An evaluation of 3,4-methylenedioxy phenyl replacements in the aminopiperidine chromone class of MCHr1 antagonists

Article abstract of DOI:10.1016/j.bmcl.2006.11.065

The optimization of potent MCHr1 antagonist 1 with respect to improving its in vitro profile by replacement of the 3,4-methylenedioxy phenyl (piperonyl) moiety led to the discovery of 19, a compound that showed excellent MCHr1 binding and functional potencies in addition to possessing superior hERG separation, CYP3A4 profile, and receptor cross-reactivity profiles.

Full text of DOI:10.1016/j.bmcl.2006.11.065

Bioorganic & Medicinal Chemistry Letters 17 (2007) 874–878
An evaluation of 3,4-methylenedioxy phenyl replacements in the
aminopiperidine chromone class of MCHr1 antagonists
a,
a
a
a
*
Rajesh R. Iyengar, John K. Lynch, Mathew M. Mulhern, Andrew S. Judd,
a
a
a
a
Jennifer C. Freeman, Ju Gao, Andrew J. Souers, Gang Zhao,
Dariusz Wodka, H. Doug Falls, Sevan Brodjian,
Brian D. Dayton, Regina M. Reilly, Sue Swanson, Zhi Su,
a
a
a
a
a
c
b
b
b
b
Ruth L. Martin, Sandra T. Leitza, Kathryn A. Houseman,
Gilbert Diaz, Christine A. Collins, Hing L. Sham and Philip R. Kym
b
a
a
a
a
Metabolic Disease Research, Metabolic Disease Research, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064, USA
Integrative Pharmacology, Metabolic Disease Research, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064, USA
b
c
Exploratory Pharmacokinetics, Metabolic Disease Research, Abbott Laboratories, 100 Abbott Park Road,
Abbott Park, IL 60064, USA
Received 26 October 2006; revised 16 November 2006; accepted 20 November 2006
Available online 1 December 2006
Abstract—The optimization of potent MCHr1 antagonist 1 with respect to improving its in vitro profile by replacement of the
,4-methylenedioxy phenyl (piperonyl) moiety led to the discovery of 19, a compound that showed excellent MCHr1 binding and
functional potencies in addition to possessing superior hERG separation, CYP3A4 profile, and receptor cross-reactivity profiles.
3
Ó 2006 Elsevier Ltd. All rights reserved.
Melanin-concentrating hormone (MCH) is a cyclic 19-
amino acid peptide that is produced predominantly in
ber of small molecule MCHr1 antagonists have been
reported to be causative in the reduction of body weight
and/or food intake in rodents, which provides further
validation of the potential of MCHr1 antagonism as
1
neurons in the lateral hypothalamus and zona incerta.
Several lines of evidence involving experiments with
the MCH peptide support the role of MCH in the regu-
8
an effective anti-obesity target.
2
lation of body weight in rodents and suggest that inhi-
bition of the interaction of MCH with its receptor in the
brain would be a potential anti-obesity pharmacothera-
py. A single injection of the MCH peptide into the lat-
eral hypothalamus of rodents stimulates food intake
and chronic administration leads to increased body
A recent report from these laboratories disclosed a po-
tent MCHr1 antagonist 1 that demonstrated significant,
dose-dependent weight loss in a DIO mouse model upon
9
oral administration. Unfortunately, this compound was
later discovered to have dose-dependent QT interval pro-
longation in an pentobarbital-anesthetized dog model,
related to functional blockade at the hERG (Human
Ether-a-go-go Related Gene) channel demonstrated by
this compound. This gene encodes the potassium channel
3
,4
weight. Additionally, transgenic mice overexpressing
the MCH gene are susceptible to obesity and insulin
5
resistance. In contrast, mice lacking the gene encoding
MCH are lean, hypophagic, and maintain elevated met-
6
abolic rates. Genetically altered animals that lack the
single gene encoding the MCH receptor (MCHr1) in ro-
dents maintain elevated metabolic rates and remain lean
(I ) that is essential for ventricular repolarization and
Kr
1
0
normal cardiac function. A blockade of hERG is asso-
ciated with QT interval prolongation, torsades de pointes
and sudden cardiac death. Thus, the prospect of associa-
tion of drug agents with hERG channel blockade is an
important safety consideration in drug discovery and
development. In order to ameliorate the association of
our chemical series with hERG channel binding, elimi-
nating or significantly decreasing this affinity without
7
despite hyperphagia on a normal diet. Finally, a num-
Keywords: MCHR1; Obesity; hERG; Piperonyl replacements.
