Structure - Activity relationships of non-imidazole H3 receptor ligands. Part 1

Article abstract of DOI:10.1016/S0960-894X(02)00309-8

SAR studies for novel non-imidazole containing H₃ receptor antagonists with high potency and selectivity for rat H₃ receptors are described. A high throughput screening lead, A-923, was further elaborated in a systematic manner to clarify a pharmacophore for this class of aryloxyalkyl piperazine based compounds.

Full text of DOI:10.1016/S0960-894X(02)00309-8

Bioorganic & Medicinal Chemistry Letters 12 (2002) 2031–2034
Structure–Activity Relationships of Non-imidazole
H3 Receptor Ligands. Part 1
Ramin Faghih,* Wesley Dwight, Robert Gentles, Kathleen Phelan, Timothy
A. Esbenshade, Lynne Ireland, Thomas R. Miller, Chae-Hee Kang, Gerard B. Fox,
Sujatha M. Gopalakrishnan, Arthur A. Hancock and Youssef L. Bennani
Neuroscience Research, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL 60064-6123, USA
Received 2 November 2001; accepted 11 March 2002
Abstract—SAR studies for novel non-imidazole containing H3 receptor antagonists with high potency and selectivity for rat H3
receptors are described. A high throughput screening lead, A-923, was further elaborated in a systematic manner to clarify a
pharmacophore for this class of aryloxyalkyl piperazine based compounds. # 2002 Elsevier Science Ltd. All rights reserved.
The histamine class of receptors has been a fertile
ground for the development of important therapeutic
agents. It is well established that allergic conditions can
be controlled by blockade of H1 receptors, while relief
of gastric ulcers through modulation of H2 receptors is
highly efficacious therapy.1 Histamine mediates its
action both in the CNS and the periphery through four
distinct receptors known to date.2 Although the hista-
mine-3 receptor (H3R) was discovered over 15 years
ago, the following decade provided minimal medicinal
chemistry advancement in non-imidazole based H3
agents.3 This slow progress is partially due to the lack of
potent, selective, and safe agents which hindered
understanding of the H3R role in pathophysiology and
the delay in successful cloning of this receptor.4 The H3
receptor was originally described as a presynaptic
receptor regulating the synthesis and release of hista-
mine. H3Rs not only act as autoreceptors, but are also
involved in presynaptic regulation of the release of
acetylcholine, gamma-aminobutyric acid, dopamine,
noradrenaline and serotonin. H3R modulation could
have therapeutic utility in cognitive disorders, including
but not limited to attention deficit and hyperactivity
disorder (ADHD), and in obesity among other potential
benefits.5 The increasing interest in the therapeutic
potential of H3 agonists and/or antagonists is driving
current medicinal chemistry efforts to identify potent,
selective, therapeutically efficacious and safe agents for
clinical development.6 A-923 (Fig. 1) was identified from
high throughput screening (HTS) of the Abbott com-
pound collection as a ꢀ2 nMaffinity ligand at rat H 3R.
Its non-imidazole containing features differentiated it
from most early H3 receptor ligands, although during
the completion of this work several publications repor-
ted new non-imidazole H3 antagonists with comparable
or inferior potency compare to A-923. However, further
characterization revealed its poor selectivity versus
other histaminergic receptors. We describe here in Part I
of a two-part series of Letters (see following manu-
script) some pharmacophoric features of these non-
imidazole H3 receptor ligands.7 A systematic modifi-
cation of parts A–E of this lead molecule was conducted
using parallel synthesis when possible.
Modification of the Carbamate Functionality (section A)
Commercially available phenol 1 (Scheme 1) was treated
with 1-bromo-3-chloropropane in the presence of
K2CO3 in refluxing 2-butanone for 24 h. The resulting
O-alkyl chloride 2 (obtained in ꢀ95% yield) was further
treated, without purification, with N-Boc-piperazine to
*Corresponding author. Fax: +1-847-937-4143; e-mail: ramin.
faghih@abbott.com
Figure 1.
0960-894X/02/$ - see front matter # 2002 Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(02)00309-8

