Structure-activity relationships of arylbenzofuran H3 receptor antagonists

Article abstract of DOI:10.1016/j.bmcl.2005.03.047

An SAR study of histamine H₃ receptor antagonists based on substituted (R)-2-methyl-1-[2-(5-phenyl-benzofuran-2-yl)-ethyl]-pyrrolidines is presented.

Full text of DOI:10.1016/j.bmcl.2005.03.047

Bioorganic & Medicinal Chemistry Letters 15 (2005) 2559–2563
Structure–activity relationships of arylbenzofuran
H3 receptor antagonists
Gregory A. Gfesser,* Ramin Faghih, Youssef L. Bennani,ꢀ Michael P. Curtis,
Timothy A. Esbenshade, Arthur A. Hancock and Marlon D. Cowart
Neuroscience Research, Global Pharmaceutical Research and Development, Abbott Laboratories,
100 Abbott Park Road, Abbott Park, IL 60064, USA
Received 1 February 2005; accepted 14 March 2005
Available online 9 April 2005
Abstract—An SAR study of histamine H3 receptor antagonists based on substituted (R)-2-methyl-1-[2-(5-phenyl-benzofuran-2-yl)-
ethyl]-pyrrolidines is presented.
Ó 2005 Elsevier Ltd. All rights reserved.
In the CNS, the histamine H3 receptor (H3R) modulates
the release of neurotransmitters such as histamine, sero-
tonin, dopamine, and acetylcholine.1 H3R antagonists
induce the release of these neurotransmitters, and in ani-
mal models they have been demonstrated to enhance
attention and cognition, and influence feeding, and so
may prove useful in the treatment of attention-deficit
disorder, Alzheimerꢁs disease, schizophrenia, and obes-
ity.2 The efforts of a number of laboratories have been
directed toward discovering potent H3 antagonists for
the treatment of these and other indications.2b,3
Figure 1. Previously reported arylbenzofurans. Values in nanomolar
units.
We previously reported the benzofuran series 1, where
R = CN or C(O)-morpholine, X = CH or N, and a vari-
ety of amines were present (Fig. 1).3d One of these ana-
logs, ABT-239 (2), was potent in vitro and in animal
models showed a desirable pharmacokinetic profile
and cognition-enhancing effects at low doses.4 To ex-
plore the structure–activity relationships of the series
and to produce more potent analogs, we prepared a
variety of arylbenzofurans bearing a much wider variety
of substituents.
3-butyn-1-ol in the presence of copper (I) oxide at
100 °C to afford benzofuran 3.6 This intermediate was
then coupled with either 3-cyanophenylboronic acid or
4-fluorophenylboronic acid under Suzuki conditions,
the products were mesylated, and then converted to
the final products 4a–b by displacement of the mesylates
with (R)-2-methylpyrrolidine3d under gentle heating
(40 °C). Later, the copper-catalyzed cyclization was re-
placed by a shorter route, wherein a Sonogashira reac-
tion was run with 1-but-3-ynyl-2-methyl-pyrrolidine to
give 5. In this sequence, the terminal Suzuki reaction al-
lowed a wider variety of aromatic moieties to be readily
appended (compounds 4c–x).
Two of the first compounds were prepared in five steps
from 4-bromophenol (Scheme 1). After ortho-iodination
at 0 °C with NaI/NaOCl,5 the phenol was cyclized with
A second route began with a Suzuki reaction7 between
4-methoxyphenylboronic acid and 4-bromobenzonitriles
to afford 6 (Scheme 1). Demethylation of 6 with BBr3 at
ꢀ78 °C gave phenols (40-bromo-biphenyl-4-ol is com-
mercially available), which were either ortho-iodinated
Keywords: Histamine; H3; Arylbenzofuran.
*
Corresponding author. Tel.: +1 847 935 0109; fax: +1 847 937
9195; e-mail: greg.gfesser@abbott.com
ꢀ Present address: Vertex Pharmaceuticals, Cambridge, MA, USA.