*
Corresponding author. Tel.: + 1 847 937 9151; fax: + 1 847 938
674; e-mail: rajesh.iyengar@abbott.com
1
0
960-894X/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2006.11.065

R. R. Iyengar et al. / Bioorg. Med. Chem. Lett. 17 (2007) 874–878
875
sacrificing MCHr1 potency became a priority. Ideally,
any reduction in hERG channel affinity (IC 15.1 lM
R
O
NH
R1
5
0
F
O
O
a
b
O
N
3
N
for 1, [ H]-dofetilide assay) would be of even greater sig-
nificance when accompanied with a concomitant increase
in MCHr1 functional potency to enable a better selectiv-
ity window for our compounds (ratio of hERG IC /
H
R
N
H
2
3-10, 17-19
5
0
R2
R4
2
+
O
O
O
N
O
N
MCH Ca release IC : 520 for 1). Additionally, to
0
5
avoid potential complications due to competitive
CYP3A4 inhibition and other receptor cross-reactivity,
we also sought to improve the general cross-reactivity
profile of future compounds as compared to 1. The
CYP3A4 subfamily of isozymes is responsible for the
R
R
R
N
R3
R
R
R
N
R5
H
H
2
4
5
3
4
, R = OH, R3 = NH2
, R = NH2, R = OH
11, R ,R = -OC(Et)N-
12, R ,R = -NC(Et)O-
2
3
4
5
R2
R4
N
c
O
O
N
1
1
metabolism of about 60% of known therapeutic drugs.
R3
R5
N
N
H
H
Inhibition of CYP3A4 is frequently associated with
drug–drug interactions and sometimes associated with
adverse cardiovascular events as well. The need for a
2
3
4
5
4
5
, R = NH2, R = OH
, R = R = OH
13, R ,R = -NHC(O)O-
14, R ,R = -OC(O)O-
2
3
4
5
R2
R3
R4
R5
‘
clean’ candidate is especially relevant in the drug devel-
N
d
N
opment for anti-obesity and other metabolic disorders,
which would likely entail protracted therapy in an often
N
N
H
H
1
2
3, R = OH, R3 = NH2
, R = NH2, R = OH
2
4
5
cardiovascular-compromised patient population.
2
15, R ,R = -OCH C(O)NH-
2
3
4
5
4
16, R ,R = -NHC(O)CH2O-
Early SAR evaluation on the 7-fluorochromone-4-amin-
opiperidines had led to the discovery that the attach-
ment of the 3,4-methylenedioxy phenyl moiety with
respect to the piperidine nitrogen connectivity be an
optimal component for maintaining binding affinity
Scheme 1. Reagents and conditions: (a) R
1 3
CHO, NaBH CN, MeOH,
DCM or NaBH(OAc)
3
, THF, rt to 50 °C or R
1
CH
2
Br, DMF, rt or
0
heating, 5–90%; (b) 3-hexyn-2-one, MeOH, reflux, 15 h, 1%; (c) N,N -
carbonyldiimidazole, THF, 50 °C, 15 h, 8–15%; (d) chloroacetyl
chloride, DCM, rt, 30–50%.