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R. Faghih et al. / Bioorg. Med. Chem. Lett. 12 (2002) 2031–2034
Scheme 1. (a) Cl–(CH2)3–Br, K2CO3, 2-butanone, reflux 24 h; (b) N-Boc-piperazine, KI/K2CO3, 2-butanone, reflux 72 h; (c) TFA–CH2Cl2, 0 ꢁC to
rt, 12 h.
Table 1. Binding affinitiesa (pKi) at rat cortical H3 and human H1 and H2 receptors9
Compd:b
R
H3
H1
H2
R
H3
H1
H2
R
H3
H1
H2
4: H
5: CO2Me
6: CO2Et (A-923)
7: CO2Bu
8: CO2iPr
7.57
8.52
8.86
7.69
8.30
8.00
8.02
7.67
8.13
8.23
7.67
7.90
7.43
5.22
5.97
6.56
6.24
6.51
6.56
5.92
5.80
5.98
5.38
4.58
4.95
4.87
4.84
4.92
4.90
5.73
4.75
5.43
4.95
4.63
4.83
4.75
4.08
4.68
4.91
17: CO-Ph
7.44
7.79
7.80
7.53
7.98
8.07
8.39
7.35
8.35
7.74
7.28
7.69
8.20
6.54
7.13
7.01
7.10
6.40
6.98
7.25
5.37
6.28
5.69
6.38
6.14
6.32
4.91
4.83
5.09
4.71
4.70
4.89
4.93
4.56
4.71
4.33
4.73
4.22
4.65
30: CO-Et
31: CO-Pr
32: CO-iPr
8.50
8.19
8.35
8.67
8.50
8.00
7.96
7.24
7.56
7.80
7.87
8.03
7.78
5.72
6.06
5.40
5.75
6.45
7.25
5.96
4.67
5.47
5.65
6.18
6.34
7.22
4.5
18: CO-2-thiophene
19: CO-5-Me-2-thioph.
20: CO-3-Cl-2-thioph.
21: CO-2-furan
22: CO-3-Me-2-furan
23: CO-2-N-Me-pyrrole
24: CO-5-oxazole
25: CO-5-imidazole
26: CO-2-pyrazine
27: CO-2-pyridine
28: CO-3-pyridine
29: CO-4-pyridine
4.64
4.53
4.50
4.99
5.05
4.64
4.61
4.56
4.73
5.12
5.02
5.15
33: CO-cyclopropyl
34: CO-cyclobutyl
35: CO-CH2-Ph
36: CO-CH2S-Et
37: CO-COH(CH3)2
38: Propyl
39: CH2-cycloprop.
40: Butyl
41: Isobutyl
9: CO2iBu
10: CONH-iPr
11: CONH-Et
12: CO-pyrrolidine
13: CO-morph.
14: SO2Me
15: SO2iPr
16: SO2(4-CN)–Ph
42: CH2-2-thiazole
aValues were estimated from at least three separate competition experiments (SEM ꢂ0.2).
1
bSatisfactory H NMR, MS spectra and elemental analyses were obtained for all new compounds.
give 3 in 75–82% yield after s.g.c. TFA treatment in di-
chloromethane provided piperazine 4 ready for parallel
synthesis (Scheme 1). A group of about 75 N-acyl, N-
alkyl, sulfonamides, sulfonylureas, and ureas were pre-
pared using standard acylation chemistry or reductive
amination to give compounds 5–42. These were assayed
in a binding experiment using rat cortex in order to
probe the SAR of the H3 receptor.
dine, homopiperazine, 4-aminopiperidine, 4-piperidino-
piperidine, etc. (e.g., 67, H3R=7.20), with no significant
improvement in affinity at rat H3R. More importantly,
we demonstrated that exchange of the piperazine basic
nitrogen in A-923 to a carbon atom (68, Scheme 2)
resulted in loss of affinity at the rat H3R (pKi=4.23).
Additionally, both the length (2-, 3-, and 4-atom linker)
and substitution of the 3-carbon chain linker was
further substituted with methyl and/or aryl at either
the 1-, 2-, or 3-position in both enantiomeric forms.
This resulted in no improvement in affinity with minor
selectivity towards the R-enantiomers at either the 1-
or 2-position. The aromatic ring was examined to a
lesser degree. In this case, substitutions at the ketone
ortho-position (–NH2, –Cl, –F, –OMe) were tolerated,
whereas substitutions at meta-positions were not
additive.
Data from Table 1 indicate a fairly well defined phar-
macophore at the piperazine-N-substitution. Com-
pound 33 showed the same high affinity for the rat H3R
as the HTS lead A-923; however, with a better selectivity
for the human H1 receptor, several other substitutions
altering various physicochemical properties of the
molecule were tolerated (i.e., imidazole 25; morpholine
urea 13). Most other structural alterations resulted in
lower H3 affinities.
Modification of the Ketone Functionality (Section E)
Modifications of Sections B–D8
We next explored the ketone moiety while retaining the
ethyl carbamate functionality in order to further explore
SAR. We accessed such ketones via two routes (Scheme 2):
The basic piperazine in A-923 was replaced with a variety
of amines: morpholine, 2,6-dimethylmorpholine, pyrroli-
Scheme 2. (a) (i) Rh/Al2O3, CH3OH; (ii) (Boc)2, Hunig’s, CH2Cl2; (b) (i) 1, DEAD, PPh3, THF, 0 ꢁC to rt, 48 h; (ii) TFA–CH2Cl2, 0 ꢁC to rt, 12 h.

