Identification of biaryl sulfone derivatives as antagonists of the histamine H3 receptor: Discovery of (R)-1-(2-(4′-(3- methoxypropylsulfonyl)biphenyl-4-yl)ethyl)-2-methylpyrrolidine (APD916)

Article abstract of DOI:10.1016/j.bmcl.2011.11.075

The design of a new clinical candidate histamine-H₃ receptor antagonist for the potential treatment of excessive daytime sleepiness (EDS) is described. Phenethyl-R-2-methylpyrrolidine containing biphenylsulfonamide compounds were modified by re

Full text of DOI:10.1016/j.bmcl.2011.11.075

Bioorganic & Medicinal Chemistry Letters 22 (2012) 71–75
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Identification of biaryl sulfone derivatives as antagonists of the histamine
H3 receptor: Discovery of (R)-1-(2-(40-(3-methoxypropylsulfonyl)biphenyl-
4-yl)ethyl)-2-methylpyrrolidine (APD916)
⇑
Graeme Semple , Vincent J. Santora, Jeffrey M. Smith, Jonathan A. Covel, Rena Hayashi,
Charlemagne Gallardo, Jason B. Ibarra, Jeffrey A. Schultz, Douglas M. Park, Scott A. Estrada,
Brian J. Hofilena, Brian M. Smith, Albert Ren, Marissa Suarez, John Frazer, Jeffrey E. Edwards,
Ryan Hart, Erin K. Hauser, Jodie Lorea, Andrew J. Grottick
Arena Pharmaceuticals, 6166 Nancy Ridge Drive, San Diego, CA 92121, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The design of a new clinical candidate histamine-H3 receptor antagonist for the potential treatment of
excessive daytime sleepiness (EDS) is described. Phenethyl-R-2-methylpyrrolidine containing biphenyl-
sulfonamide compounds were modified by replacement of the sulfonamide linkage with a sulfone. One
compound from this series, 2j (APD916) increased wakefulness in rodents as measured by polysomnog-
raphy with a duration of effect consistent with its pharmacokinetic properties. The identification of a
suitable salt form of 2j allowed it to be selected for further development.
Received 24 October 2011
Revised 14 November 2011
Accepted 18 November 2011
Available online 30 November 2011
Keywords:
Histamine-H3 antagonist
Sleep
Ó 2011 Elsevier Ltd. All rights reserved.
Wakefulness
CNS
hERG
Clinical candidate
The biogenic amine histamine acts through four distinct G-pro-
tein coupled receptors (GPCR’s, H1–H4)1 to modulate a diverse
range of biological functions both in the brain and in the periphery.
One central role of histamine is in the modulation of sleep and
wake states, as demonstrated by the close relationship between
the firing rate of histamine neurons and the sleep–wake cycle.2
Brain permeable H1 receptor antagonists are sedative, suggesting
that the sleep-promoting effects of histamine are largely mediated
by the H1 receptor. H3 receptors on the other hand are located pre-
synaptically in the CNS and regulate histamine synthesis and
release through a process of negative feedback. Hence, inhibiting
H3 receptor function increases histamine release and H1 receptor
activation leading to increased wakefulness.3 The H3 receptor also
acts as a heteroreceptor to influence the release of other neuro-
transmitters such as noradrenaline, serotonin, dopamine, gluta-
mine, GABA, and acetylcholine.4 Recently, the wakefulness effects
of an H3 receptor antagonist have been demonstrated in human
subjects with a compound shown to have similar effects in preclin-
ical species.5
Multiple structurally diverse series of H3 antagonists have been
described6 and we have previously reported the design of a series
of biphenyl sulfonamide compounds incorporating a phenethyl-
R-2-methylpyrrolidine moiety (1, Fig. 1) as potent and selective
antagonists of the H3 receptor.7 Compounds of this type however
all generated, to a greater or lesser extent, a common metabolite
in rodents in vivo. This metabolite (the primary sulfonamide, i.e.,
1, R = H) had significant inverse agonist activity at the H3 receptor,
a long pharmacokinetic half life in rat, and accumulated in brain
tissue. As a consequence the profile of the sulfonamide series did
not fit with our objective of a short duration of action so as to avoid
the potential for extended duration pharmacology that may lead to
insomnia in patients. We therefore looked for an alternative series
of compounds that could not be metabolized by simple alkyl cleav-
age from the sulfonamide in the same fashion, and chose to target
the closely analogous sulfone derivatives 2.