9
with good functional potency. This structure–activity
evaluation had also revealed that differential functional-
ization on the terminal phenyl ring, including changes to
the methylenedioxy group itself, seemed to have an im-
pact limited to either MCHr1 potency or hERG affinity
sized from the respective benzylic methyl precursors
1
3
using standard protocols and then condensed with
the amine under alkylation conditions. In other instanc-
es, initial condensates were further modified to construct
heterocyclic rings on the phenyl terminus. Thus, ring
forming reactions were carried out on the corresponding
3,4-dihydroxy phenyl or o-amino phenol precursors to
synthesize analogs 11–16.
and with 1 possessing the best overall in vitro profile
9
(
Fig. 1). We decided to expand this exploration to alter-
native bicyclic termini replacements to the piperonyl
moiety while retaining the optimized 7-fluorochro-
mone-4-minopiperidine core of 1. To this end, several
compounds in different benzofused bicyclic families were
designed, synthesized, and evaluated in MCHr1 and
hERG in vitro assays.
Although several of the initially assayed heterocyclic
benzofused bicyclic compounds possessed good binding
affinity and functional potency against MCHr1, most of
them also displayed an increased affinity for hERG
channel binding as compared to 1 (compounds 6–9,
Table 1). The benzoxazole analog 10 was the only com-
pound in the initial subset that displayed the in vitro
selectivity profile that was desired although it was still
Compounds 3–10 and 17–19 (Scheme 1 and Table 1)
were generally prepared by an alkylation reaction on
9
the piperidine nitrogen of the previously described
7
-fluorochromone-4-aminopiperidine core 2 using com-
mercially available benzaldehydes or alkyl halides. In
some cases, the aldehydes or alkyl halides were synthe-
2
+
not better than 1 (hERG IC50/MCH Ca release IC50
ratio: 426 for 10). However, it was of interest to us to
note that the affinity for hERG channel seemed to rea-
1
4
sonably track the polarity of the bicyclic termini.
Hence, in subsequent examples, we sought to incorpo-
rate polarity at this site as a strategy to perhaps decrease
the affinity of the compounds to bind to the hERG
channel while retaining or improving MCHr1 activi-
9
,14,15
ty.
ing the in vitro profile of benzoxazole-bearing analogs,
1 and 12 were synthesized and evaluated to see if this
To investigate the possibility of further improv-
1
moiety tolerated further substitution. This derivatiza-
tion of 10, however, resulted in the loss of MCHr1
potency. Only the corresponding benzoxazolone analog
1
1
1
3 regained some of the MCHr1 potency displayed by
0. The analogous benzodioxalone-bearing compound
4 showed a dramatic decrease in its hERG channel
Figure 1. 7-Fluorochromone-4-aminopiperidine-based orally active
MCHr1 antagonist 1.
affinity albeit losing most of its MCHr1 affinity as well.
It was interesting to note that between compounds 11

876
R. R. Iyengar et al. / Bioorg. Med. Chem. Lett. 17 (2007) 874–878
a
Table 1. SAR of piperonyl replacements of 1
O
N
R
F
O
O
N
H
b
2+
c
d
2+
hERG/Ca ratio
Compound
R
MCHr1 IC50 (lM)
Ca IC50 (lM)
hERG IC50 (lM)
6
0.007
0.035
5.28
1.37
6.08
2.53
151
24
O
S
7
8
9
0.004
0.038
0.005
0.010
0.057
0.110
0.066
0.106
55
N
H
H
N
38
O
N
O
N
e
1
1
1
1
1
1
1
1
1
1
0
1
2
3
4
5
6
7
8
9
34.6
326
>2
e
e
1.267
>10
26.7
20
Et
Et
N
O
0.095
0.043
1.38
14
H
N
0.569
25
44
O
O
O
O
O
f
f
f
2.01
5.59
85.2
15
O
f
e
0.166
2.41
nt
—
N
O
H
H
N
O
e
e
e
0.019
0.233
5.79
25
O
H
N
O
e
0.007
0.003
0.001
0.162
0.044
0.046
85.8
530
1030
1110
N
O
O
O
47.4
51.1
a
1
All compounds were >95% pure by HPLC and characterized by H NMR and HRMS. All values are mean values (n P 3 unless specified
otherwise).
