Synthesis and evaluation of potent pyrrolidine H3 antagonists

Article abstract of DOI:10.1016/S0960-894X(02)00685-6

The synthesis and biological evaluation of novel antagonists of the rat H₃ receptor are described. These compounds differ from prototypical H₃ antagonists in that they do not contain an imidazole moiety, but rather a substituted aminopyrrolidine moiety. A systematic modification of the substituents on the aminopyrrolidine ring was performed using pre-formatted precursor sets, where applicable, to afford several compounds with high affinity and selectivity for the H₃ receptor.

Full text of DOI:10.1016/S0960-894X(02)00685-6

Bioorganic & Medicinal Chemistry Letters 12 (2002) 3055–3058
Synthesis and Evaluation of Potent Pyrrolidine H3 Antagonists
Anil Vasudevan,* Scott E. Conner, Robert G. Gentles, Ramin Faghih, Huaqing Liu,
Wesley Dwight, Lynne Ireland, Chae Hee Kang, Timothy A. Esbenshade,
Youssef L. Bennani and Arthur A. Hancock
Neuroscience Research, Global Pharmaceutical Research and Development, Abbott Laboratories, 100 Abbott Park Road,
Abbott Park, IL 60031, USA
Received 7 May 2002; accepted 6 August 2002
Abstract—The synthesis and biological evaluation of novel antagonists of the rat H3 receptor are described. These compounds
differ from prototypical H3 antagonists in that they do not contain an imidazole moiety, but rather a substituted aminopyrrolidine
moiety. A systematic modification of the substituents on the aminopyrrolidine ring was performed using pre-formatted precursor
sets, where applicable, to afford several compounds with high affinity and selectivity for the H3 receptor.
# 2002 Published by Elsevier Science Ltd.
Histamine is thought to exert its actions in the CNS and
periphery via the modulation of at least four distinct
receptor subtypes.1 The demonstration of the existence
of the H1 and the H2 receptors, followed by an under-
standing of the physiological role of these receptors has
resulted in the clinical applications of selective antago-
nists of these receptors in the treatment of allergic con-
ditions (H1 receptor antagonists) and gastric ulcers (H2
receptor antagonists). Since the identification of the H3
receptor in 1983,2 several efforts aimed at gaining a
better understanding of the functions modulated by this
receptor subtype via the synthesis of selective ligands
have been underway.3 It has been found that H3 recep-
tors not only regulate the release of histamine, but also
act as heteroreceptors involved in the regulation of the
release of other neurotransmitters such as acetylcholine,
dopamine, noradrenaline and serotonin.4 Radiolabeling
studies have shown the highest concentration of H3
receptors to be in distinct areas of the CNS, suggesting a
potential role for selective ligands of this receptor sub-
class in the treatment of various neurological and psy-
chiatric diseases, such as epilepsy, schizophrenia, and
attention deficit disorder (ADD).5
Figure 1. Most of the initial approaches have focused
on structural modification of the endogenous ligand,
histamine, and have resulted in a series of very potent
imidazole-containing H3 antagonists, such as thioper-
amide,6 GT-2331,7 FUB 470,8 and ciproxifan.9 It has
been speculated recently that the basic imidazole moiety
of these compounds interacts with an active site aspar-
tate.10 Replacement of the potentially toxic isothiourea
moiety in ligands similar to thioperamide resulted in the
identification of guanidine containing compounds such
as JB 98064.11 Unsubstituted-imidazole containing
compounds are known to interact with, and inhibit the
cytochrome P450 system.12 Though this feature can
potentially be modulated by judicious substitution on
the imidazole ring,13 we have focused on developing
non-imidazole H3 antagonists. While this work was in
progress, reports of non-imidazole containing H3
antagonists have appeared in the literature.14
Attempts to identify selective ligands for the H3 recep-
tor have resulted in the identification of several potent
and selective inhibitors, some of which are shown in
Compound A-923 was identified via high-throughput
screening of the Abbott compound collection as a
potent (Ki=2 nM) rat H3 antagonist.
*Corresponding author. Fax: +1-847-935-0310; e-mail: anil.vasudevan
@abbott.com
0960-894X/02/$ - see front matter # 2002 Published by Elsevier Science Ltd.
PII: S0960-894X(02)00685-6