The two general methods for the synthesis of our initial series of
sulfone derivatives are outlined in Scheme 1. (R)-4-(2-(2-Methyl-
pyrrolidin-1-yl)ethyl)phenylboronic acid 5, was prepared as previ-
ously described,7 and this intermediate underwent Suzuki coupling
with bromo-aryl sulfones 8, that in general were prepared by
simple alkylation of 4-bromobenzenethiol (6) and oxidation of
the resultant thioether 7, with either 3-chloro perbenzoic acid
⇑
Corresponding author. Tel.: +1 858 453 7200; fax: +1 858 453 7210.
E-mail address: gsemple@arenapharm.com (G. Semple).
0960-894X/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2011.11.075

72
G. Semple et al. / Bioorg. Med. Chem. Lett. 22 (2012) 71–75
into the alkyl chains. We therefore prepared a series of such ana-
logues in the sulfone series which indeed reduced hERG channel
inhibition, but which retained high affinity for rat H3 receptor
(Table 1). Of the linear analogues, 2g–k, in addition to 2a, appeared
to have the most promising early profiles. An additional linear
ether analogue, 2o had somewhat lower affinity for the rat H3
receptor and was not pursued further. A number of cyclic ether
analogues (2l–n) were also prepared but at least in the case of 2l,
the issues with hERG channel activity resurfaced.
N
N
As had been observed previously with several series,9 the
enantiomeric analogues, in which the 2-methylpyrrolidine was of
the S-configuration, had significantly lower H3-receptor affinity
(e.g., S-antipode of 2g, Ki = 13.2 nM, n = 4; S.D. = 0.41).
O
HN
S
O
R
O
S
R
O
2
1
At this stage we had also begun testing compounds in an
acute rat behavioral assay. In this assay,10 prevention of H3 agonist
Figure 1. Biphenyl sulfones 2 were designed using knowledge of the metabolism of
the previously reported biaryl sulfonamides 1.
(R)-a-methyl histamine (RAMH)-induced dipsogenia by pre-
administration with an H3 antagonist is assessed. When the antag-
onist is dosed per orally, the model can be used to rapidly assess a
combination of both oral bioavailability and brain partitioning.
Hence, test compounds were administered to rats 0.5 h prior to
injection of RAMH (10 mg/kg, SC) and the volume of water con-
sumed over a 20-min period measured. A significant inhibition of
agonist-induced drinking was observed for all compounds at either
of the two screening doses, 1 or 0.3 mg/kg PO (Table 1, see also
Figure 2 for 2g and 2j). Thus, a number of compounds remained
of interest for further progression, having been shown to be func-
tional antagonists of the H3 receptor in vivo while maintaining an
adequate hERG profile. As we had previously decided that the
pharmacokinetic profile of any compound selected would be para-
mount, and moreover that compound exposure should mirror the
in vivo pharmacodynamic antagonist effect in duration, we next
examined the PK profiles of a number of compounds using two
methods. The first was a routine examination of the PK parameters
after both IV and PO administration to rats. The second assessed
brain/plasma (b/p) partitioning of test compounds at 0.75, 1 and
2 h post dose using three animals at each time point. The estimate
of b/p ratios, as shown in Table 2, was taken from the mean of all
nine such b/p determinations for each compound.
(mCPBA) or oxoneÒ. Alternatively, in the few cases where the boro-
nic acid was commercially available, the Suzuki coupling was per-
formed in the opposite sense, whereby the bromide 4 was coupled
with the requisite arylsulfone boronic acid.
We first prepared a number of simple alkyl sulfones (Table 1).
These compounds had comparable binding affinity for the rat H3
receptor (using an isolated rat cortex preparation) with the
sulfonamide series.7 As was also previously observed, a range of
different sized groups in this position were all well tolerated and
did little to affect binding affinity. The prototypical compound 2a
was also only a weak inhibitor of the hERG channel (Table 1), an
off target activity that has plagued some of our previous efforts
to identify compounds of interest.7,8 As with the sulfonamide ser-
ies, increasing the size of the alkyl group R maintained excellent
affinity for the rat H3 receptor, but caused a significant increase
in hERG channel interaction such that all of the other simple alkyl
and benzyl examples tested significantly inhibited hERG channel
activity in a patch clamp assay at 3 lM. Our previous experience
with the sulfonamide series suggested that hERG inhibition could
be decreased by the incorporation of ether or alcohol substituents
SH
OH
(v)
R
Br
S
Br
Br
3
6
7
8
(i)
(vi)
O
S
N
Br
R
O
Br
4
(iv)
(ii)
N
N
(iii)
HO
B
O
S
O
2
R
OH
5
Scheme 1. Synthesis of biphenyl sulfone derivatives. Reagents and conditions: (i) (a) MsCl, DIEA, DCM; (b) (R)-2-methylpyrrolidine, Na2CO3, CH3CN,
D; (ii) (a) nBuLi, THF,
ꢀ78 °C; b) (iPrO)3B, ꢀ78 °C to rt; (iii) 8, Pd(PPh3)4, EtOH, benzene, microwave heating; 20–70% yield; (iv) 4-RSO2Ph-B(OH)2, Pd(PPh3)4, EtOH, benzene, microwave heating 20–
40% yield; (v) RBr, NaH, DMF; >80% yield; (vi) mCPBA, DCM; >90% yield.

