Novel benzamide-based histamine H3 receptor antagonists: The identification of two candidates for clinical development

Article abstract of DOI:10.1021/ml5005156

The preclinical characterization of novel phenyl(piperazin-1-yl)methanones that are histamine H₃ receptor antagonists is described. The compounds described are high affinity histamine H₃ antagonists. Optimization of the physical properties of these histamine H₃ antagonists led to the discovery of several promising lead compounds, and extensive preclinical profiling aided in the identification of compounds with optimal duration of action for wake promoting activity. This led to the discovery of two development candidates for Phase I and Phase II clinical trials.

Full text of DOI:10.1021/ml5005156

Letter
pubs.acs.org/acsmedchemlett
Novel Benzamide-Based Histamine H3 Receptor Antagonists: The
Identification of Two Candidates for Clinical Development
Michael A. Letavic,* Leah Aluisio, Richard Apodaca, Manoj Bajpai, Ann J. Barbier, Anne Bonneville,
Pascal Bonaventure, Nicholas I. Carruthers, Christine Dugovic, Ian C. Fraser, Michelle L. Kramer,
Brian Lord, Timothy W. Lovenberg, Lilian Y. Li, Kiev S. Ly, Heather Mcallister, Neelakandha S. Mani,
Kirsten L. Morton, Anthony Ndifor, S. Diane Nepomuceno, Chennagiri R. Pandit, Steven B. Sands,
Chandra R. Shah, Jonathan E. Shelton, Sandra S. Snook, Devin M. Swanson, and Wei Xiao
Janssen Pharmaceutical Company, a division of Johnson & Johnson Pharmaceutical Research & Development L.L.C., 3210 Merryfield
Row, San Diego, California 92121, United States
S
* Supporting Information
ABSTRACT: The preclinical characterization of novel
phenyl(piperazin-1-yl)methanones that are histamine H3
receptor antagonists is described. The compounds described
are high affinity histamine H3 antagonists. Optimization of the
physical properties of these histamine H3 antagonists led to the
discovery of several promising lead compounds, and extensive
preclinical profiling aided in the identification of compounds
with optimal duration of action for wake promoting activity.
This led to the discovery of two development candidates for Phase I and Phase II clinical trials.
KEYWORDS: Histamine H3 antagonists, phenyl(piperazin-1-yl)methanones, histamine
ollowing the discovery that the histamine H3 receptor is
phospholipidosis, a phenomenon that has also been noted by
Fabundantly expressed in the brain, numerous research other researchers in the field.7,10
groups have investigated the effects of modulation of the
histamine H3 receptor on brain function. These efforts have
demonstrated that histamine H3 receptors regulate the sleep-
wake cycle and that histamine H3 antagonists promote wake
and have potential utility for the treatment of a variety of
indications, including excessive daytime sleepiness, narcolepsy,
and attention deficit hyperactivity disorder (ADHD), among
others.1 More recently, several pharmaceutical companies
embarked on medicinal chemistry efforts to advance histamine
H3 antagonists into the clinic for a variety of indications, and
numerous clinical trials have been conducted over the past 5−
As it is well-known that phospholipidosis can be associated
10 years. The details of these efforts have been reviewed
multiple times.1−6
with cationic amphiphilic drugs, efforts to generate optimized
histamine H3 antagonists with respect to physical properties
and duration of action were pursued in order to advance
compounds into the clinic devoid of phospholipidosis potential
while maintaining a duration of action appropriate for a
compound that promotes wakefulness. This report describes
one aspect of the progress toward those goals with a series of
phenyl(piperazin-1-yl)methanones.
Select examples of compounds that have been reported to
advance into the clinic include the GSK compound GSK-
189,254 (1), Pfizer’s PF-03654746 (2),7 A-331440 (3) from
Abbott, and JNJ-39220675 (4).8 Several of these compounds
have advanced into Phase II trials for therapeutic intervention
in narcolepsy, ADHD, and allergic rhinitis. To date, the most
advanced candidate appears to be pitolisant (5).9
Janssen’s efforts toward the preclinical characterization and
clinical development of histamine H3 antagonists have been
ongoing for quite some time. During this research a variety of
potent histamine H3 antagonists were discovered, and several
compounds advanced into preclinical toxicology studies.
