Identification of a novel and orally available benzimidazole derivative as an NPY Y5 receptor antagonist with in vivo efficacy

Article abstract of DOI:10.1016/j.bmcl.2012.09.025

Optimization of lead compound 2 is described, mainly focusing on modification at the C-2 position of the benzimidazole core. Replacement of the phenyl linker of 2 with saturated rings resulted in identification of compound 8b which combines high Y5 recept

Full text of DOI:10.1016/j.bmcl.2012.09.025

Bioorganic & Medicinal Chemistry Letters 22 (2012) 6554–6558
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Identification of a novel and orally available benzimidazole derivative
as an NPY Y5 receptor antagonist with in vivo efficacy
Yuusuke Tamura a, , Naoki Omori a, Naoki Kouyama a, Yuji Nishiura a, Kyouhei Hayashi a,
⇑
Kana Watanabe a, Yukari Tanaka b, Takeshi Chiba c, Hideo Yukioka a, Hiroki Sato a, Takayuki Okuno a
a Medicinal Research Laboratories, Shionogi & Co., Ltd. 1-1, Futabacho 3-chome, Toyonaka, Osaka 561-0825, Japan
b Drug Developmental Research Laboratories, Shionogi & Co., Ltd. 1-1, Futabacho 3-chome, Toyonaka, Osaka 561-0825, Japan
c Innovative Drug Discovery Research Laboratories, Shionogi & Co., Ltd. 1-1, Futabacho 3-chome, Toyonaka, Osaka 561-0825, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 20 July 2012
Revised 20 August 2012
Accepted 7 September 2012
Available online 15 September 2012
Optimization of lead compound 2 is described, mainly focusing on modification at the C-2 position of
the benzimidazole core. Replacement of the phenyl linker of 2 with saturated rings resulted in identifi-
cation of compound 8b which combines high Y5 receptor binding affinity with a good ADME profile lead-
ing to in vivo efficacy.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Obesity
NPY Y5 receptor antagonist
Benzimidazole
Morpholine
In vivo efficacy
Obesity is associated with several comorbidities, including
hypertension, type 2 diabetes (DM), osteoarthritis, dyslipidemia,
obstructive sleep apnea, and some cancers. Many of these diseases
can be prevented or ameliorated by a reduction in body weight.
However, diet and exercise strategies alone, although successful
in the short term, are difficult to maintain in the long term for
the majority of patients. Given these limitations in achieving
weight control, medications and alternative treatment options
have been sought.1
done moiety as their linkers and having high binding affinity and
attractive in vitro profiles with respect to CYP450 inhibition, solu-
bility and metabolic stabilities (Fig. 1).16 Despite these attractive
properties, pyridone analogues exhibited only little absorption
after oral administration.17 We thought that replacing the aromatic
linker with corresponding saturated rings, such as pyrrolidine,
piperidine, piperazine, morpholine, tetrahydropyran and lactam,
might lead us to structurally novel series of compounds without
impairing their high binding affinity and attractive in vitro ADME
profiles (Fig. 1). Herein we report our efforts to identify a novel
and orally available Y5 antagonist endowed with in vivo efficacy.
Representative synthetic routes for derivatives 4–8 are shown
in Scheme 1. 2-Bromobenzimidazole 12 and phenylenediamine
14 were prepared according to the preceding report.16 2-Bromo-
benzimidazole 12 was coupled with various secondary amines 13
to afford derivatives 4–8a. To evaluate the Structure–Activity Rela-
tionship (SAR) focused on R1 and R2 groups of 8, phenylenediam-
ines 14 and 16 were treated with CDI, followed by chlorination
in POCl3 to give 2-chlorobenzimidazoles 15 and 17, respectively.