G. Semple et al. / Bioorg. Med. Chem. Lett. 22 (2012) 71–75
73
Table 1
Receptor binding affinity, hERG screening data and in vivo efficacy for sulfone analogues
Compound
R
Rat H3 Ki (nM)
n
LogS.D.
hERG inhibition
[% @ 3 lM, n = 2] (IC50)
MED in RAMHa
(mg/kg PO)
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
2o
–Me
1.3
0.9
0.6
2.65
0.6
1.0
1.4
1.2
1.0
0.7
0.8
0.17
1.1
0.2
2.44
6
6
3
3
3
3
20
10
6
24
9
6
3
3
0.20
0.22
0.10
0.06
0.11
0.17
0.30
0.11
0.19
0.32
0.28
0.27
0.22
0.20
0.15
13
75
73
65
0.3
0.3
0.3
n.d.
n.d.
n.d.
0.3
1
0.3
0.3
1
0.3
1
–Et
–nPr
–iPr
–CH2Ph
95
–cPent
n.d.
29 (7.4
25 (7.7
45
14 (11
(>30
64 (3.1
n.d.
n.d.
n.d.
–(CH2)2OMe
–(CH2)2OH
–(CH2)2OEt
–(CH2)3OMe
–(CH2)3OH
–CH2(4-THP)
–(4-THP)-
CH2(2-THP)
–CH2OMe
l
l
M)
M)
lM)
l
M)
l
M)
n.d.
n.d.
3
n.d. = not determined.
a
Minimum efficacious dose to fully inhibit drinking response induced by SC administration of the H3 agonist RAMH (R-a-methylhistamine).
brain in our screening assay (Table 2). At this stage we favored 2j
based on its modestly higher dose-adjusted Cmax and somewhat
greater b/p ratio and as this compound had moderate plasma pro-
tein binding (74% in both rat and human plasma) we expected that
a significant portion of the whole brain concentration would be
unbound.
Further experiments confirmed that both 2j and 2g completely
prevented the RAMH-induced drinking response after oral doses of
0.3 mg/kg but not 0.1 mg/kg, where both compounds showed only
a partial effect. At the 0.3 mg/kg dose in rat, the brain concentra-
tion of 2j at the 1 h time point (the time approximately coinciding
with the measurement of the drinking effect) was measured to be
17 ng/mg tissue. Assuming that the free fraction in brain was
approximately equal to that in plasma, this would provide a free
concentration of 9–10 nM in brain. Based on the binding Ki for
the rat receptor of 0.7 nM, this concentration in brain should pro-
vide >90% receptor occupancy.
Compounds 2j and 2g were then progressed into the first dura-
tion of action study which again used the RAMH-induced drinking
assay. In this paradigm the compounds were dosed orally (0.6 mg/
kg; i.e., twice the minimum fully efficacious dose) at selected time
points prior to injection of RAMH. The inhibition of RAMH-induced
drinking diminished with increasing time before injection of the
agonist, from maximal inhibition at the 0.5 and 1 h time points
to less than 20% inhibition when RAMH was injected 6 h post
administration of either 2g or 2j (Fig. 3), leading us to conclude
that the pharmacodynamic profile of both of these compounds
showed a good correlation with the pharmacokinetic profile of
3.0
2.5
2.0
1.5
1.0
0.5
0.0
**
VEH VEH 2j 2g
0.3 mg/kg PO
RAMH
Figure 2. Attenuation of RAMH-induced polydipsia in the rat with an acute 0.3 mg/
kg dose of either 2j or 2g. Bars represent means SEM. ⁄⁄p <0.01.
The prototypical compound 2a was shown to have good brain
partitioning and excellent oral bioavailability in these studies.
However, the compound had a high volume of distribution and
somewhat long half life (Table 2). In addition, there was a clear de-
lay in the time to achieve Cmax after oral administration. Thus we
did not believe that this compound would have the appropriate
PK profile for our selected indication. Both the volume of distribu-
tion and the plasma half-life could be reduced by increasing the
size of the sulfone substituent. However, as has already been noted
above, these modifications generally increased hERG inhibition.
