Discovery of 2-substituted benzoxazole carboxamides as 5-HT3 receptor antagonists

Article abstract of DOI:10.1016/j.bmcl.2010.09.038

A new class of 2-substituted benzoxazole carboxamides are presented as potent functional 5-HT₃ receptor antagonists. The chemical series possesses nanomolar in vitro activity against human 5-HT₃A receptors. A chemistry optimization program was conducted and identified 2-aminobenzoxazoles as orally active 5-HT₃ receptor antagonists with good metabolic stability. These novel analogues possess drug-like characteristics and have potential utility for the treatment of diseases attributable to improper 5-HT₃ receptor function, especially diarrhea predominant irritable bowel syndrome (IBS-D).

Full text of DOI:10.1016/j.bmcl.2010.09.038

Bioorganic & Medicinal Chemistry Letters 20 (2010) 6538–6541
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Discovery of 2-substituted benzoxazole carboxamides as 5-HT3
receptor antagonists
Zhicai Yang a, David J. Fairfax a, Jun-Ho Maeng a, Liaqat Masih a, Alexander Usyatinsky a, Carla Hassler a,
Soshanna Isaacson a, Kevin Fitzpatrick a, Russell J. DeOrazio a, Jianqing Chen a, James P. Harding a,
Matthew Isherwood a, Svetlana Dobritsa a, Kevin L. Christensen a, Jonathan D. Wierschke a, Brian I. Bliss a,
Lisa H. Peterson a,b, Cathy M. Beer a, Christopher Cioffi a, Michael Lynch a, W. Martin Rennells a,
Justin J. Richards a, Timothy Rust a, Yuri L. Khmelnitsky a, Marlene L. Cohen b, David D. Manning a,
⇑
a Discovery R&D AMRI, 26 Corporate Circle, PO Box 15098, Albany, NY 12212-5098, USA
b Creative Pharmacology Solutions LLC, 10532 Coppergate, Carmel, IN 46032, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A new class of 2-substituted benzoxazole carboxamides are presented as potent functional 5-HT3 recep-
tor antagonists. The chemical series possesses nanomolar in vitro activity against human 5-HT3A recep-
tors. A chemistry optimization program was conducted and identified 2-aminobenzoxazoles as orally
active 5-HT3 receptor antagonists with good metabolic stability. These novel analogues possess drug-like
characteristics and have potential utility for the treatment of diseases attributable to improper 5-HT3
receptor function, especially diarrhea predominant irritable bowel syndrome (IBS-D).
Ó 2010 Elsevier Ltd. All rights reserved.
Received 23 August 2010
Revised 7 September 2010
Accepted 8 September 2010
Available online 16 September 2010
Keywords:
5-HT3 receptor antagonist
Irritable bowel syndrome
IBS
Diarrhea
Alosetron
Ramosetron
Benzoxazole
Diarrhea predominant irritable bowel syndrome (IBS-D) is a
painful, debilitating disorder of the bowel that diminishes the
quality of life for millions of men and women each day. The typical
sufferer of IBS-D exhibits symptoms which include multiple daily
diarrhea attacks and severe abdominal cramps. Secondary effects
may include urgency, panic attacks, depression, withdrawal from
social and family activities and malnutrition. It is estimated that
IBS management in the US costs eight billion dollars in direct med-
ical costs alone.1 Effective pharmacological treatment of this disor-
der has been elusive.
One agent that has demonstrated relief for this population is
LotronexÒ (alosetron hydrochoride), a serotonin type 3 (5-HT3)
receptor antagonist.2 This first-in-class drug was voluntarily with-
drawn from the market shortly following its launch due to the
appearance of rare incidents of ischemic colitis, a life-threatening
ailment of the gastrointestinal tract.3
effectiveness for many patients and to the unmet need in IBS
therapy. Alosetron remains unavailable to the majority of IBS
patients.