125
b
c
d
Displacement of [ I]-MCH from MCHr1 expressed in IMR-32 (I3.4.2) cells (MCH binding K = 0.66 ± 0.25 nM, Bmax = 0.40 ± 0.08 pmol/mg).
2+
Inhibition of MCH-mediated Ca release in whole IMR-32 cells (MCH EC50 = 62.0 ± 3.6 nM).
3
d
Displacement of [ H]-dofetilide from hERG/HEK membrane homogenates at six concentrations, 1/2 log apart, in duplicate using a 96-well plate
design. IC50 values calculated using Graphpad Prizm software.
e
f
(n = 2).
(n = 1).
and 12, the MCHr1 potency resided with one regioisom-
er, which bore the nitrogen at the meta-position with re-
spect to the aminopiperidine connectivity. This
regioisomeric theme was similarly reflected in the analog
The application of this observation to the corresponding
quinolone-bearing analog resulted in 17, which showed
a dramatic improvement in MCHr1 potency with
2
+
similar hERG separation as 1 (hERG IC /MCH Ca
5
0
1
6
sets 8–9 and 15–16.
release IC50 ratio: 530 for 17). Subsequent exploration

R. R. Iyengar et al. / Bioorg. Med. Chem. Lett. 17 (2007) 874–878
877
of this finding was directed towards the evaluation of an
N-alkyl quinolone analog to clarify the need of an intact
quinolone –NH group. We were quite pleased to find
that the corresponding N-methyl quinolone analog 18
was even better than the parent in terms of its MCHr-
6. Shimada, M.; Tritos, N. A.; Lowell, B. B.; Flier, J. S.;
Maratos-Flier, E. Nature 1998, 396, 670.
7
. (a) Marsh, D. J.; Weingarth, D. T.; Novi, D. E.; Chen, H.
Y.; Trumbauer, M. E.; Chen, A. S.; Guan, X.-M.; Jiang,
M. M.; Feng, Y.; Camacho, R. E.; Shen, Z.; Frazier, E.
G.; Yu, H.; Metzger, J. M.; Kuca, S. J.; Shearman, L. P.;
Gopal-Truter, S.; MacNeil, D. J.; Strack, A. M.; MacIn-
tyre, D. E.; Van der Ploeg, L. H. T.; Qian, S. Proc. Natl.
Acad. Sci. U.S.A. 2002, 99, 3240; (b) Chen, Y.; Hu, C.;
Hsu, C.-K.; Zhang, Q.; Bi, C.; Asnicar, M.; Hsiung, H.
M.; Fox, N.; Slieker, L. J.; Yang, D. D.; Heiman, M. L.;
Sh, Y. Endocrinology 2002, 143, 2469.
1
potency and its selectivity profile was further improved
2
+
(
hERG IC /MCH Ca release IC50 ratio: 1030 for 18).
50
Finally, 19, the corresponding coumarin-bearing analog,
designed as a structural analog of the quinolones, not
only had a very potent MCHr1 activity profile, but also
possessed much decreased hERG channel affinity
2
+
8
. (a) Borowsky, B.; Durkin, M. M.; Ogozalek, K.; Marza-
badi, M. R.; DeLeon, J.; Lagu, B.; Heurich, R.; Lichtblau,
H.; Shaposhnik, Z.; Daniewska, I.; Blackburn, T. P.;
Branchek, T. A.; Gerald, C.; Vaysse, P. J.; Forray, C. Nat.
Med. 2002, 8, 779; (b) 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; (c) Souers,
A. J.; Gao, J.; Brune, M.; Bush, E.; Wodka, D.;
Vasudevan, A.; Judd, A. S.; Mulhern, M. 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.
(
hERG IC /Ca release IC50 ratio: 1110 for 19).