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A. Vasudevan et al. / Bioorg. Med. Chem. Lett. 12 (2002) 3055–3058
Figure 1.
This compound demonstrated poor oral bioavailability,
as well as a lack of selectivity for other G-protein cou-
pled receptors. We have previously reported on the
structure–activity relationships of piperazine-containing
H3 antagonists, aimed at tackling some of these issues.15
As part of our continuing effort to identify efficacious,
orally bioavailable, non-imidazole containing ligands at
the H3 receptor, we wish to report preliminary results of
novel ring-contracted analogues of A-923 wherein the
piperidine ring was replaced with a pyrrolidine moiety.
Prior SAR15 had demonstrated that the methyl ketone
of A-923 was equipotent, and hence preliminary SAR
investigations were performed with this variant.
ferential binding for the d-amino acids as compared to
the l-amino acids, contrary to that observed in prior
studies.15 Conformational restriction of these side-chain
amino acids via incorporation into hydantoins 10 and
11, did not result in an improvement in binding affinity
compared to the amino acids.
Most lead-optimization exercises tend to traditionally
fall into two categories. In the first approach, some
knowledge of the interactions between the ligand and
the protein is available, either from prior SAR or struc-
tural information. In cases like this, a more structured
or focused experimental design involving traditional
analoging strategies outlined by Topliss,16 Craig,17
Wermuth,18 and others is desirable. The second and
perhaps more common lead-optimization exercise is one
in which no ligand-protein information exists, which
necessitates the synthesis of a diverse set of analogues,
with the purpose of identifying an unexpected group or
functionality that addresses some deficiency in the lead
structure. We have recently reported on the feasibility of
streamlining the experimental design comprising these
two types of experiments to generate a set of automated
medicinal chemistry approaches that can be applied for
rapid and efficient lead-optimization.19 The starting
point for the delineation of optimal substitution pat-
terns on the pyrrolidine nitrogen was the observation
that the 3-S-amino isomer was about 35-fold more
potent than the 3-R isomer in its binding affinity to the
rat H3 receptor (30 nM vs 811 nM, respectively, data
not shown). Since the ring-contracted analogues were
deemed to be a novel structural class, a concise set of
experiments aimed at probing diverse substituents and
linking elements, commencing with amides, attached to
the pyrrolidine nitrogen of Series I was attempted.
Incorporation of l and d-amino acids (Table 1, 5–9)
resulted in a significant reduction in binding affinity at
the H3 receptor. Further, there was only a modest pre-
Acylation of the exocyclic amine with aryl groups afforded
compounds 12–15 with reasonable binding affinity, but in
general, these compounds were weaker than the original
screening hit. Replacement of the acetyl moiety with a
cyclopropyl ketone, as in 16 did not afford a measurable
improvement in binding affinity at the H3 receptor.
A representative synthesis of cyclopropyl-substituted
compounds from Series I is shown in Scheme 1. Base-
promoted cyclopropanation of 1, followed by alkylation
with 1-bromo-3-chloropropane, and a second alkylation
with 3-N(tert-butoxycarbonyl)-amino pyrrolidine, affor-
ded, after TFA treatment, the scaffold 4, for investiga-
tion of the optimal substituent on the pyrrolidine ring.
Replacing the pyrrolidine ring in these compounds with
the (R,R) enantiomer of 2,5-diazabicyclo[2.2.1]heptane,
followed by acylation, afforded interesting results (Table 2).
The receptor demonstrates a 7-fold preference for the Boc-
protected d-amino acid compared to the d-amino acid
side chain, while the deprotected compounds are equi-
potent (17–20). Acylation with alkyl, aryl and hetero-
aryl groups afforded equipotent compounds; however,
branching beta to the carbonyl of the amide with hydro-
phobic groups results in a precipitous drop in potency.
Incorporation of a b-alanine residue afforded 27 and 28,
which are the most potent compounds in this series.

A. Vasudevan et al. / Bioorg. Med. Chem. Lett. 12 (2002) 3055–3058
3057
Table 1. Binding affinities (Ki, nM) at rat cortical H3 receptors and human H1 and H2 receptors21
Compd
R
X
R1
H3
H2
H1
5
6
7
8
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CO
CO
CO
CO
CO
—
Boc l-Ala
Boc d-Ala
901
307
587
310
151
1721
676
202
37
55
40
50
6
24,000
40,000
46,000
100,000
22,000
50,000
31,000
5000
3500
6200
6100
4000
2300
1600
1200
1550
1600
500
60,000
56,000
75,000
80,000
43,000
90,000
100,000
10,000
7400
11,000
13,000
37,000
14,000
20,000
9100
9400
5900
9200
4500
3600
2500
6200
8900
16,000
6600
5500
4400
2300
1500
2300
91,000
Boc l-Ser
Boc d-Ser
l-Ser
—
—
2-Pyrazinyl
3-Pyridyl
9
10
11
12
13
14
15
16
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
—
CO
CO
CO
CO
CO
SO2
SO2
SO2
SO2
SO2
SO2
SO2
SO2
SO2
SO2
SO2
SO2
SO2
SO2
SO2
SO2
SO2
SO2
SO2
CH3
CH3
4-Thiazol[2-(3-pyridyl)]yl
p-CN phenyl
4-Thiazol[2-(3-pyridyl)]yl
p-CN phenyl
p-CN phenyl
Phenyl
CH3
Cyclopropyl
CH3
Cyclopropyl
Cyclopropyl
Cyclopropyl
Cyclopropyl
Cyclopropyl
Cyclopropyl
Cyclopropyl
Cyclopropyl
Cyclopropyl
Cyclopropyl
Cyclopropyl
Cyclopropyl
Cyclopropyl
Cyclopropyl
Cyclopropyl
Cyclopropyl
Cyclopropyl
Cyclopropyl
4
3
2.7
o-F phenyl
m-F phenyl
p-F phenyl
o-Cl phenyl
m-Cl phenyl
p-Cl phenyl
1.6
3.5
3.7
3.0
3.8
11
2.8
11
2.7
4.2
2.9
5.2
5
1000
700
290
710
o-CN phenyl
m-CN phenyl
o-CH3 phenyl
m-CH3 phenyl
p-CH3 phenyl
p-OCH3 phenyl
4-(t-butyl) phenyl
p-Br phenyl
4-(CH2CH3) phenyl
N-CH3-imidazol-4-yl
900
2200
1800
380
1000
730
290
330
7100
4.6
10
Scheme 1. (a) NaOH, heat; (b) Cl–(CH2)3–Br, K2CO3, 2-butanone-reflux, 24 h; (c) 3S-(À)-3-(tert-butoxycarbonylamino)pyrrolidine, KI/K2CO3,
2-butanone, reflux, 64 h; (d) 5% TFA/CH2Cl2, 3 h; (e) R1COOH, PS-DCC, cat. DMAP, DMF, (f) R1SO2Cl, PS-DMAP, CH2Cl2, 12 h.
Changing the linking element between the pyrrolidine
nitrogen and the pendant substitution to a sulfonamide
afforded significantly more potent compounds than the
corresponding amides (15 vs 31). Given the increased
metabolic stability, water solubility as well as hydrogen
bonding potential of sulfonamides compared to
amides,20 these results were quite encouraging. Further,
since it was observed that replacement of the acetyl
functionality with a cyclopropyl ketone afforded com-
parable binding affinity at the H3 receptor (31 and 32),
all subsequent investigations were performed with the
cyclopropyl ketone functionality. The sulfonyl chloride
precursor inventory comprising both focused as well as
diverse monomers (designed based on approaches men-
tioned previously) was used to synthesize sulfonamides,
and several potent H3 antagonists were identified from