The underlying cause of ischemic colitis in IBS patients is under
much debate. A target-based explanation is not persuasive since a
number of commercial 5-HT3 blockers have safely and effectively
been used to treat chemotherapy-induced nausea and vomiting
(CINV) for years with no reports of ischemic colitis.5 To this point,
a re-purposed CINV agent, ramosetron hydrochloride, was ap-
proved in 2008 for the treatment of IBS-D in Japan.6 No reports
of ischemic colitis have appeared for this 5-HT3 receptor antagonist
suggesting that new 5-HT3 receptor modulators may overcome the
problems observed for alosetron.
One postulate for alosetron’s failings may be linked to the com-
pound’s complex metabolic profile. Alosetron package labeling
indicates the compound is heavily metabolized by the liver.7 In-
deed, alosetron is contraindicated for patients with severe hepatic
impairment. Studies conducted with radiolabelled alosetron iden-
tified 28 discrete metabolites.8 At least 13 alosetron metabolites
have been identified in humans, several of which are active at
the 5-HT3 receptor.9 The pharmacodynamic and toxicological ef-
fects of alosetron’s metabolites are not fully understood.
Strong patient advocacy helped return alosetron to the market-
place, albeit with severe use restrictions.4 Such a reinstatement
was a first in FDA’s history and is a testimony to the drug’s
⇑
Corresponding author. Tel.: +1 518 512 2129; fax: +1 518 512 2081.
E-mail address: David.Manning@amriglobal.com (D.D. Manning).
0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2010.09.038

Z. Yang et al. / Bioorg. Med. Chem. Lett. 20 (2010) 6538–6541
6539
CO2Me
CO2Me
CO2Me
N
MeN
N
H
NH2
a
b
N
N
S
Cl
O
N
O
N
O
O
O
N
R1
OH
H
O
H
O
8
9
7 R = H
H
7a R = Cl
Cl
N
H
O
H
Cl
O
N
CO2H
R1
N
Zatosetron
Azasetron
Palonosetron
R2
R3
N
O
R2
c, d
e
N
N
R3
Bicyclic Amine
O
11
HN
O
N
10
H
X
O
N
N
Scheme 2. General synthesis of 2-aminobenzoxazole carboxamides. Reagents and
conditions: (a) EtOCS2K, pyridine, reflux; (b) POCl3, PCl5, 95 °C; (c) R2NHR3, THF; (d)
2 N NaOH, THF, rt; (e) R1NH2, EDCꢀHCl, HOBt, Et3N, DMF, rt. For R2 = R3 = H: (f)
di(1H-imidazoyl-1-yl)methanimine, THF; (g) Boc2O, CH2Cl2; (h) R1NH2, EDCꢀHCl,
HOBt, Et3N, DMF; (i) TFA, CH2Cl2.
R
Y
Type I: X = N; Y = O
Type II: X = O; Y = N
N
Alosetron
2-Substituted Benzoxazoles
Figure 1. Type I and type II 2-substituted benzoxazoles.
2-Amino-3-hydroxybenzoic acid 7 was treated with potassium
O-ethylxanthate to provide thione 8. The thione was then con-
verted to 2-chlorobenzoxazole 9 by reaction with phosphorus
pentachloride in phosphorus oxychloride. Displacement of the
chloride 9 with different amines followed by hydrolysis of the
methyl ester yielded 2-aminobenzoxazoles 10. EDC coupling of
the acid 10 with the requisite G or Q amine in the presence of
HOBT in DMF provided 2-aminobenzoxazole carboxamides 11.
For 2-NH2 substituted benzoxazoles (R2 = R3 = H), methyl 2-ami-
no-3-hydroxybenzoate or methyl-2-amino-5-chloro-3-hydroxy-
benzoate were treated with di(1H-imidazol-1-yl)methanimine14
followed by ester saponification and amidation.