However, while advancing these compounds it was noted that
some of the compounds induced varying degrees of
These piperazine amides shown were synthesized by one of
the two routes shown in Scheme 1. As such, 4-formylbenzoic
acid (6) was combined with tert-butyl piperazine-1-carboxylate
Received: December 18, 2014
Accepted: March 13, 2015
© XXXX American Chemical Society
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a
Scheme 1. Synthesis of Compounds 11
Table 1. Binding Data for the Human H3 Receptor for
Compounds 11
a
Reagents and conditions: (a) (dimethylamino)propyl)-3-ethylcarbo-
diimide hydrochloride, 1-hydroxybenzotriazole hydrate, N-methylmor-
pholine, tert-butyl piperazine-1-carboxylate, CH2Cl2; (b) R2R3NH,
HOAc, NaBH(OAc)3, CH2Cl2; (c) trifluoroacetic acid, CH2Cl2; (d)
various aldehydes, HOAc, NaBH(OAc)3, CH2Cl2; (e)
(dimethylamino)propyl)-3-ethylcarbodiimide hydrochloride, 1-hy-
droxybenzotriazole hydrate, various piperazines, CH2Cl2.
to form 7, which was then condensed with an amine to form 8.
Removal of the protecting group followed by a reductive
amination gave the desired compounds 11. Alternately, 4-
formylbenzoic acid reacts with a substituted piperazine to
directly install R1, and the resulting aldehyde 9 is converted to
the desired compounds 11 via reductive amination. The
required piperazines can be made from tert-butyl piperazine-
1-carboxylate by known methods.
The initial set of structures that were prepared were high
affinity compounds with human binding affinities of <100 nM
(11a−11d, Table 1).11 The histamine H3 receptor affinity
could be further improved by installing larger/more lipophilic
substituents on the benzyl amine (i.e., 11e−g); however, efforts
focused on the smallest/most polar groups that provided
sufficient histamine H3 affinity to move forward. This work led
to the preparation of the morpholine derivatives 11h−11j, all of
which are high affinity human histamine H3 antagonists. In
addition, since one focus of these efforts was to modify the
physical properties of our leads, a few 4-fluoropiperidines were
made (11k−11m) and were also found to be high affinity
antagonists. The morpholines 11h−j and the 4-fluoropiper-
idines 11k−m were expected to have pKas lower than the
piperidine 11g, and the 4-fluoropiperidines have the highest A
log Ps as shown in Table 1. As two examples, comparing 11g to
11h (piperidine vs morpholine) installation of the morpholine
lowers the A log P and the pKa of the benzyl nitrogen, whereas
comparing 11h to 11k (piperidine vs 4-fluoropiperidine) the A
log P is higher for the 4-fluoropiperidine and the calculated pKa
of the benzyl nitrogen is slightly lower.12
Next, focusing on the basicity of the piperazine nitrogen,
several cyclopropyl and cyclobutyl piperazines were prepared
and profiled. Again, high affinity compounds were obtained
(11i−11j, 11l−11m), and again, these changes (i.e., isopropyl
to cyclopropyl or cyclobutyl) were expected to modulate the
pKa of the piperazine nitrogen to which these groups were
attached.
a
b
Calculated A log P. Kis are the mean of at least three experiments in
c
d
triplicate, unless otherwise stated. n = 1 (in triplicate), n = 2 (in
Rat affinity data for a select group of the compounds in Table
1 as well as pA2 data in rat and human, which demonstrate that
the key compounds in this series are all high affinity histamine
H3 antagonists, are detailed in Table S1 in the Supporting
Information.