0960-894X/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2005.03.047

2560
G. A. Gfesser et al. / Bioorg. Med. Chem. Lett. 15 (2005) 2559–2563
Scheme 1. Reagents: (a) NaOCl, NaI, NaOH, aq MeOH; (b) 3-butyn-1-ol, Cu2O, Py/NMP; (c) ArB(OH)2, Pd(PPh3)4, Na2CO3, aq dioxane; (d) (i)
MsCl, Et3N, CH2Cl2, (ii) (R)-2-methylpyrrolidine tartrate, Cs2CO3, MeCN; (e) 325 mesh K2CO3, MeCN, 55 °C, sealed bottle 2 days; (f) Pd(OAc)2,
PPh3, CuI, i-Pr2NH, MeCN; (g) ArB(OH)2, Pd(PPh3)4, Na2CO3, H2O/EtOH/PhH, or, ArB(OH)2, PdCl2(PPh3)2, Na2CO3, aq i-PrOH; (h) R1C6H4Br,
Pd(PPh3)4, Na2CO3, H2O/EtOH/PhH; (j) (i) BBr3, CH2Cl2, (ii) NaOCl, NaI, NaOH, aq MeOH, or NIS, DMF; (k) (2R)-1-but-3-ynyl-2-
methylpyrrolidine, CuI, Pd(OAc)2, PR3, i-Pr2NH, MeCN.
at 0 °C with NaI/NaOCl or at room temperature with
NIS (R2 = 2-F, 2-Me) to provide intermediates 7, which
were then reacted under Sonogashira reaction condi-
tions to give final target products 8a–g.
Other target molecules were prepared from 2 or struc-
turally related nitriles 4a and 8c (Scheme 2). Cyclopro-
pyl ketones 15a–b were prepared from the nitriles with
cyclopropyl magnesium bromide in the presence of
CuI;8 in other H3 antagonists, such as ciproxifan,
cyclopropyl ketones have been found to increase po-
tency. Compound 2 was iodinated at the 3-position
of the benzofuran ring with NIS in TFA to give 16.
Compound 2 could also be chlorinated with NCS in
TFA, to give a four-to-one ratio of chloroarenes 17a
and 17b. The use of trifluoroacetic acid to protonate
the pyrrolidine nitrogen and protect it from oxidation
was also important in the synthesis of bromides 18a–b.
Compound 18a (R1 = H) was further reacted with
several boronic acids under Suzuki conditions to give
19a–f. Product 19f was reduced by NaBH4 to afford
20.
Additional analogs of 4v were then prepared (Scheme 2).
The preparation of alcohols 9–10, acid 11, and Weinreb
amide 12 have been described.4a This flexible intermedi-
ate (12) was treated with Grignard reagents (EtMgBr, i-
BuMgCl, or 3-F–C6H4–MgBr) to give the expected
ketones 13a–c. Treatment of 12 with cyclopentyl magne-
sium bromide afforded a low yield of the unexpected
aldehyde 13d, likely arising from hydride transfer from
the Grignard reagent to the nitrile. Target oxime ana-
logs (14a–d) were produced by condensation of methylke-
tone 4v with hydroxylamine at 70 °C or with alk-
oxyamines at 20 °C.
Scheme 2. Reagents: (a) RMgX, THF; (b) H2NORÆHCl, Na2CO3, MeOH; (c) c-PrMgBr, CuI, THF; (d) NIS, TFA; (e) NCS, TFA; (f) Br2, TFA; (g)
ArB(OH)2, Pd(PPh3)4, Na2CO3, aq DME; (h) (i) NaBH4, MeOH, (ii) aq HCl.