Initially, type I and type II 2-aryl benzoxazole 5-HT3 receptor
SAR was examined to determine whether a preference existed for
either of the heterocyclic isomers (Table 1). The 5-HT3 receptor
binding data show a trend favoring the type I isomer. The type I
benzoxazole was therefore selected for initial lead optimization.
A subset of 2-aryl, 2-alkyl and 2-amino type I benzoxazoles were
compared head-to-head for drug-like potential in a number of
assessments to establish a preferred 2-substituent class. Key
assessments included 5-HT3 receptor affinity and selectivity, car-
diovascular risk (hERG), cytochrome P450 inhibition, microsomal
stability, mutagenicity potential (mini Ames), pharmacokinetic
profile and confirmation of in vivo efficacy.
New structural types of 5-HT3 receptor modulators with im-
proved metabolic profiles are needed. Herein, we report early find-
ings in support of our goal to identify improved 5-HT3 receptor
modulators for IBS.
The benzoxazole scaffold depicted in Figure 1 was conceived
through the hypothesis that a potential hydrogen bonding interac-
tion between the carboxamide NH and the ring heteroatom of the
core heterocycle may be important for a preferred binding config-
uration.10 This feature may be operating for certain potent 5-HT3
receptor antagonists (e.g., zatosetron11 and azasetron12) and mim-
ics the constrained geometry of the second generation anti-emetic
palonosetron.10b The carboxamide benzoxazole scaffold had not
been previously explored as a 5-HT3 receptor ligand and therefore
the benzoxazole platform was of interest to us as a starting point.13
Additionally, the compound class is structurally distinct from
alosetron, an element in line with our program objective.
The type I and type II isomers (Fig. 1) of the benzoxazole hetero-
cycle were briefly investigated as well as three classes of 2-position
substituents (R = alkyl, aryl or amino). 2-Substituted aryl and alkyl
benzoxazoles were obtained in good yield by treatment of 1 or 4
with either an aryl or alkyl chloride in pyridine/CH2Cl2 followed
by ring closure with p-toluene sulfonic acid in refluxing toluene
(Scheme 1). The amide was prepared by condensation of an appro-
priate amine, either endo-9-methyl-9-azabicyclo[3.3.1]nonan-3-
amine (G) or (S)-quinuclidin-3-amine (Q), with the carboxylic acid
using a carbodiimide mediated coupling.
Table 2 summarizes select profiling data for G- and Q-derived
compound pairs (20–25). Collectively, the three chemical series
have overall good properties as starting points compared to the
reference commercial 5-HT3 receptor antagonists. In addition, oral
A general synthesis of 2-amino substituted benzoxazoles is
described in Scheme 2.
Table 1
Type I versus type II 2-aryl benzoxazoles
R2
G
G
NH
NH
O
O
O
NH
CO2H
CO2H
NH2
O
N
N
O
N
a,b
c
R1
R1
Ar
Ar
N
O
OH
O
I
II
1
2
3
Comp.
Type
Ar
Ph
Kia (nM)
R2
O
NH
12
13
14
15
16
17
18
19
I
I
I
I
II
II
II
II
15.1 4.9
16.3 1.5
18.0 12.7
18.8 7.3
40.4 9.4
94.9 48.4
73.8 30.8
58.5 6.5
CO2H
CO2H
40-F-Ph
OH
40-Cl-Ph
O
N
O
a,b
c
R1
R1
40-OMe-Ph
Ph
NH2
N
40-F-Ph
40-Cl-Ph
40-OMe-Ph
4
5
6
Scheme 1. General synthesis of 2-aryl and 2-alkyl 2-aminobenzoxazole carbox-
amides. Reagents and conditions: (a) ArCOCl or alkylCOCl, pyridine, CH2Cl2, rt; (b)
p-TsOH, toluene, reflux; (c) R2NH2, EDCꢀHCl, HOBt, Et3N, CH2Cl2, rt.