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A. Vasudevan et al. / Bioorg. Med. Chem. Lett. 12 (2002) 3055–3058
Table 2. Binding affinities (Ki, nM) at rat cortical H3 receptors and
human H1 and H2 receptors21
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Compd
R
X
R1
Ki
311
17
18
19
20
21
22
23
24
25
26
27
28
50
51
Cyclopropyl
Cyclopropyl
Cyclopropyl
Cyclopropyl
Cyclopropyl
Cyclopropyl
Cyclopropyl
Cyclopropyl
Cyclopropyl
Cyclopropyl
Cyclopropyl
Cyclopropyl
Cyclopropyl
Cyclopropyl
–CO—
–CO—
–CO—
–CO—
–CO—
–CO—
–CO—
–CO—
–CO—
–CO—
–CO—
–CO—
–SO2—
–SO2—
Boc d-Ala
Boc l-Ala
d-Ala
l-Ala
Cyclohexyl
Phenyl
p-F phenyl
2-Pyridyl
2-Furyl
CH2C(CH3)3
Boc b-Ala
b-Ala
2182
413
232
134
344
258
191
208
10,000
71
7. Tedford, C. E.; Hoffmann, M.; Seyedi, N.; Maruyama, R.;
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17
120
19
CH2CH3
Phenyl
11. Linney, I. D.; Buck, I. M.; Harper, E. A.; Kalindjian,
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this exercise, some of which are depicted in Table 1.
Further, several substituents (F, Cl, CN, CH3, OCH3,
and CH2CH3), which would be expected to impart
varying pharmakokinetic and pharmacodynamic prop-
erties were identified. In addition, these compounds
showed significant selectivity for the H3 receptor com-
pared to the H1 and H2 receptors (Table 1).
Incorporating similar substitution patterns in Series II
did not improve the binding affinity as much as in the
monocyclic pyrrolidine compounds, suggesting the
importance of the hydrogen on the 3-amino substituent
or the attenuated basicity of this series compared to
Series I as being critical for affinity at the H3 receptor.
As a result, these compounds were not evaluated against
H1 and H2 receptors.
16. Topliss, J. G. Perspect. Drug Disc. Des. 1993, 1, 253.
17. (a) Craig, P. N. In The Basis of Medicinal Chemistry;
Wolf, M. E., Ed.; Wiley-Interscience: New York, 1980; p 331.
(b) Austel, V. In Steric Effects in Drug Design; Charton, M.,
Motoc, I. Ed.; Lange and Springer: Berlin, 1984; p 8.
18. Wermuth, C. G. Agressologie 1966, 7, 213.
In conclusion, a novel series of H3 antagonists has been
identified commencing with ring-contracted analogues of
a screening hit, followed by systematic lead-optimization
exercises using pre-formatted precursor sets to generate
several extremely potent sulfonamide containing H3
antagonists. Detailed in vivo studies on compounds iden-
tified from this study will be reported in the near future.
19. Gentles, R.; Wodka, D.; Park, D. C.; Vasudevan, A. J.
Comb. Chem. In press.
20. Tozer, M. J.; Harper, E. A.; Kalindjian, S. B.; Pether,
M. J.; Shankley, N. P.; Watt, G. F. Bioorg. Med. Chem. Lett.
1999, 9, 1825.
References and Notes
21. Hancock, A. A.; Esbenshade, T. A. In Current Protocols
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