Table 2 shows liver microsomal stability, hERG data, and
Caco-2 data for some of the more interesting compounds that
were prepared. The compounds have moderate to high liver
microsomal stability, none have significant interactions with the
triplicate); Ki SD is reported.
hERG channel, and all compounds tested were highly
permeable with low to moderate efflux potential. Consequently,
these compounds were tested in vivo for oral exposure,
duration of action, and target engagement as measured by ex
vivo autoradiography.
In order to further demonstrate the specificity of these
compounds, 11g−j were also tested in a commercial panel of
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approximately ten times less basic than aliphatic amines;14
however no direct experimental evidence has been reported
(although one reported calculation corroborates the literature
suggestion).15 Illustrating the point, the measured pKa values
for 11j were significantly lower than that predicted through
calculation (using the Pallas software package from Compu-
Drug, Inc.) and also were significantly lower than that measured
for 11h and 11i. The data here corroborate literature
suggestions.
Next, key compounds were profiled for their ability to
distribute into the rat brain and bind to the histamine H3
receptor. To do this, drug was administered and drug
concentrations in the brain and plasma were measured along
with histamine H3 receptor occupancy. These data are shown in
Table 5. As shown, all the compounds were able to penetrate
Table 2. RLM and HLM Stability, and in Vivo Data for
Compounds 11g−m
a
b
c
d
compd
RLM stability
HLM stability
hERG
Caco-2
11g
11h
11i
n.d.
n.d.
>30 μM
>10 μM
>10 μM
>10 μM
>10 μM
>10 μM
>10 μM
12.4/14.8
22.4/20.9
71.2/22.4
108/37.8
n.d.
n.d.
65.0%
85.4%
96.1%
84.8%
n.d.
49.6%
44.1%
50.0%
n.d.
11j
11k
11l
n.d.
11m
26.8%
83.6%
n.d.
a
Stability in rat liver microsomes. Data reported as percent remaining
b
after a 15 min incubation. Stability in human liver microsomes. Data
c
reported as percent remaining after a 15 min incubation. hERG IC50
as measured in an [3H]-astemizole competition binding assay in HEK-
d
293 cells expressing the hERG channel. Data shown are Papp A−B/
B−A (×10−6) cm/s.
Table 5. Drug Levels in Rat Brain and Plasma and Levels of
ex Vivo H3 Receptor Occupancy for Compounds 11
50 ion channel, receptor, and transporter assays (Eurofins-
CEREP, http://www.eurofins.com/). None of the compounds
had any significant affinity (at 1 μM) for any of these targets.
Table 3 shows rat PK parameters for compounds 11g−m.
The i.v. t1/2s trend as expected. Comparing 11g with 11h, a
ac
,
bc
,
compd
conc. (brain)
R.O.
90
11g
11h
11i
0.48 0.14
5.37 1.09
8.10 0.53
2.54 0.36
1.82 0.51
0.54 0.14
2
1
2
8
2
86
96
58
92
11j
Table 3. Rat Pharmacokinetic Parameters for Compounds
11g−m
11k
11m
25 25
a
a
b
c
d
Concentration in μM at 1 h in brain following a 3 mg/kg p.o. dose.
Receptor Occupancy at 1 h Following a 3 mg/kp p.o. Dose. Mean
compd Cl (mL/min/kg)
Vss (L/kg)
t1/2 (h)
%F
52 26
62
b
c
11g
11h
11i
26.1 5.3
12.8 5.5
34.9 12.9
21.6 1.8
44.2 12.5
113.3 13.6
39.4 8.0
3.6 1.6
6.4 2.9
1.7 0.1
20.0 4.7
3.2 0.1
2.1 0.1
0.9 0.1
7.6 1.1
2.1 0.6
SD.
1
85 26
the brain and occupy the histamine H3 receptor.16 Distribution
into the brain varied, but the brain concentrations measured for
all compounds was high, and with the exception of compound
11m, all of the compounds in Table 5 showed good receptor
occupancy.