Next, 15 and 17 were coupled with 13 (Y = O) to afford derivatives
8b, 8f and 8i–l. To explore the other R1 groups, 2-chlorobenzimi-
dazole 18 was coupled with 13 (Y = O), then various alkylthio
(R1S) groups were introduced at the C-5 position of the benzimid-
azole core using a coupling reaction,18 followed by oxidation to the
corresponding alkylsulfonyl (R1SO2) groups. As shown in Scheme 2,
the synthesis of 9a commenced from the Prins reaction.19 The
Neuropeptide Y (NPY) is a 36-amino acid peptide2 which is
widely distributed in the central3–5 and peripheral nervous sys-
tems.6–8 The biological effects of NPY are mediated through its
interaction with five G-protein coupled receptors (Y1, Y2, Y4, Y5
and Y6).9 Among them, the Y5 receptor is thought to play a key role
in the central regulation of food intake and energy balance.10–13
Recently, two Y5 antagonists, MK-0577 and Velneperit in Figure 1,
have advanced to clinical trials. While clinical data of MK-0577
showed modest efficacy,14 Velneperit was proved to be an agent
that have a statistically significant effect on weight loss.15 There-
fore, antagonism of the Y5 receptor represents an attractive target
for potential therapeutic application against obesity.
Recently, we reported the optimization of HTS hit 1 and the dis-
covery of novel NPY Y5 receptor antagonists 3a–c bearing the pyri-
⇑
Corresponding author. Tel.: +81 6 6331 6247; fax: +81 6 6332 6385.
E-mail address: yuusuke.tamura@shionogi.co.jp (Y. Tamura).
0960-894X/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2012.09.025

Y. Tamura et al. / Bioorg. Med. Chem. Lett. 22 (2012) 6554–6558
6555
O
CF3
N
O
N
Y5IC50 : 4.6 nM
CYP inhibition : clean
Solubility (pH = 6.8) : 1.6 µg/ml
N
N
H
N
H
N
O O
S
F
O
N
H
Velneperit
MK-0577
O
O O
O O
S
Ph
S
N
N
N
S
O
N
H
N
H
Cl
2
HTS hit 1
O O
S
Ph
O O
R1
Ph
N
R1
S
N
N
O
N
N
H
H
(linker)
3
CYP450 inhibition (µM)
Y5 IC50 (nM)a
19.8
Solubility (µM)b hMs / rMs (%)c
compds
1A2 / 2C19 / 2C9 / 2D6 / 3A4
1
2
6.7 / 0.19
68.6 / 57.1
88.5 / 78.6
94.2 / >99.9
94.7 / 93.6
>20 / 0.4 / 1.5 / 11 / 1.9
8.9
0.50
43.3
9.4
0.43
2.7 / 19 / 9.5 / >20 / 6.0
All > 20
3a (R1=n-Pr)
3b (R1=t-Bu)
1.93
7.50
All > 20
3c (R1=CF3CH2)
0.29
All > 20
7.7
a Concentration of the compound that inhibited 50% of total specific binding of125 I-PYY as a ligand to mouse NPY
Y5 receptors; obtained from the mean value of two or more independent assays.
b Solubility was measured as kinetic solubility using 1% DMSO solution at pH 6.8.
c Metabolic stability in human or rat liver microsomes was measured as the percentage of the compound remaining
after 30 min incubation.
Figure 1. Structures of MK-0577, Velneperit and benzimidazole derivatives.
R2
Y
O O
S
O O
S
R2
Y
a, b
N
N
Br
12
N
HN
N
H
N
H
( )n
( )n
4-8a
13
(HCl)m
Y = CH2, NCbz, NMe or O
n = 0-1, m = 0-2
O O
O O
O O
O O
S
c, d
c, d
S
S
NH2
NH2
F
F
S
F
F
NH2
NH2
N
N
Cl
Cl
17
F
F
N
H
N
H
14
15
16
e
e
R2
O O
S
Br
N
R1
N
e, f, g
Cl
18
N
O
N
H
N
H
8b-l
Scheme 1. Representative synthetic routes for compounds 4–8. Reagents and conditions: (a) K2CO3, CH3CN, 120 °C (microwave); (b) Y = NCbz: Pd/C, H2, MeOH, rt; (c) CDI,
THF, rt; (d) POCl3, 100 °C; (e) 13, K2CO3, CH3CN, 120 °C (microwave); (f) R1SH, Hunig’s base, Pd2(dba)3, xantphos, dioxane, 130 °C (microwave); (g) m-CPBA, CH2Cl2, 0 °C to rt.