G. A. Gfesser et al. / Bioorg. Med. Chem. Lett. 15 (2005) 2559–2563
2561
Table 1. Binding affinitiesa (Ki) of substituted arylbenzofurans at rat cortical H3 receptors and cloned human H3 receptors
c
Compd
Benzofuran substituent
Phenyl substituent
rH3
hH3
0.45
2b
4ab
4b
H
40-CN
30-CN
3.2
2.5
65
H
0.27
3.2
2.2
6.3
5.0
5.3
5.7
3.9
7.9
2.7
4.1
7.6
H
40-F
30-F
4c
4d
H
17
82
H
40-Cl
4e
H
30-Cl
48
24
4f
4g
H
20-Cl
H
40-CF3
150
95
4h
4i
H
30-CF3
H
40-Me
160
30
4j
4k
H
30-Me
H
20-Me
33
4l
H
40-OCF3
200
130
56
4m
4n
H
30-OCF3
11
H
40-OMe
9.1
1.2
4o
4p
H
30-OMe
23
76
H
20-OMe
15
4q
4r
H
30-Cl, 40-Cl
30-Cl, 50-Cl
30-Me, 40-Me
30-Me, 50-Me
40-COOMe
30-C(O)Me
40-CH2OH
30-CH2OH
40-Br
40-CN, 20-Me
40-CN, 30-Me
40-CN, 30-F
40-CN
110
24
3.6
5.0
H
4s
H
65
19
5.9
3.6
4t
H
4u
H
42
1.9
4vb
4wb
4xb
8a
H
0.44
0.084
0.88
0.49
7.7
H
4.1
2.8
H
H
300
31
2.6
8b
8c
H
2.0
H
0.28
0.64
0.43
1.1
8d
8e
H
7-F
9.3
5.7
8f
8g
9b
10b
11
7-Me
6-Me
40-CN
40-CN
16
4.2
2.8
1.3
0.77
0.44
0.25
H
30-CH(OH)Me
30-C(OH)Me2
30-COOH
30-C(O)N(Me)OMe
30-C(O)Et
30-C(O)CH2CHMe2
30-C(O)–(300-F)C6H4
30-CHO
H
H
66
15
12
H
4.9
2.3
0.62
0.23
0.68
2.6
13ab
13b
13c
13d
14a
14b
14c
14d
15ab
15bb
16
H
H
19
53
3.3
H
H
0.40
0.49
0.42
3.2
H
30-C(@NOH)Me
30-C(@NOMe)Me
30-C(@NOEt)Me
30-C(@NO–t-Bu)Me
40-C(O)–c-Pr
30-C(O)–c-Pr
40-CN
3.1
4.5
H
H
51
41
6.4
H
4.3
H
0.26
0.21
0.51
0.39
0.83
0.29
1.3
H
3-I
2.5
8.4
3.7
9.7
3.4
17a
17b
18a
18b
19a
19b
19c
19d
19e
19f
20
3-Cl
3-Cl, 6-Cl
40-CN
40-CN
3-Br
3-Br
40-CN
40-CN, 30-Me
40-CN
16
3-Ph
390
840
18
21
3-(300,500-DiMeC6H3)
3-(300-Pyridyl)
3-(200-Furyl)
3-(300-Thienyl)
3-(300(200CHO)thienyl)
3-(300(200CH2OH)thienyl)
40-CN
60
13
40-CN
40-CN
42
41
2.8
2.1
40-CN
40-CN
5.8
20
0.73
1.9
40-CN
a Values reported are in nanomolar units, converted from the average of at least three pKi determinations (pKi SEM < 0.25).
b The data for these compounds at cloned rat and human H3Rs has been reported.4a
c The source of rH3 was membranes from rat cortex.

2562
G. A. Gfesser et al. / Bioorg. Med. Chem. Lett. 15 (2005) 2559–2563
The synthesized compounds were tested for binding at
both the rat cortical (rH3) and human clonal (hH3)
receptors, with the data shown in Table 1. In every in-
stance H3 receptor binding was more potent at hH3 than
at rH3, although SAR trends were similar at hH3 and
rH3. Because potency was weaker at the rat receptor
and because pharmacokinetic assays and behavioral
models were to be run in rats, potency at the rat receptor
was the primary constraint in choosing compounds for
further advancement.
attached. Again, the trend was more pronounced at
rH3 than at hH3. Oxime 14a and O-methyl oxime 14b
showed higher affinity than the O-ethyl and O-t-butyl
analogs 14c–d for both rH3 (3.1–4.5 nM vs 41–51 nM)
and hH3 (0.42–0.49 nM vs 3.2–4.3 nM). Larger ketones
13b–c (rH3 = 19–53 nM, hH3 = 0.68–2.6 nM) were less
potent than cyclopropyl ketones 15a–b and ethyl ketone
13a (rH3 = 2.3–6.4 nM, hH3 = 0.21–0.26 nM), which
were in turn less potent than the methyl ketone 4v
(rH3 = 0.44 nM, hH3 = 0.084 nM). However, the 30-
alcohol series 10 [C(OH)Me2], 9 [CH(OH)Me], and 4x
[CH2OH] showed no such trend upon the removal of
methyl groups; each possessed a potency similar to 2,
as did nitrile 4a, amide 12, and aldehyde 13d
(rH3 = 1.3–4.9 nM, hH3 = 0.25–0.62 nM).