Interestingly, 2c was rapidly converted to the hydroxylated ana-
logue 2k in vivo, such that the parent compound was barely ob-
served in plasma. Although 2k was seen to be cleared relatively
rapidly, the delay in Tmax and the modest brain partitioning meant
that we did not consider dosing of 2c as a prodrug of 2k to be a via-
ble approach.
short Tmax and moderate T .
½
We were finally able to differentiate between the two com-
pounds by their cross-species metabolism and PK profiles. In these
studies, 2j had good to excellent oral bioavailability and a pharma-
cokinetic half-life in dog, monkey, and mouse (Table 3) which
would predict suitability for once daily oral administration in hu-
man. For both compounds however, two major metabolites were
identified that were common to all species following oral adminis-
tration. The first, resulting from oxidative cleavage of the methyl
pyrrolidine moiety to produce the phenyl acetic acid derivatives
was of little concern as neither had any affinity for the H3 receptor
(see Supplementary data). The second metabolite, resulting from
simple demethylation of the ether group (i.e., 2k was generated
from 2j and 2h was generated from 2g), were most predominant
in mouse and rat and exposure was much higher for 2h (2k mea-
sured as 52% of the AUC of 2j in mouse and 27% in rat; 2h measured
as 145% of the AUC of 2g in mouse and 100% in rat). As these com-
Dosing of the two ether analogues 2g and 2j that had each sat-
isfied both the in vitro and in vivo activity and hERG selectivity
requirements, showed them both to be rapidly adsorbed with
moderate elimination half-lives and significantly lower volumes
of distribution than the prototype antagonist in this series, 2a. In
addition both compounds showed excellent partitioning into the

74
G. Semple et al. / Bioorg. Med. Chem. Lett. 22 (2012) 71–75
Table 2
PK parameters for selected compounds in rat
Compound
Dose (mg/Kg)
Tmax (h)
Plasma Cmax
(lg/mL)
iv T1/2 (h)
Vss (L)
%Fc
b/pa (dose, mg/kg)
2a
2b
2c
2g
2h
2j
10
3
3
10
1
3
4
0.218
0.057
0.006
0.184
0.122
0.104
0.449b
3.6
1.4
0.3
0.7
3.2
1.9
—
19.8
14.3
5.9
7.6
5.0
7.5
—
ꢁ100
46
3.03 (10)
1.75 (3)
- (3)
0.3
0.1
0.3
0.5
0.5
3b
<0.1
68.5
53.6
27.3
—
1.73 (10)
0.72 (1)
3.3 (3)
2k
—
0.7 (N.A.b)
N.A. = Not Applicable.
a
Mean of ratio of brain (lg/mg) and plasma (lg/mL) concentration at 3 time points (0.75, 1.5 and 3 h) following a 3 mg/kg PO dose.
Parameters for exposure of 2k following administration of 2c (3 mg/kg PO).
Bioavailability based on the ratio of AUCpo/AUCiv.
b
c
3.0
2.5
2.0
1.5
1.0
0.5
0.0
3.0
2.5
2.0
1.5
1.0
0.5
0.0
*
*
**
**
VEH VEH 0.5
time after 2j (hr)
RAMH + 2j (0.6 mg/kg)
2
4
6
VEH VEH 0.5
2
4
6
time after 2g (hr)
RAMH + 2g (0.6 mg/kg)
Figure 3. Blockade of RAMH-induced polydipsia over time after an acute 0.3 mg/kg dose of 2g (left panel) and 2j (right panel). Bars represent means SEM. ⁄p <0.05, ⁄⁄p
<0.01.
pounds were active at the receptor, it is conceivable, particularly in
the case of 2h, that they would have made some contribution to
the pharmacological effect in these species. Both metabolites 2h
and 2k were cleared at approximately the same rate as the parent
so the risk of accumulation was deemed to be low. Fortunately,
whereas the active metabolites were rather abundant in rodents,
only very low levels (<5% AUC of parent) of 2k were observed in
dog and monkey, whereas the exposure of the metabolite 2h fol-
lowing dosing of 2g remained significantly higher in both these
species (20% and 12% of 2g in monkey and dog, respectively).