resulting alcohol 20 was mesylated and subsequently substituted
with cyanide, followed by hydrolysis of the resulting cyano group
under basic condition to afford 21. Carboxylic acid 21 was treated
with phenylenediamine 22 in the presence of HATU and Et3N to
produce a mixture of regioisomeric amides. The amides were sub-
sequently cyclized in acetic acid to construct the benzimidazole
core, followed by oxidation of the n-propylthio group with m-CPBA
to provide 9a. As for the synthesis of 10a, a similar route to 9a re-
sulted in N-acetyl morpholine 24. Hydrolysis of the acetyl group
and Boc-protection of the resulting amine were conducted to ob-

6556
Y. Tamura et al. / Bioorg. Med. Chem. Lett. 22 (2012) 6554–6558
Ph
O
Ph
O
a
b-d
e-g
OH
HO
HO2C
20
21
19
S
NH2
NH2
O O
Ph
O
S
N
22
N
H
9a
O O
S
P
Ph
Boc
S
g, j, k
e, f
N
N
N
N
N
HO2C
N
H
O
N
H
O
10a
O
23
24 : P = Ac
25 : P = Boc
h, i
O O
S
Ph
S
NH
N
N
g, m, n
e, l, f
NH
N
N
O
HO2C
O
O
N
H
PMB
27
11a
26
Scheme 2. Representative synthetic routes for compounds 9–11. Reagents and conditions: (a) PhCHO, conc.H2SO4, H2O, 0 °C to rt; (b) MsCl, Et3N, THF, 0 °C; (c) NaCN, TBNI,
DMF, 100 °C; (d) 28% NaOMe in MeOH, 100 °C then H2O; (e) 22, HATU, Et3N, DMF, 0 °C to rt; (f) AcOH, 80 °C to 150 °C (microwave); (g) m-CPBA, CH2Cl2, 0 °C to rt; (h) 28%
NaOMe in MeOH, 100 °C; (i) Boc2O, CH2Cl2, rt; (j) TFA, CH2Cl2, rt; (k) PhI, Pd2(dba)2, RuPhos, t-BuOK, dioxane, 100 °C; (l) p-Methoxybenzaldehyde, NaBH(OAc)3, AcOH, rt; (m)
PhI, CuI, N,N-dimethylglycine, K2CO3, DMA, 170 °C (microwave); (n) TFA, 110 °C (microwave).
Table 1
IC50 values, CYP450 inhibition profiles, solubilities and metabolic stabilities of compounds 2 and 4–11a
O O
S
Ph
N
N
H
(linker)
compds
linker
Y5 IC50a (nM)
0.43
CYP450 inhibition (
2.7/19/9.5/>20/6.0
>20/>20/17/>20/14
>20/12/9.4/13/6.9
l
M) 1A2/2C19/2C9/2D6/3A4
Solubilityb
0.50
(l
M)
hMs/rMsc (%)
68.6/57.1
74.9/19.2
45.2/2.2
2
4a
5a
1.01
15.4
N
N
N
N
N
0.29
19.1
6a
7a
8a
9ad
6.82
4.99
0.6
All >20
All >20
>50
>50
>50
>50
64.4/44.0
21.9/21.1
77.9/45.9
65.0/74.0
NH
NMe
O
>20/19/>20/>20/>20
>20/20/>20/>20/>20
17.2
O
N
10a
11a
15.9
193
All >20
All >20
>50
>50
66.1/7.5
O
N
81.1/62.0
O
a
Concentration of the compound that inhibited 50% of total specific binding of 125I-PYY as a ligand to mouse NPY Y5 receptors; obtained from the mean value of two or
more independent assays.
b
Solubility was measured as kinetic solubility using 1% DMSO solution at pH 6.8.