50
The CEREP profiling of this compound revealed a clean
cross-reactivity profile, similar to 1, across a panel of
1
7
GPCR receptors and ion channels. Furthermore, ana-
logs 18 and 19 possessed an improved CYP3A4 profile
as compared to 1 (18, IC50 = 60 lM; 19, IC50 = 62.1 lM
1
8
versus 1, IC50 = 23.5 lM). Finally, analog 19 was eval-
uated in a patch-clamp assay of functional hERG block-
1
9
ade. In this definitive in vitro hERG assay, 19
demonstrated < 20% current block at 30 lM, a robust
improvement over 1 (90% current block at 7 lM).
2
005, 48, 1318; (d) Kym, P. R.; Iyengar, R. R.; Souers, A.
J.; Lynch, J. K.; Judd, A. S.; Gao, J.; Freeman, J. C.;
Mulhern, M. M.; Zhao, G.; Vasudevan, A.; Wodka, D.;
Blackburn, C.; Brown, J.; Che, J. L.; Cullis, C.; Lai, S. J.;
LaMarche, M.; Marsilje, T.; Roses, J.; Sells, T.; Geddes,
B.; Govek, E.; Patane, M.; Fry, D.; Dayton, B. D.;
Brodjian, S.; Falls, D.; Brune, M.; Bush, E.; Shapiro, R.;
Knourek-Segel, V.; Fey, T.; McDowell, C.; Reinhart, G.
A.; Preusser, L. C.; Marsh, K.; Hernandez, L.; Sham, H.
L.; Collins, C. A. J. Med. Chem. 2005, 48, 5888; (e) Kym,
P. R.; Souers, A. J.; Campbell, T. J.; Lynch, J. K.; Judd,
A. S.; Iyengar, R.; Vasudevan, A.; Gao, J.; Freeman, J. C.;
Wodka, D.; Mulhern, M.; Zhao, G.; Wagaw, S.; Napier,
J. J.; Brodjian, S.; Dayton, B. D.; Reilly, R. M.; Segreti, J.;
Fryer, R. M.; Preusser, L. C.; Reinhart, G. A.; Hernandez,
L.; Marsh, K. C.; Sham, H. L.; Collins, C. A.; Polakowski,
J. S. J. Med. Chem. 2006, 49, 2339; (f) McBriar, M. D.;
Guzik, H.; Shapiro, S.; Paruchova, J.; Xu, R.; Palani, A.;
Clader, J. W.; Cox, K.; Greenlee, W. J.; Hawes, B. E.;
Kowalski, T. J.; O’Neill, K.; Spar, B. D.; Weig, B.;
Weston, D. J.; Farley, C.; Cook, J. J. Med. Chem. 2006,
In summary, several bicyclic replacements of the 3,4-
methylenedioxy phenyl moiety in 1 have been evaluated.
Compound 19, in particular, possessed one of the best
overall in vitro profiles in terms of MCHr1 potency,
receptor cross-reactivity, reduction of CYP liability
and lack of hERG channel affinity of the compounds
evaluated in our program. While some of bicyclic
replacements came at the cost of MCHr1 functional
potency and/or increased hERG channel affinity, we dis-
covered a set of piperonyl replacements that were com-
parable to or significantly better than 1 in terms of its
potency and several other parameters.
Acknowledgments
The authors thank Christopher Ogiela and Dennis Fry
for preparing the IMR-32 cells and aiding with the exe-
cution of the binding and functional assays, Paul Rich-
ardson and J.J. Jiang for MCH production, and James
Napier for the scale-up and supply of 2.
4
9, 2294; For excellent reviews on the subject, see (g)
Kowalski, T. J.; McBriar, M. D. Expert Opin. Invest.
Drugs 2004, 13, 1113; (h) Browning, A. Expert Opin. Ther.
Pat. 2004, 14, 313; (i) Collins, C. A.; Kym, P. R. Curr.
Opin. Invest. Drugs 2003, 4, 386.