Examination of the in vitro data (Table 1) for SAR re-
vealed that addition of a methyl or halogen to either
aromatic ring of 2 did not increase binding. In most
cases (8c–e, 8g, 16, 17a–b, 18a) the binding potencies
were comparable to the parent or slightly weaker
(rH3 = 2.6–9.7 nM, hH3 = 0.28–0.83 nM); however,
appending a methyl group to either the 20 (8b) or 7
(8f) positions, or appending both a 30-methyl and 3-bro-
mo (18b) resulted in compounds with greater reductions
in potency (rH3 = 16–31 nM, hH3 = 1.1–2.0 nM). It was
also seen that appending an aromatic ring to position 3
of the benzofuran did not increase binding. Except for
one case (19f) where binding was similar to the parent
2, these molecules showed lower affinity for the H3Rs
(19a–e, 20; rH3 = 18–840 nM, hH3 = 1.9–60 nM).
It seems likely that some open space exists in the binding
pocket around both the benzofuran and phenyl rings,
based on the finding that the addition of substituents
on either ring (e.g., 4v–x, 8c–e, 16–17, 19f) can be toler-
ated. Although the addition of hydrophobic substituents
results in compounds which retain (e.g., 8c, 8g) or, more
frequently, lose (e.g., 8a, 19a) potency, the addition of
small hydrophilic substituents on the phenyl ring may
be advantageous (4v, 10). These data also leave open
the possibility that at a short distance from this ring
hydrogen-bond acceptors are the species preferred.
Replacement of the nitrile in the parent species with a
bromide (8a), a fluoride (4b–c), one or two chlorides
(4d–f, 4q–r) or methyls (4i–k, 4s–t), a trifluoromethyl
(4g–h) or trifluoromethoxy moiety (4l–m), a methoxy
group (4n–p), a methyl ester (4u), or a carboxylic acid
(11) resulted in compounds with modest to weak bind-
ing (rH3 = 17–300 nM, hH3 = 1.2–15 nM). The larger,
more hydrophobic bromide, trifluoromethyl, and trifluoro-
methoxy substituents possessed the lowest potencies,
and compounds with any of the above groups in posi-
tion 40 bound less easily to rH3 than those with groups
at position 30 or 20, with the exception of methyl ether
4p. This trend toward reduced potency extended even
to the disubstituted 4q–t, where 30,40 substitution was
weaker than 30,50. Potency at hH3 also diminished, but
was less affected by these substituents.
The pharmacokinetic (PK) properties of select com-
pounds were also examined (Table 2). Whereas reference
compound 2 and its regioisomer 4a both had good PK
in rat,4a another close analog which differed from 2 only
by the addition of a methyl group (8c) had poor PK, with
a low Cmax and AUC p.o., and a bioavailability of only
9%. The most potent compound in the series, 4v, also
gave very poor data in rat. Oral bioavailability was bet-
ter in dog (F = 27%) and very good in monkey
(F = 72%), and we hypothesized that the high clearance
rate of this methyl ketone in rats resulted from rapid he-
patic metabolism [as in primary alcohols 4w–x and oxi-
mes 14a–b (Frat = 0ꢀ9%)] directed toward the ketone
moiety. In order to test this hypothesis, we examined
the PK profile of secondary alcohol 9, tertiary alcohol
10, and cyclopropyl ketones 15a–b, and found that each
possessed very good bioavailability coupled with both
high Cmaxs (p.o.) and good AUCs (i.v. and p.o.). Fur-
thermore, both 4a and 15b were active in a five-trial
inhibitory avoidance model for learning.4a
Certain molecules with more hydrophilic substitution on
the phenyl group—such as ketones and alcohols—
bound more tightly to the H3Rs, and usually showed a
decrease in potency as larger hydrophobic groups were
Table 2. Pharmacokinetic properties of selected arylbenzofurans
Compd
1 mg/kg i.v.
1 mg/kg p.o.
t1/2, h
Vb, L/kg
AUC0–1, ng h/mL
CLb, L/h kg
Cmax, ng/mL
t1/2, h
AUC0–1, ng h/mL
F %
2
5.3
4.3
3.0
3.2
7.6
5.6
9.3
5.0
12
673
835
1.5
1.2
8.5
2.0
2.1
2.6
0.61
0.86
29
27
5.2
5.5
UC
UC
9.4
9.0
13
349
320
10
53
38
6
4a
4v
8c
9
7.5
27
160
510
ꢁ2
ꢁ8
24
11
23
50
9
482
391
265
315
788
828
55
81
48
70
10
15a
15b
21
38
31
8.2
6.2
1649
1177
76
5.1
Selected data for some of these compounds were previously reported4a but are included to present a more complete profile. UC = uncalculated.