Metabolic stability in human or rat liver microsomes was measured as the percentage of the compound remaining after 30 min incubation.
Cis/trans mixture.
c
d

Y. Tamura et al. / Bioorg. Med. Chem. Lett. 22 (2012) 6554–6558
6557
Table 2
IC50 values, CYP450 inhibition profiles, solubility and metabolic stabilities of compounds 8a–l
R2
O
O O
R1
S
N
N
N
H
compds
R1
R2
Y5 IC50a (nM)
CYP450 inhibition (lM) 1A2/2C19/2C9/2D6/3A4
Solubilityb
(lM)
hMs/rMsc (%)
8a
8b
8c
8d
8e
8f
8g
8h
8i
n-Pr
Et
i-Pr
t-Bu
i-Bu
CF3
CH2CF3
C(CH3)2CF3
Et
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
0.60
0.43
1.33
4.27
0.28
0.73
0.21
1.43
1.05
0.85
0.80
3.03
>20/19/>20/>20/>20
All >20
>50
>50
>50
10.7
43.2
3.7
>50
11.6
>50
38.1
21.6
>50
77.9/45.9
89.0/76.1
87.0/49.5
78.5/56.4
55.1/2.4
81.7/67.9
85.0/63.5
60.2/37.8
92.4/87.1
94.6/87.2
87.8/34.0
81.0/48.0
15/19/>20/>20/16
>20/>20/>20/>20/14
>20/>20/17/>20/9.3
17/1.7/4.5/5.5/2.3
>20/>20/>20/>20/15
18/17/11/18/8.2
All >20
9.2/9.1/>20/18/13
>20/17/>20/>20/>20
All >20
4-F-Ph
4-Cl-Ph
4-Me-Ph
4-OMe-Ph
8j
8k
8l
Et
Et
Et
a, b,
c
See Table 1.
tain 25. Oxidation of the n-propylthio group of 25 with m-CPBA,
followed by acidic deprotection of the Boc-group and introduction
of an outer phenyl group using the Buchwald–Hartwig reaction
provided 10a. The synthesis of 11a commenced from condensation
of 26 with 22, followed by protection with a p-methoxybenzyl
(PMB) group, and cyclization to produce a mixture of 1- and 3-
PMB protected benzimidazoles 27. Oxidation of the n-propylthio
group with m-CPBA, followed by introduction of an outer phenyl
group using the Ullmann reaction20 and then removal of the PMB
group provided 11a.
In the course of our program, the hit to lead SAR study gener-
ated biphenyl derivative 2 as a lead compound which showed
attractive Y5 receptor binding affinity, but possessed CYP450 inhi-
bition profiles and low solubility. While our previous efforts to im-
prove the issues related to 2 led us to identify the attractive
pyridone analogues 3, the oral absorption of 3 was insufficient.
Although the reason was unclear, we tried to find a second-gener-
ation derivative with in vitro profiles comparable to 3 but having
improved oral absorption. Our strategy was to replace the aromatic
linker of 2 with several saturated rings to reduce structural planar-
ity and change the ADME profiles (Fig. 1).21–23
As shown in Table 1, almost all of saturated derivatives showed
moderate to appreciable improvement in the CYP450 inhibition
profiles and the solubility. Piperidine 5a exhibited sub-nanomolar
binding affinity, which was equipotent to 2. Pyrrolidine 4a was
threefold less potent than 5a. These results suggest that the
right-hand part, which is similar in shape to the biphenyl moiety
of 2, is important for the binding affinity. While 5a afforded the
best potency, its metabolic stabilities in human and rat liver micro-
somes were unacceptable. The metabolic instablility of 5a may
arise from the aliphatic carbon around the benzylic position. This
hypothesis prompted us to incorporate heteroatoms into the piper-
idine moiety, which provided piperazine 6–7a and morpholine 8a.
