating polarity as a
mean to achieve hERG selectivity, it also clearly underlines that
subtle structural modifications can have a dramatic effect on hERG
potency. According to the data accumulated, it became evident
that increasing polarity was effective at reducing hERG inhibition
and MCH-R1 antagonism, whereas hydrophobic, preferably aro-
matic, groups contributed to high hERG and MCH-R1 affinity. We
thus resolved to investigate whether a side chain providing both
hydrophobic and polar elements could offer potent MCH-R1 antag-
onists with improved hERG separation, as presented in Table 4.
Compounds 27–40 were prepared according to Scheme 1, as de-
tailed elsewhere.19 The full synthetic pathway to 32 is outlined
in Scheme 2.
Introduction of a branched chain, providing a phenyl ring as
hydrophobe and a N-containing heterocycle as polar moiety, re-
sulted in highly potent MCH-R1 antagonists with varying degrees
of hERG inhibition (27–34, Table 4). Imidazole derivatives (29, 30
and 33) offered better hERG selectivity than the pyrazine (27),
pyrrole (28) and pyrazole (31, 33) counterparts. Interestingly, per-
mutation of triazole (32) to pyrazole (31) transformed a com-
between MCH-R1 antagonism (IC50 = 35 nM), hERG (IC50
=
23.9 M) and 3A4 (IC50 = 20.6 M) inhibition (37, Table 4). Unfor-
l
l
tunately, when dosed in rats to verify its pharmacokinetic profile,
37 was rapidly metabolized (CL = 154 ml/min/kg; N = 2) and it
was therefore impractical to evaluate its effect on weight loss
in rodents models.
The present study clearly demonstrated that, while simulta-
neous optimization of MCH-R1 and hERG binding was achieved
in the present series, the structural and physicochemical require-
ments for MCH-R1 potency and hERG inactivity usually correspond
with one another, rendering optimization at MCH-R1 while mini-
mizing hERG inhibition a significant challenge. It was therefore
the fine-tuning of polarity coupled with subtle structural modifica-
tions that allowed the successful optimization of 4-piperidin-yl-
urea analogs as potent MCH-R1 antagonists with minimized hERG
inhibition ability.
Acknowledgment
pound devoid of hERG affinity into a 4 lM hERG inhibitor,
highlighting once again the beneficial effect of increased polarity,
in the form of minor modifications. Furthermore, 34 afforded a
25 nM MCH-R1 antagonist with a 1180-fold separation over hERG
affinity. Replacement of the phenyl ring of 34 with isopropyl (35)
maintained similar hERG affinity, whereas the marked reduction
in lipophilicity associated with substitution to methyl (36) com-
pletely abolished hERG inhibition (Table 4). Combination of polar
hydroxyl group and hydrophobic phenyl ring was also found to
affect hERG inhibition: the S-enantiomer 37 maintained good
MCH-R1 potency (IC50 = 35 nM) and a promising 682-fold hERG
separation. Intriguingly, the R-enantiomer, 38, displayed weaker
MCH-R1 antagonism (IC50 = 152 nM) but virtually no change in
hERG inhibition (Table 4). Introduction of ionic groups had also
confounding effects on MCH-R1 and hERG affinity: here formation
of a zwitterion via a carboxylic acid function (39) produced a
weak MCH-R1 antagonist with undetectable hERG inhibition,
while addition of a second positive charge in the molecule (40)
yielded a compound with opposite binding characteristics. While
the introduction of an imidazole ring reduced hERG inhibition in
the present series, it also had a marked effect on CYP450 inhibi-
tion, as shown in Table 4 for the human 3A4 isoform. Not surpris-
The authors would like to thank Nidhal Selmi for his help with
the synthetic schemes.
References and notes
1. Saito, Y.; Nothacker, H.-P.; Civelli, O. Trends Endocrinol. Metab. 2000, 11, 299.
2. Schwartz, M. W.; Woods, S. C.; Porte, D., Jr.; Selley, R. J.; Baskin, D. G. Nature
2000, 404, 661.
3. Gomori, A.; Ishiara, A.; Ito, M.; Mashiko, S.; Matsuhita, H.; Yumoto, M.; Ito, M.;
Tanaka, T.; Tokita, S.; Moriya, M.; Iwaasa, H.; Kanatani, A. Am. J. Physiol.:
Endocrinol. Metab. 2003, 284, E583.
4. Ludwig, D. S.; Tritos, N. A.; Mastaitis, J. W.; Kulkarni, R.; Kokkotou, E.; Elmiqst,
J.; Lowell, B.; Flier, J. S.; Maratos-Flier, E. J. Clin. Invest. 2001, 107, 379.
5. Shimada, M.; Tritos, N. A.; Lowell, B. A.; Flier, J. S.; Maratos-Flier, E. Nature 1998,
396, 670.
6. Rivera, G.; Bocanegra-Garcia, V.; Galiano, S.; Cirauqui, N.; Ceras, J.; Perez, S.;
Aldana, I.; Monge, A. Curr. Med. Chem. 2008, 15, 1025.
7. Kowalski, T. J.; Sasikumar, T. Biodrugs 2007, 21, 311.
8. Rokosz, L. L. Expert Opin. Drug Discovery 2007, 2, 1301.
9. Souers, A. J.; Gao, J.; Brune, M.; Bush, E.; Wodka, D.; Vasudevan, A.; Judd, A. S.;
Mulhern, M.; Brodjian, S.; Dayton, B.; Shapiro, R.; Hernandez, L. E.; Marsh, K. C.;
Sham, H. L.; Collins, C. A.; Kym, P. R. J. Med. Chem. 2005, 48, 1318.
10. Takekawa, S.; Asami, A.; Ishihara, Y.; Terauchi, J.; Kato, K.; Shimomura, Y.; Mori,
M.; Murakoshi, H.; Kato, K.; Suzuki, N.; Nishimura, O.; Fujino, M. Eur. J.
Pharmacol. 2002, 438, 129.
11. Mendez-Andino, J. L.; Wos, J. A. Drug Discovery Today 2007, 12, 972.