9
. Lynch, J. K.; Freeman, J. C.; Judd, A. S.; Iyengar, R.;
Mulhern, M.; Zhao, G.; Napier, J. J.; Wodka, D.;
Brodjian, S.; Dayton, B. D.; Falls, D.; Ogiela, C.; Reilly,
R. M.; Campbell, T. J.; Polakowski, J. S.; Hernandez, L.;
Marsh, K. C.; Shapiro, R.; Knourek-Segel, V.; Droz, B.;
Bush, E.; Brune, M.; Preusser, L. C.; Fryer, R. M.;
Reinhart, G. A.; Houseman, K.; Diaz, G.; Mikhail, A.;
Limberis, J. T.; Sham, H. L.; Collins, C. A.; Kym, P. R.
J. Med. Chem. 2006, 49, 6569.
References and notes
1
2
3
. Saito, Y.; Nothacker, H-P.; Civelli, O. Trends Endocrinol.
Metab. 2000, 11, 299.
. Schwartz, M. W.; Woods, S. C.; Porte, D. Jr.; Selley, R. J.;
Baskin, D. G. Nature 2000, 404, 661.
. Gomori, A.; Ishihara, A.; Ito, M.; Mashiko, S.; Matsush-
ita, H.; Yumoto, M.; Ito, M.; Tanaka, T.; Tokita, S.;
Moriya, M.; Iwaasa, H.; Kanatani, A. Am. J. Physiol.
Endocrinol. Metab. 2003, 284, E583.
10. For reviews of hERG blockade and QT prolongation,
see (a) Finalyson, K.; Witchel, H. J.; McCulloch, J.;
Sharkey, J. Eur. J. Pharmacol. 2004, 500, 129; (b)
Fermini, B.; Fossa, A. A. Nat. Rev., Drug Disc. 2003,
2, 439.
4
. Della-Zuana, O.; Presse, F.; Ortola, C.; Duhault, J.;
Nahon, J. L.; Levens, N. Int. J. Obesity 2002, 26,
1
289.
11. For a review of inhibition of cytochrome P450 3A4 by
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Pharmacokin. 2004, 44, 279.
5
. Ludwig, D. S.; Tritos, N. A.; Mastaitis, J. W.; Kulkarni,
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1
2. For a review of relationships of metabolic syndrome,
E.; Shapiro, R.; Droz, B.; Knourek-Segel, V.; Hernandez,
L. E.; Marsh, K. C.; Sham, H. L.; Collins, C. A.; Kym, P.
R. Bioorg. Med. Chem. Lett. 2006, submitted; (d) Judd, A.
S.; Souers, A. J.; Wodka, D.; Zhao, G.; Mulhern, M. M.;
Iyengar, R. R.; Gao, J.; Lynch, J. K.; Freeman, J. C.;
Falls, H. D.; Brodjian, S.; Dayton, B. D.; Reilly, R. M.;
Gintant, G. A.; Limberis, J. T.; Mikhail, A.; Leitza, S. T.;
Houseman, K. A.; Diaz, G.; Bush, E. N.; Shapiro, R.;
Knourek-Segel, V.; Hernandez, L. E.; Marsh, K. C.;
Sham, H. L.; Collins, C. A.; Kym, P. R. Bioorg. Med.
Chem. Lett. 2006, submitted.
obesity, heart disease with related therapies, see: Rana, J.
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Diabetes, Obesity and Metabolism, online early, DOI:
10.1111/j.1463-1326.2006.00594.x.
1
3.
O
O
N
NBS, benzoyl peroxide
CCl4, reflux, 5h, 68%
Br
N
R
N
1
.
m
-CPBA, ethyl acetate, rt,
N
5h then Ac O, 140 ˚C, 4h, 27%
O
2
Br
16. Instances of regioisomerism resulting in improved MCHr1
potency were seen in other compound sets as well. For
example,
2
. For R = H, NBS, CCl , AIBN
4
8
0 ˚C, 6h, (6:1, mono:di), 80%
or
R = H or Me
CHO
For R = Me, first NaH, MeI, rt, 75%
then NBS (4.5:1, mono:di), 70%
2+
Ca
Compound
MCHr1
hERG
IC50 (lM) IC50 (lM) IC50 (lM)
O
O
O
O
SeO2, 80 ˚C, 73%
1
0
.7
>10
47.7
60.7
1
4. The modulation of compound polarity/lipophilicity to
attenuate hERG channel binding is precedented. For a
recent review of hERG optimization in medicinal chem-
istry, see: Jamieson, C., Moir, E. M., Rankovic, Z.,
Wishart, G. J. Med. Chem. 2006, 49, 5029.