Among them, derivatives 6a and 8a showed improvement in met-
abolic stabilities. While piperazine 6a exhibited a 20-fold decrease
in the binding affinity, morpholine 8a was equipotent to piperidine
5a. On the other hand, replacement of the central phenyl linker of 2
by tetrahydropyran, regioisomeric morpholine or a lactam moiety
resulted in a decrease of the Y5 receptor binding affinity (9–11a).
These results combined with the SAR study of pyridone analogues
3 suggest that the sp3 hybridized carbon atoms, which directly
bonded with the C-2 position of benzimidazole core, have a nega-
tive influence on the binding affinity.
To further explore the potential of morpholine 8a, we investi-
gated some other compounds (Table 2). Initial investigations were
focused on the left-hand part of 8a, namely alkyl substitutions on
the sulfonyl group (R1SO2). The replacement of n-PrSO2 with EtSO2
led to equipotent compound 8b with further improved metabolic
stabilities. The binding affinity decreased as the bulkiness of the
a-position of the alkylsulfonyl group become larger (8b–d). In con-
trast, the bulkiness of the b-position of the alkylsulfonyl group
showed a positive effect on the binding affinity (8e and 8g). While
8g showed high Y5 binding affinity with appreciable CYP450 pro-
files and high solubility, the CF3CH2SO2 moiety was found to be
easily hydrolyzed under basic condition due to the strong acidity
of the
a
-proton (Fig. 2).24 An attempt to improve the physicochem-
-position of CF3CH2SO2 group
ical stability of 8g by hindering the
a
worsened the CYP450 inhibition profiles and the solubility (8h).
The influence of various substituents on the right-hand phenyl ring
of 8b was also investigated (Table 2). While all substituents, such
as fluoro, chloro, methyl and methoxy, on the outer phenyl ring
led to retaining of Y5 binding affinities, 8j showed CYP450 inhibi-
tion potential and 8k–l were metabolically unstable in rat liver
microsomes.
On the basis of these results, morpholine 8b was selected for
further investigation. An in vivo cassette study in rats for 8b
(0.5 mg/kg iv, 1.0 mg/kg po) was conducted to examine the oral
absorption25 and showed acceptable plasma exposure with moder-
ate blood clearance (Cmax = 64.2 ng/ml, CLtot = 9.9 ml/min/kg), indi-
cating some effect of the saturated linker on the PK profiles. To
H2O
F
O
F
O O
S
O O
O O
S
F
F
S
F
HO
H
Figure 2. Mechanism for decomposition of 8g.

6558
Y. Tamura et al. / Bioorg. Med. Chem. Lett. 22 (2012) 6554–6558
Figure 3. (i) Effect of 8b (12.5 mg/kg) on Y5 agonist-stimulated food intake in diet-induced obese mice. (ii) Effect of (R)-8b (12.5 mg/kg) on Y5 agonist-stimulated food intake
in diet-induced obese mice. ⁄⁄p >0.01 versus Y5 agonist and vehicle treated group. n = 2.
Ph
O
O O
S
Ph
O
5. Wahlestedt, C.; Reis, D. Annu. Rev. Pharmacol. Toxicol. 1993, 32, 309.
6. Grundemar, L.; Hakanson, R. Gen. Pharmacol. 1993, 24, 785.
7. Lungberg, J.; Franco-Cerecada, A.; Lacroix, J. S.; Pernow, J. Ann. N. Y. Acad. Sci.
1990, 611, 166.