G. A. Gfesser et al. / Bioorg. Med. Chem. Lett. 15 (2005) 2559–2563
2563
Pharmacol. 2004, 487, 183; (g) Fox, G. B.; Pan, J. B.;
Esbenshade, T. A.; Bennani, Y. L.; Black, L. A.; Faghih,
R.; Hancock, A. A.; Decker, M. W. Behav. Brain Res. 2002,
131, 151.
The results here show that among the wide variety of
new arylbenzofurans synthesized and described, many
of the compounds had nanomolar potency at rat and
human H3 receptors. Good pharmacokinetic properties
were found for a subset of the most potent analogs
tested, offering the possibility that analogs of ABT-239
having favorable behavioral efficacy and PK properties
could be used to further explore the potential clinical
efficacy of H3R antagonists.
3. (a) Cowart, M. D.; Altenbach, R. A.; Black, L. A.; Faghih,
R.; Zhao, C.; Hancock, A. A. In Mini-Reviews in Medicinal
´
Chemistry; Leurs, R., Ed., 2004; 4, p 997; (b) Miko, T.;
Ligeau, X.; Pertz, H. H.; Arrang, J.-M.; Ganellin, C. R.;
Schwartz, J.-C.; Schunack, W.; Stark, H. Bioorg. Med.
Chem. 2004, 12, 2727; (c) Chai, W.; Breitenbucher, J. G.;
Kwok, A.; Li, X.; Wong, V.; Carruthers, N. I.; Lovenberg,
T. W.; Mazur, C.; Wilson, S. J.; Axe, F. U.; Jones, T. K.
Bioorg. Med. Chem. Lett. 2003, 13, 1767; (d) Cowart, M.;
Pratt, J. K.; Stewart, A. O.; Bennani, Y. L.; Esbenshade, T.
A.; Hancock, A. A. Bioorg. Med. Chem. Lett. 2004, 14, 689;
(e) Aslanian, R.; wa Mutahi, M.; Shih, N.-Y.; Piwinski, J.
J.; West, R.; Williams, S. M.; She, S.; Wu, R.-L.; Hey, J. A.
Bioorg. Med. Chem. Lett. 2003, 13, 1959; (f) Zaragoza, F.;
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Acknowledgements
We thank John Baranowski, Tracy Carr, Tom Miller,
and David Witte for performing binding assays; Kennan
Marsh and Jill Wetter for pharmacokinetic analysis; and
Gerard B. Fox, Jia Bao Pan, Angela Lewis, and Michael
Buckley for conducting behavioral work.
4. (a) Cowart, M.; Faghih, R.; Curtis, M. P.; Gfesser, G. A.;
Bennani, Y. L.; Black, L. A.; Pan, L.; Marsh, K. C.;
Sullivan, J. P.; Esbenshade, T. A.; Fox, G. B.; Hancock, A.
A. J. Med. Chem. 2005, 48, 38; (b) Esbenshade, T. A.; Fox,
G. B.; Krueger, K. M.; Miller, T. R.; Kang, C. H.; Denny,
L. I.; Witte, D. G.; Yao, B. B.; Pan, L.; Wetter, J.; Marsh,
K.; Bennani, Y. L.; Cowart, M. D.; Sullivan, J. P.;
Hancock, A. A. J. Pharmacol. Exp. Ther. 2005, 313, 615;
(c) Fox, G. B.; Esbenshade, T. A.; Pan, J. B.; Radek, R. J.;
Krueger, K. M.; Yao, B. B.; Browman, K. E.; Buckley, M.
J.; Ballard, M. E.; Komater, V. A.; Miner, H.; Zhang, M.;
Faghih, R.; Rueter, L. E.; Bitner, R. S.; Drescher, K. U.;
Wetter, J.; Marsh, K.; Lemaire, M.; Porsolt, R. D.;
Bennani, Y. L.; Sullivan, J. P.; Cowart, M. D.; Decker,
M. W.; Hancock, A. A. J. Pharmacol. Exp. Ther. 2005, 313,
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