h5-HT3A (n P 3).18
a

6540
Z. Yang et al. / Bioorg. Med. Chem. Lett. 20 (2010) 6538–6541
Table 2
Table 4
Profile data for representative 2-substituted benzoxazoles
Acyclic 2-amino benzoxazoles
d
Bicyclic aminea, 2-R group Kib
3A4c CLint
hERGe %Ff
Compd
Amine
R
Kia
20 G, morph.
40.0 5.5
165 25
47.3 14.8 >50
14.9 6.4 1.1
32.7 18.8 >100
8.3 4.0
3.4 1.7
0.5 0.1
>50
>100
1.0
0.6
10.1
2.8
4.5
23.5
5.8
1.4
3.2
0.2
0.4
0.7
0.2
0.4
2.3
35
42
43
44
45
46
47
48
Q
Q
Q
Q
Q
Q
Q
NEt2
i-PrNMe
NMe2
NHEt
NHMe
NH2
12.4 7.3
66.5 32.8
18.2 4.5
36.4 20.3
36.4 19.2
13.8 4.2
4.7 1.7
21 Q, morph.
22 Q, 20-OMePh
23 G, 20-OMePh
24 Q, c-C3H5
25 G, c-C3H5
Ondansetron
100
100
44
13
32
>50
11
0.6
21
100
6-Cl, NH2
Alosetron
3.0
a
h5-HT3A (n P 3).
a
Type
I 2-benzoxazole (see Fig. 1), Q = (S)-quinuclindinyl, G = endo-granisyl,
morph = morpholine.
b
h5-HT3A (nM), n P 3.
c
Human CYP 3A4 inhibition IC50 (l
M).19
Table 5
Profile of compounds 41, 47 and 48
d
Compounds were incubated with human liver microsomes; data reported in
l
L/min/mg.20
Compd
Kia
CYPb
CLint
hERGd
Bezold–Jarische
c
e
5-point IC50 (lM) reported from HEK cells stably expressing the hERG potas-
sium channel by the patch clamp technique on a Molecular Devices Patch Express
41
47
48
2.4 0.6
1.4, 2C19
>100
>30
9.3, 3A4
0.6, 3A4
<2
<2
3
5
3
6.4
>30
4.8
0.4
2.3
0.85
1.08
0.40
0.54
0.02
7000 (MDS).21
13.8 4.2
4.7 1.7
3.4 1.7
0.5 0.1
f
Data from rats (n = 3 per group) dosed either 10 mg/kg po or 1 mg/kg iv.
Ondansetron
Alosetron
a
activity was confirmed for all compounds at 30 mg/kg po as dem-
onstrated by inhibition of the 5-HT induced bradycardia reflex in
mice, the so-called Bezold–Jarisch model.15 2-Aminobenzoxazoles
20 and 21 exhibited the best starting profile for a hit to lead opti-
mization campaign. For example, compound 20 has excellent
in vitro metabolic stability and CYP inhibition properties. The ini-
tial low intrinsic clearance (CLint) in human liver microsomes
h5-HT3A (nM, n P 3).
Human CYP inhibition IC50
b
(l
M). CYP isoforms tested: 1A2, 2B6, 2C9, 2C19, 2D6,
3A4, CYP isoforms showing IC50 <10
lM are specified.
c
Compounds were incubated with human liver microsomes; data reported in
l
L/min/mg.
d
5-point IC50 (lM) reported from HEK cells stably expressing the hERG potas-
sium channel by the patch clamp technique on a Molecular Devices Patch Express
7000.
e
Compounds were dosed po to mice one hour prior to 0.1 mg/kg 5-HT challenge.
was attractive. No significant inhibition (>50% inhibition at 1 lM)
ED50 determined by 4-point dose–response, n = 5 mice per dose.
for off-target receptors16 was observed in a 68-membered panel.