8. McDermott, B. J.; Millat, B. C.; Peper, H. M. Cardiovasc. Res. 1993, 27, 893.
9. Blomqvist, A. G.; Herzog, H. Trends Neurosci. 1997, 20, 294.
10. Kamiji, M. M.; Inui, A. Endocr. Rev. 2007, 28, 664.
N
N
N
N
H
(R)-8b : 0.31 nM
(S)-8b : 4.76 nM
11. Ladyman, S. R.; Woodside, B. Physiol. Behav. 2009, 97, 91.
12. Levens, N. R.; Galizzi, J.-P.; Félétou, M. Drug Targets CNS Neurol. Disord. 2006, 5,
263.
Figure 4. Effect of chirality.
13. Marsh, D. J.; Hollopeter, G.; Kafer, K. E.; Palmiter, R. D. Nat. Med. 1998, 4,
718.
evaluate in vivo efficacy, compound 8b (12.5 mg/kg) was orally
administered 1 h before the mice were treated with Y5 selective
agonist26 (0.1 nmol icv) and cumulative food intake was measured
for the following 4 h. As shown in Figure 3, compound 8b blocked
the increase in food intake in this feeding model. This result
prompted us to verify the effect of the stereochemistry at the C-2
position of morpholine for in vivo efficacy. Thus, (R)-8b and (S)-
8b were prepared separately27 and their Y5 receptor binding affin-
ities were investigated. Figure 4 reveals a strong preference for (R)-
8b, which was 10-fold more potent than the corresponding (S)-iso-
mer. Although not directly compared, the in vivo efficacy of (R)-8b
was also tested and resulted in enhanced efficacy, correlating with
its high binding affinity (Fig. 3 and 4).
In summary, replacement of the phenyl linker of lead com-
pound 2 with corresponding saturated linkers resulted in several
potent derivatives. Among them, morpholine 8b showed in vivo
efficacy in the agonist-induced food intake model. Extensive SAR
exploration revealed a preference for the (R)-isomer. At present,
further investigation of this compound is underway.
14. (a) Nonaka, K.; Erondu, N.; Kanatani, A. Biol. Clin. 2006, 21, 1199; (b) Erondu, N.;
Gantz, I.; Musser, B.; Suryawanshi, S.; Mallick, M.; Addy, C.; Cote, J.; Bray, G.;
Fujioka, K.; Bays, H.; Hollander, P.; Sanabria-Bohórquez, S. M.; Eng, W.-S.;
Långström, B.; Hargreaves, R. J.; Burns, H. D.; Kanatani, A.; Fukami, T.; MacNeil,
D. J.; Gottesdiener, K. M.; Amatruda, J. M.; Kaufman, K. D.; Heymsfield, S. B. Cell
Metab. 2006, 4, 275; (c) Erondu, N.; Addy, C.; Lu, K.; Mallick, M.; Musser, B.;
Gantz, I.; Proietto, J.; Asreup, A.; Toubro, S.; Rissannen, A. M.; Tonstad, S.;
Haynes, W. G.; Gottesdiener, K. M.; Kaufman, K. D.; Amatruda, J. M.;
Heysmfield, S. B. Obesity 2007, 15, 2027.
15. (a) Puopolo, A.; Heshka, S.; Karmally, W.; Alvarado, R.; Kakudo, S.; Ochiai, T.;
Archambault, W. T.; Kobayashi, Y.; Albata, B. Obesity Soc. Ann. Sci. Meeting 2009,
214-P; (b) Smith, D.; Heshka, S.; Karmally, W.; Doepner, D.; Narukawa, Y.;
Ochiai, T.; Archambault, W. T.; Kobayashi, Y.; Albata, B. Obesity Soc. Ann. Sci.
Meeting 2009, 221-P; (c) Okuno, T.; Takenaka, H.; Aoyama, Y.; Kanda, Y.;
Yoshida, Y.; Okada, T.; Hashizume, H.; Sakagami, M.; Nakatani, T.; Hattori, K.;
Ichihashi, T.; Yoshikawa, T.; Yukioka, H.; Hanasaki, K.; Kawanishi, Y. Abstr. Pap.
