Bioorganic & Medicinal Chemistry Letters
Synthesis and SAR studies of benzimidazolone derivatives
as histamine H3-receptor antagonists
Qingbei Zeng, Stuart B. Rosenblum, Zhaoxia Yang, Yueheng Jiang, Kevin D. McCormick,
Robert G. Aslanian, Luli Duguma, Joseph A. Kozlowski, Neng-Yang Shih, John A. Hey, Robert E. West Jr.,
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Walter A. Korfmacher, Michael Berlin, Christopher W. Boyce
Merck Research Laboratories, 126 E. Lincoln Avenue, Rahway, NJ 07065, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Available online xxxx
A novel series of benzimidazolone-containing histamine H3-receptor antagonists were prepared and their
structure–activity relationship was explored. These benzimidazolone analogs demonstrate potent
H3-receptor binding affinities, no P450 enzyme inhibition, and strong H3 functional activity. Compound
Keywords:
1o exhibits the best overall profile with H3Ki = 0.95 nM and rat AUC = 12.9 lM h.
H3-antagonists
Benzimidazolone
P450 inhibition
Ó 2013 Elsevier Ltd. All rights reserved.
The H3 receptor is a G-protein coupled receptor in the histamine
receptor family. It was originally characterized as an autoreceptor
to regulate the synthesis and release of histamine from histaminer-
gic neurons.1 Thereafter it was also shown to mediate other neuro-
transmitters such as dopamine,2 serotonin,3 noradrenaline,4
GABA,5 and acetylcholine.6 Therefore, histamine H3 receptor li-
gands have been proposed as potential therapeutics for several
central nervous system (CNS) indications such as obesity, attention
deficit/hyperactivity disorder (ADHD), Alzheimer’s disease, and
schizophrenia.7
Known histamine H3 antagonists can be structurally divided
into imidazole (GT-2227, and SCH 79687) and nonimidazole-based
analogs (UCL 1972, Fig. 1).8 Although some of the imidazole-based
antagonists show good potency and acceptable exposure, they
have not advanced in the clinic because of their significant cyto-
chrome P450 (CYP) enzyme inhibition liability. SCH 79687 was
the first imidazole-based H3 antagonist lead from our laboratories.
While SCH 79687 showed excellent binding affinity, strong H3
functional activity, and good oral bioavailability,8c it also, unsur-
prisingly, significantly inhibited P450 enzymes and lowered cho-
lesterol levels in rat toxicology studies, and as a result, was not
advanced for development.
acceptable oral exposure in rats. In addition, many of them exhib-
ited unacceptable levels of CYP3A4 and CYP2D6 inhibition. This
communication details the structure–activity relationship (SAR)
of compounds of general structure 1 with significantly improved
enzyme profiles and pharmacokinetic properties.
The pharmacophore consists of four cyclic elements, that is, a
benzimidazol-2-one moiety, two piperidine rings, and a pyridine
heterocycle. The survey of a number of potential structural scaf-
folds on the right-hand side indicated that pyridine moiety is
essential to binding affinity. The key change was the introduction
of the 2-amino group in the pyridine which significantly improves
the P450 enzyme profile. With this discovery, we focused on the
modifications in the benzimidazol-2-one region to improve phar-
macokinetic profile.
The preparation of benzimidazol-2-one-based H3 antagonists of
type 1 is illustrated in Scheme 1. Commercially available amino-
pyridine 3 was protected as the di-N-tert-butoxycarbonyl (BOC)
derivative 4. Compound 4 was brominated under standard N-bro-
mosuccinimide (NBS) conditions to produce bromide 5, which, in
turn, was reacted with methyl isonipecotate to generate ester 6.
The hydrolysis of 6 with lithium hydroxide in tetrahydrofuran
(THF) and water provided lithium salt 7 for the further coupling
reactions without purification.
Diamines 8 were prepared conveniently from a substituted
nitrobenzene and ethyl 4-amino-1-piperidinecarboxylate accord-
ing to the literature method.10 When the diamines 8 were treated
with triphosgene in dichloromethane in the presence of triethyl-
amine at 0 °C, benzimidazolones 9 were obtained in good yields.
The available N-positions of benzimidazolones 9 were alkylated
under two different conditions. One method was the biphasic
In order to minimize the P450 enzyme liability, we decided to
explore a new class of nonimidazole analogs. In the previous com-
munication, a novel series of nonimidazole H3 antagonists (2,
Fig. 2) was reported.9 Although many of these antagonists showed
good in vitro activity, none of these compounds achieved an
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Corresponding author.
0960-894X/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.