The compound was neither mutagenic nor cytotoxic in a mini
Ames screen (TA98 and TA100 S9) up to 100 l
M.17 Increasing
the binding affinity for the 5-HT3 receptor was an area for initial
improvement.
The initial SAR study in the 2-amino series focused on preparing
alkyl substituted morpholines as shown in Table 3. 5-HT3 receptor
binding is sensitive to the position and stereochemistry of alkyl
substituents on the cyclic amine. An (S)-substituent is preferred
Table 3
In vitro 5-HT3 receptor binding data: cyclic amine SAR
R1
CH3
N
O
R2
N
R4
X
H
N
N
Q =
G =
Figure 2. Duration of action in mice. Compounds were compared at ED80 po doses
(1.9 mg/kg 41, 1.3 mg/kg 47, 0.56 mg/kg 48, 0.05 mg/kg alosetron) for the ability to
inhibit 5-HT induced bradycardia in mice.
N
O
R3
R2
R5
Compd
R1
R3
R4
R5
X
Kia (nM)
20
21
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
G
(S)-Q
G
G
G
G
G
G
G
G
(S)-Q
G
G
G
G
G
G
G
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
O
O
O
O
O
O
O
O
O
O
O
O
40.0 5.5
165 25
12.9 3.7
92.6 13.7
4.6 1.6
3.9 0.8
5.0 1.1
3.5 0.9
2.0 0.3
0.6 0.3
6.8 6.4
1.0 0.2
35.3 18.1
72.2 4.0
16.5 8.7
37.3 21.0
59.4 24.1
2.4 0.6
over an (R)-substituent at the R3 position (compare 26 and 27). Lar-
ger alkyl groups at R3 improve the binding affinity (28–32). An
additional (S)-substituent at R2 further increased affinity for the
5-HT3 receptor (33–35), but there was no obvious advantage for
substituents at R4 and R5 (36). Application of the morpholine SAR
trends to piperazine analogues gave similar results. For example,
(2S,6S)-dimethyl substitution on the piperazine ring (41) increased
potency for the 5-HT3 receptor 30-fold compared to the unsubsti-
tuted parent piperazine, 37. The cis-2,6-disubstituted piperazine
39 was not more potent than the singly substituted compound
38. The (2R,6R)-dimethyl piperazine 40 was also a much weaker
binder than 41, highlighting the stereochemical preference.
Considering the success in optimizing cyclic amines, simple
acyclic amines were prepared and tested for 5-HT3 receptor activ-
ity (Table 4).18 Compared to the cyclic starting point morpholine
20, alicyclic side chains gave 5-HT3 receptor binding potencies
(S)-Me
(R)-Me
(S)-Et
(S)-n-Pr
(S)-i-Pr
(S)-i-Bu
(S)-t-Bu
(S)-Me
(S)-Me
(S)-Et
H
(S)-Me
(S)-Me
(S)-Me
H
H
H
cis-Me
(R)-Me
(S)-Me
(R)-Me
(S)-Me
O
H
H
H
H
H
H
H
H
H
H
H
NH
NH
NH
NH
NH
(S)-Me
Me
(R)-Me
(S)-Me
a
h5-HT3A (n P 3).

Z. Yang et al. / Bioorg. Med. Chem. Lett. 20 (2010) 6538–6541
6541
similar in magnitude to that of singly methyl-substituted morpho-
References and notes
line 26 or piperazine 38. For compound 44, it was observed that,
following incubation with mammalian microsomes for 4 h, prod-
ucts resulting from N-demethylation, including di-N-demethyla-
tion for some species, were detected by LC/MS. In total, eight
metabolites were detected in vitro for this compound. Since one
goal of the project was to deliver an end product with a simple
metabolite profile, the 2-amino analogs, 47 and 48, were prepared
to eliminate the dealkylation pathway.22 A subsequent metabolism
study using human liver microsomes confirmed that only 2 and 3
metabolites were now detected by LC/MS for 47 and 48, respec-
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7. Current label information can be found at Drugs@FDA.