Unfortunately because of the very low turnover of 2j in liver micro-
Compound 2j was tested for its ability to increase wakefulness in
the rat using subjects implanted with chronically indwelling corti-
cal electrodes. Specifically, 2j was administered orally at the same
dose as in the antagonist duration of action study (0.6 mg/kg) dur-
ing the animals subjective night (approximately four hours after
lights on) and wake time measured over an 8 h period. As can be
seen in Fig. 4, 2j increased total wake time significantly during
the first 2 h after administration, but consistent with the data ob-
tained from the in vivo antagonist duration of action experiments,
the effect was no longer significant at the 4 h time point and be-
yond. A dose response study (data not shown) also confirmed that
0.3 mg/kg was the minimum efficacious dose to increase wakeful-
ness over the first 1 h, however the effect was not significant at this
dose if the first 2 h were taken into consideration. Thus, we believed
that we had demonstrated that 2j was a potent but relatively short
acting antagonist of the histamine H3 receptor that was able to in-
crease wakefulness in the rat after oral administration.
somes from any species (T >1 h in all species), any correlation to
½
provide an estimate of how much of the active metabolite 2k may
be generated in human was not possible, but the risk of observing
any contribution of the metabolite to a pharmacological effect in
human was regarded as very low for 2j but of moderately higher
risk for 2g based on the data from the cross species PK experi-
ments. We therefore elected to move 2j forward for further
profiling.
As all the screening thus far had used rat tissue binding, we next
tested the affinity of 2j for the cloned human H3 receptor and con-
Table 3
Selected PK parameters for 2j in 4 species
Species
PO Dose (mg/kg)
Tmax (hr)
Cmax
(lg/mL)
T1/2 (hr)
%Fb
Cl (L/hr/kg) (% of HBF)a
Vss (L/kg)
Mouse
Rat
Monkey
Dog
3
3
3
3
1.0
0.5
2.3
0.8
0.08
0.10
0.55
0.60
1.5
1.9
6.9
5.0
35.4
27.3
67.5
ꢁ100
4.36 (78%)
4.46 (106%)
0.37 (14%)
0.82 (43%)
2.54
7.54
2.16
2.89
a
% of hepatic blood flow in each species.
Bioavailability based on the ratio of AUCpo/AUCiv. The iv dose in each species was 2 mg/kg.
b

G. Semple et al. / Bioorg. Med. Chem. Lett. 22 (2012) 71–75
75
60
50
40
30
20
10
0
process we identified only two solid products that were character-
ized as a citrate salt (poorly crystalline, mp ꢁ100 °C) and a dicitrate
salt that in early studies was a highly soluble (>150 mg/mL in
water), non-hygroscopic and highly crystalline salt of sufficiently
high melting point (148–150 °C) for further development. It was
also demonstrated that the in vivo antagonist effect of the dicitrate
and hydrochloride salts were identical (see Supplementary data).
We were initially concerned about the physical integrity of this
unusual salt form under stress conditions, but we observed no
change in the PXRD pattern after grinding with a mortar and pestle
(see Supplementary data), including in the presence of a range of
excipients. In addition, the stability of the salt form was further
confirmed by compressing the ground salt at high pressure to mi-
mic a tableting process and on particle size reduction (Fitz mill,
8000 rpm, 20 mesh screen). Finally, slurrying of the crystalline
material with a range of solvents (40 °C, 4 days) did not induce a
change in crystalline form as assessed by PXRD, DSC or IR.
**
1
2
3
4
5
6
7
8
time relative to injection of 2j (hr)
Figure 4. Effect of 2j (0.6 mg/kg PO) on wakefulness in the rat over an eight hour
period. Bars represent means SEM. ⁄⁄p <0.01, vehicle (s), 2j (d).
Thus, having identified a viable salt form and with positive
pharmacology data in hand that matched the pharmacokinetic
profile appropriately, 2j (APD916) was selected for preclinical
development and was eventually progressed into clinical studies.
The results of these studies and a further, more extensive pharma-
cological profile will be reported elsewhere.11
firmed that it was in a similar range to that observed for the rat
(human H3 Ki = 4.2 1.6 nM; n = 3). In addition, in a functional as-
say (GTPcS binding) also using the cloned human H3 receptor, 2j
behaved as a potent full inverse agonist (IC50 = 0.7 nM; n = 2).
Broader testing against a standard panel of 80 receptors (that in-
cluded the closely related histamine H1, H2 and H4 receptors) re-
vealed no binding in excess of 50% of control, at a concentration
Supplementary data
of 10
Compound 2j did not inhibit any of the five major CYP isoforms
(IC50 >40 M), showed no mutagenic potential in a micro-Ames
test, and was only a moderate inhibitor of the hERG channel in a
patch clamp assay (IC50 = 11 M; n = 2). In dose-escalating PK
lM, for any other target tested.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2011.11.075.
l
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l
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