Am. Chem. Soc. 2010, 240, 284.
16. (a) Tamura, Y.; Omori, N.; Kouyama, N.; Nishiura, Y.; Hayashi, K.; Watanabe, K.;
Tanaka, Y.; Chiba, T.; Yukioka, H.; Sato, H.; Okuno, T. Bioorg. Med. Chem. Lett.
2012, 22, 5498; Potent Y5 receptor antagonists bearing benzimidazole core
was also reported: (b) Ogino, Y.; Ohtake, N.; Nagae, Y.; Matsuda, K.; Moriya, M.;
Suga, T.; Ishikawa, M.; Kanesaka, M.; Mitobe, Y.; Ito, J.; Kanno, T. Bioorg. Med.
Chem. Lett. 2008, 18, 5010.
17. To further characterize the pyridone analogues 3a–c, in vivo cassette studies
(0.5 mg/kg iv, 1.0 mg/kg po) were conducted. Unfortunately, these compounds
exhibited low plasma levels with high clearance in spite of their acceptable
solubility and high metabolic stability in rat liver microsomes. The poor
correlation between the metabolic stability in liver microsomes and the in vivo
clearance suggest that extrahepatic clearance routes may have been operating.
18. Itoh, T.; Mase, T. Org. Lett. 2004, 6, 4587.
Acknowledgments
We thank our colleagues Yasunori Yokota, Yumiko Saito, Kyoko
Kadono, Tohru Mizutare, Hirohide Nambu, Hideki Tanioka, Naomi
Umesako, and Izumi Fujisaka for support in the characterization
of the compounds described.
19. Yadav, J. S.; Subba Reddy, B. V.; Narayana Kumar, G. G. K. S.; Aravind, S.
Synthesis 2008, 3, 395.
20. Zhang, H.; Cai, Q.; Ma, D. J. Org. Chem. 2005, 70, 5164.
21. Lovering, F.; Bikker, J.; Humblet, C. J. Med. Chem. 2009, 52, 6752.
22. Ishikawa, M.; Hashimoto, Y. J. Med. Chem. 2011, 54, 1539.
23. Gleeson, M. P. J. Med. Chem. 2008, 51, 817.
References and notes
1. Powell, A. G.; Apovian, C. M.; Aronne, L. J. Clin. Pharmacol. Ther. 2011, 90, 40.
2. Tatemoto, K.; Carlquist, M.; Mutt, V. Nature 1982, 296, 659.
24. King, J. F.; Gill, M. S. J. Org. Chem. 1996, 61, 7250.
25. The rats (n = 2) were dosed at 0.5 mg/kg iv and 1.0 mg/kg po.
26. [cPP1–7, NPY19–23, Ala31, Aib32, Gln34]-human pancreatic polypeptide.
27. Zindell, R.; Riether, D.; Bosanac, T.; Berry, A.; Gemkow, M. J.; Ebneth, A.; Löbbe,
S.; Raymond, E. L.; Thome, D.; Shih, D. T.; Thomson, D. Bioorg. Med. Chem. Lett.
2009, 19, 1604.
3. Adrian, T. E.; Allen, J. M.; Bloom, S. R.; Ghatei, M. A.; Rossor, M. N.; Roberts, G.
W.; Crow, T. J.; Tatemoto, K.; Polak, J. M. Nature 1983, 306, 585.
4. O’Donohue, T. L.; Chronwall, B. M.; Pruss, R. M.; Mezey, E.; Kiss, J. Z.; Eiden, L. E.;
Massari, V. J.; Tessel, R. E.; Pickel, V. M.; Dimaggio, D. A.; Hotchkiss, A. J.;
Crowley, W. R.; ZukowskaGrojec, Z. Peptides 1985, 6, 755.