11j
112 35
11k
11l
29.2 10.2
20.3 5.2
3.9 1.7
17
7
31 41
11m
41.4 17.1
1.1 0.2
14 10
a
b
c
d
Clearance. Volume of distribution at steady state. i.v. half-life. All
Considering the overall rat PK and distribution parameters
observed, compounds 11g−k and 11m were all eventually
chosen for further profiling. Toward that end, time course ex
vivo H3 receptor occupancy data in rat was generated for these
compounds and are shown in Figure 1. This data provides an
indication of duration of action. Dose response related to
receptor occupancy is shown in Figure S1 and PK parameters
for canine and mouse are shown in Table S2 (detailed in the
Supporting Information). All of the compounds show robust
target engagement, and as expected based on the half-lives
reported in Table 3, the compounds had varying duration of
data are mean SD.
change from piperidine to morpholine substantially reduced the
half-life, and as expected, this appears to be driven primarily by
a reduction in Vss, which can be attributed to a reduction in log
P and pKa. Similarly, comparing 11h to 11j, the half-life is
reduced as the expected pKa is reduced even further.
The PK profile of both cyclobutyl compounds (11i and 11l)
appears to be influenced by a combination of log P, pKa, and
increased clearance, possibly due to oxidation of the cyclobutyl
group. Similar trends are observed with the 4-fluoropiperidine
compounds 11k−m.
The pKas, log Ps and log D7.4s of select compounds were
calculated in order to confirm earlier estimations. A summary of
this data is shown in Table 4.
The measured data confirmed the assumption that a
cyclopropyl substituent would substantially reduce the pKa
with little effect on log P, although as shown the calculated
pKa did not predict this observation.13 There is at least one
literature report that suggests that cyclopropyl amines are
Table 4. Physical Chemical Data for Compounds 11h−j
compd
pKa (calcd)
pKa (meas)
log P
log D7.4
11h
11i
11j
8.5, 6.2
7.8, 6.2
8.5, 6.2
7.6, 6.2
7.4, 6.5
6.5, 5.3
0.55
2.09
0.89
0.13
1.77
0.86
Figure 1. Ex vivo H3 receptor occupancy with compounds 11g−k and
11m at 3 mg/kg in rat striatum: time dependency after oral
administration.
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action. In addition, the PK trends in canine and mouse are
similar to those observed in rat. As an example, focusing on a
comparison of 11h and 11j, volume, clearance, and t1/2 were
reduced in both cases for 11j, which results in a reduced half-
life observed for 11j. Figure 1 compares compounds 11h and
11j demonstrating the shorter duration of action for the
cyclopropyl compound 11j.
Compounds 11a−11h were the first set of compounds to be
prepared and profiled; of that set it appeared that 11h had the
most desirable balance of potency, PK, target engagement, and
duration of action. Therefore, this was the first compound in
this series to be advanced into rat and dog safety toleration
studies.
In order to support preclinical toleration studies and other
first in human enabling studies, compound 11h was prepared
on larger scale by a slightly different synthetic route than the
one used to enable medicinal chemistry profiling. The synthesis
is described in detail in the Supporting Information.
Compound 11h is a BCS Class I nonhygroscopic crystalline
solid as the bis-maleate salt. It has a very high free fraction in
human plasma (% bound 12.4%), and no CYP interactions
were noted (IC50s all >40 μM at CYP 1A2, 2C9, 2C19, 2D6,
and 3A4). Numerous additional in vitro and in vivo safety
studies were completed in order to support potential first in
human studies, and a summary of those studies is reported
here.
In rats, after oral administration, 11h penetrates the blood−
brain barrier and occupied histamine H3 receptor sites. As
expected for this class of compound, administration of 11h in
rats during the light sleep phase produced a significant increase
in time spent awake (∼1 h) during the first 6 h post-treatment,
and this was associated with a decrease in NREM sleep
duration while REM sleep was not affected (Figure S2 in the
Supporting Information). This occurred in the absence of any
increase in locomotor activity and differentiates the compound
from amphetamine like stimulants. Administration of 11h also
increased acetylcholine (ACh) levels in the frontal cortex of
freely moving rats and in a 7-trial passive avoidance model, 11h
decreased the number of trials needed to increase the latency to
enter the aversive chamber, consistent with pro-cognitive effects
(data not shown).