R. Faghih et al. / Bioorg. Med. Chem. Lett. 12 (2002) 2031–2034
Table 2. Binding affinitiesa (pKi) at rat cortical H3 and human H1 and H2 receptors
2033
H2
Compd: R
H3
H1
H2
R
H3
H1
H2
R
H3
H1
48: –CH3
8.30
8.27
8.43
8.10
8.33
7.60
8.14
5.65
5.78
6.25
6.30
5.85
6.22
6.03
4.40
4.25
5.67
5.57
4.10
5.10
4.16
55: –CH2CH2CH3
56: –CH¼(CH3)2
57: –C(CH3)¼CH2
58: –CH2Ph
59: – p-F–Ph
60: –(o,m)-di-F–Ph
8.44
7.41
7.26
7.16
7.17
7.60
6.13
6.45
6.01
6.03
6.68
5.99
4.65
4.66
4.65
4.90
4.37
4.76
61: –p-Me—S–Ph
62: –p-MeO–Ph
63: –p-tBu–Ph
7.23
7.40
7.88
6.54
8.20
8.14
6.35
6.09
6.25
6.42
6.37
6.21
5.21
5.08
5.81
5.43
4.60
5.17
49: –CH2CH3
50: –C7H15
51: –C8H17
52: –Cyclopropyl
53: –Cyclohexyl
54: –i-Bu
64: –m-Me–Ph
65: –t-CH¼CH–30-pyrid.
66: –t-CH¼CH–40-MeO–Ph
aValues were estimated from at least three separate competition experiments (SEM ꢂ0.2).
Scheme 3. (a) Cl–(CH2)3–Br, K2CO3, 2-butanone, reflux 24 h; (b) EtOCO-piperazine, KI/K2CO3, 2-butanone, reflux 72 h; (c) (i) BnBr, K2CO3,
DMF; (ii) NaOH; (iii) (COCl)2, cat. DMF, CH2Cl2; (iv) MeONHMe, Et3N, CH2Cl2; (v) H2, Pd/C, CH3OH; (d) (i) EtOCO-piperazine, KI/K2CO3,
2-butanone, reflux 72 h; (ii) RMgX, THF.
commercially available 4-hydroxyphenyl ketones were
treated under basic conditions with 1-bromo-3-chloro-
propane followed by piperazine-N-ethylcarbamate to
give the desired products. Alternatively, 4-hydroxy-
benzoic acid was O-benzyl alkylated and esterified in a
one-pot reaction with BnBr–K2CO3 followed by hydro-
lysis. The carboxylic acid, thus obtained, was treated
with oxalyl chloride followed with N-methoxy-N-
methylamine to give the corresponding Weinreb amide.10
Further O-debenzylation under hydrogen/Pd conditions
followed by O-alkylation and N-ethylcarbamate piper-
azine-N-alkylation (see above) gave the template amide.
The latter was treated with various Grignard reagents to
provide the corresponding ketones (Scheme 3).
bioavailability, receptor selectivity, CNS-penetration
and in vivo biological efficacy.
References and Notes
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cophore would be a tertiary amine, preferably a 4-atom-
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stitution patterns around this core system should allow
for optimizing physicochemical features to improve oral

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