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11. Robertson, D. W.; Lacefield, W. B.; Bloomquist, W.; Pfeifer, W.; Simon, R. L.;
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12. Fukuda, T.; Setoguchi, M.; Inaba, K.; Shoji, H.; Tahara, T. Eur. J. Pharmacol. 1991,
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13. 2-Piperazine substituted benzoxazoles have been reported as 5-HT3 receptor
partial agonists. . J. Med. Chem. 2005, 48, 7075.
14. Wu, Y.-Q.; Limburg, D. C.; Wilkinson, D. E.; Hamilton, G. S. J. Heterocycl. Chem.
2003, 40, 191.
15. (a) Saxena, P. R.; Lawang, A. Arch. Int. Pharmacodyn. 1985, 277, 235; (b) Yamano,
M.; Ito, H.; Kamato, T.; Miyata, K. Arch. Int. Pharmacodyn. Ther. 1995, 330, 177.
16. MDS LeadProfilingScreenÒ, unpublished data. No binding with human nicotinic
receptors was observed.
17. Cerep catalog numbers 900-21, 900-21c, 900-21b, 900-21bs, 900-21a, and
900-21as.
18. For experimental procedures, physical data and a description of the binding
assay, see U.S. Patent 7,307,094, U.S. Patent 7,553,846 or U.S. Patent 7,781,430.
19. Yan, Z.; Caldwell, G. W. In Optimization in Drug Discovery; Humana Press, 2004;
p 215. Chapter 14.
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Biophys. J. 1998, 74, 230.
22. The NH2 group may be viewed as a metabolic liability or potential toxicophore.
In this case, the NH2 functionality has a calculated pKa of 14.0 and is therefore
predicted to be amide-like. No reactive metabolites were detected using three
trapping agents (glutathione, semicarbazide and KCN) for either 47 or 48 at
tively. In
metabolites.
a similar study, piperazine 41 gave three human
Compounds 41, 47 and 48, had a balance of desirable in vitro
properties such as improved 5-HT3 receptor binding, low CYP inhi-
bition, low intrinsic clearance in human liver microsomes, and
1000-fold or greater separation from hERG functional activity that
resulted in their selection for further in vivo testing (Table 5).
To assess in vivo functional activity, the compounds were mea-
sured for efficacy and duration of action in the murine von Bezold–
Jarisch reflex assay.23 The compounds are able to block 5-HT in-
duced transient bradycardia when dosed orally and exhibit efficacy
similar to ondansetron. The duration of action study compared
AMRI compounds to alosetron (Fig. 2), each at their respective
ED80 oral doses. The duration study indicated that all three com-
pounds were longer acting than alosetron. Compounds 41 and 48
exhibited long duration of action in that they were able to inhibit
5-HT induced transient bradycardia up to 8 h after oral dosing.
2-Aminobenzoxazole carboxamides 41, 47 and 48 were identi-
fied as potent 5-HT3 receptor antagonists in a hit to lead optimiza-
tion campaign. Early profiling suggests these 2-aminobenzoxazole
carboxamides have drug-like properties. The compounds are active
by the oral route in mice, blocking 5-HT induced transient brady-
cardia. Compounds 41 and 48 show extended duration of action
in the mouse. The findings demonstrate the series can produce
compounds with oral efficacy, long duration of action and a re-
duced number of metabolites relative to alosetron.
100
compounds were neither mutagenic nor cytotoxic in a mini Ames screen (TA98
and TA100 S9) up to 100 M.
lM in incubations with human liver microsomes. In addition, these
Acknowledgments
l
23. Animal data was obtained at MDS Pharma according to: Saxena, P. R.; Lawang,
The authors would like to thank Kristen Ryan, Ph.D. for assis-
tance with the preparation of the Letter.
A. Arch. Int. Pharmacodyn. Ther. 1985, 277, 235.