Compound 11h had no effect in models predictive of
cardiovascular toxicity, including hERG channel binding and
models of QTc prolongation. Overall, the compound was well
tolerated in the mouse, rat, and dog. Administration of up to
250 mg/kg of 11h orally to rats for up to 28 days induced mild
and sporadic salivation and decreased activity. Minor decreases
in body weight, food consumption, and clinical pathology
alterations were considered related to 11h treatment but
nonadverse. The rat NOAEL was 25 mg/kg/day. In dogs,
administration of 11h for 5 days within the dose range of 10 to
75 mg/kg/day resulted in no adverse findings. These data
supported progression to first in human studies. In human, the
mean elimination half-life for the 2 and 5 mg dose groups of
11h was 49.1 and 56.1 h, respectively. Given these data, and
that fact that significant insomnia was reported upon dose
escalation, the team looked for back-up compounds with
significantly reduced duration of action.
human liver microsomes, 11j is not a potent inhibitor of the
various CYPs. In rats, 11j penetrates the blood−brain barrier
after systemic administration and effectively occupies histamine
H3 receptor sites (>80% receptor occupancy at 10 mg/kg SC,
corresponding to a maximum plasma concentration [Cmax] of
1933 ng/mL) (Figure S1, Supporting Information). Therefore,
the anticipated plasma concentration for maximal receptor
occupancy in humans was anticipated to be approximately 200
ng/mL as the potency of 11j is about 10-fold higher for the
human receptor than for the rat receptor.
In the rat, the administration of 11j resulted in a significant
increase in time spent awake, an increase in acetylcholine
(ACh) levels in frontal cortex, and pro-cognitive effects in a 7-
trial passive avoidance model.
Compound 11j was devoid of any cardiovascular liability in
preclinical species including QTc prolongation. The compound
(Bavisant) was also well tolerated in rats and dogs and the
safety margins supported first in human dosing for this
compound. No evidence of phospolipidosis was observed in
these studies. Following single oral doses, 11j was rapidly
absorbed with peak concentrations observed 0.5 to 4 h
postdose. The Cmax increased dose-proportionally over 100 to
400 mg. The area under the concentration−time curve
extrapolated to infinity (AUCinf) was dose-proportional
between 10 and 30 mg and in the 100 to 400 mg dose
range. The mean t1/2 ranged from 13.9 to 22.1 h. The reduced
human t1/2 observed with 11j validates our assertion that
reduced duration of action in human could be achieved by
modification of the physical properties of this series of H3
antagonists.
In conclusion, we identified a series of novel, potent
histamine H3 antagonists that demonstrated that improved
human pharmacokinetic profiles can be obtained by tuning the
physical properties of these ligands in order to reduce tissue
retention time and t1/2 in vivo. Optimization of these ligands
led to the discovery of Bavisant, a histamine H3 ligand useful for
clinical investigation of the utility of histamine H3 antagonists.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental details and analytical data for compounds 11a−
m, additional Figures and Tables. This material is available free
of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: mletavic@its.jnj.com. Tel: 1-858-450-2302.
■
Author Contributions
The manuscript was written through contributions of all
authors.
Notes
The authors declare no competing financial interest.
ABBREVIATIONS
ADHD, attention deficit hyperactivity disorder; i-Pr, isopropyl;
c-Pr, cyclopropyl; c-Bu, cyclobutyl; CYPs, cytochrome P450s
■
One such compound, 11j, appeared promising since this
compound had significantly reduced duration of action in all
preclinical species (Tables 3 and S2 (Supporting Information),
and Figure 1). Compound 11j is also a BCS Class I
nonhygroscopic crystalline solid as the bis-HCl salt. In
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