.047
0.551
Most of our analogs also showed good correlation
between compound lipophilicity and affinity for hERG
channel binding, as depicted in the table below. Com-
pound 16 was the only gross outlier in this subset.
1
7. Compounds were evaluated for cross-reactivity in 75
GPCR receptors and ion channels panel at 10 lM run
by CEREP (www.cerep.com). A sample subset of the 75
panel assay is shown below.
CEREP panel % inhibition at 10 lM
1
19
Compound
ClogP (Calcd)
hERG IC50 (lM)
Adenosine, A1(h)
Adrenergic, a1
Adrenergic, a2
8
32
18
21
43
26
65
16
55
42
48
66
48
ꢀ6
17
11
1
6
7
8
2.47
3.06
3.53
2.49
1.77
2.57
1.52
1.35
1.23
1.17
1.65
1.77
15.1
5.28
1.37
6.08
34.6
20
13
28
16
7
Adrenergic, b2
Dopamine, D1(h)
DA transporter (h)
Histamine, H1 (central)
Histamine, H2
1
1
1
1
1
1
1
1
0
2
3
4
6
7
8
9
67
36
21
16
15
45
43
25
5
25
85.2
5.79
85.8
47.4
51.1
Muscarinic, M1 (h)
Muscarinic, M2 (h)
NE transporter (h)
Opiate, j (h)
Seratonin, 5HT1A (h)
5HT1B
5HT2A (h)
1
5. For recent publications on modulating hERG channel
binding via aryl group modifications in the context of
MCHr1 antagonists, see: (a) McBriar, M. D.; Guzik, H.;
Shapiro, S.; Xu, R.; Paruchova, J.; Clader, J. W.; O’Neill,
K.; Hawes, B.; Sorota, S.; Margulis, M.; Tucker, K.;
Weston, D. J.; Cox, K. Bioorg. Med. Chem. Lett. 2006, 16,
ꢀ10
37
10
72
17
Sigma (nonselective)
104
31
2
Ca Channel (L, verapamil site)
+
+
Na Channel (site 2)
91
ꢀ20
+
K
Channel (SK + Ca Channel)
4
262; (b) Meyers, K. M.; Kim, N.; M e´ ndez-Andino, J. L.;
Hu, X. E.; Mumin, R. N.; Klopfenstein, S. R.; Wos, J. A.;
Mitchell, M. C.; Paris, J. L.; Ackley, D. C.; Holbert, J. K.;
Mittelstadt, S. W.; Reizes, O. Bioorg. Med. Chem. Lett.
18. CYP3A4 subfamily enzyme’s inhibition was determined as
the concentration of compound needed for competitive
inhibition of [ H]-terfenadine oxidation in human hepatic
3
2006, ASAP, DOI:10.1016/j.bmcl.2006.10.053; (c) Souers,
microsomes.
A. J.; Iyengar, R.; Judd, A. S.; Beno, D. W. A.; Gao, J.;
Zhao, G.; Brune, M. E.; Napier, J. J.; Mulhern, M. M.;
Lynch, J. K.; Freeman, J. C.; Wodka, D.; Chen, C. J.;
Falls, H. D.; Brodjian, S.; Dayton, B. D.; Diaz, G.; Bush,
19. Effects of compound were evaluated based on tail currents
measured during a 3-s depolarizing pulse to 0 mV followed
by a 4-s repolarization test pulses to ꢀ50 mV using
HEK293 cells stably expressing hERG.