Novel H3 receptor antagonists with improved pharmacokinetic profiles

Article abstract of DOI:10.1016/j.bmcl.2008.05.086

A new series of H₃ antagonists derived from the natural product Conessine are presented. Several compounds from these new series retain the potency and selectivity of earlier diamine based analogs while exhibiting improved PK characteristics. O

Full text of DOI:10.1016/j.bmcl.2008.05.086

Bioorganic & Medicinal Chemistry Letters 18 (2008) 4133–4136
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Novel H3 receptor antagonists with improved pharmacokinetic profiles
a
a
a
a
Vincent J. Santora a, , Jonathan A. Covel , Rena Hayashi , Brian J. Hofilena , Jason B. Ibarra ,
Michelle D. Pulley a, Michael I. Weinhouse a, Graeme Semple a, Albert Ren a, Guilherme Pereira a,
Jeffrey E. Edwards b, Marissa Suarez c, John Frazer c, William Thomsen c, Erin Hauser c, Jodie Lorea c,
Andrew J. Grottick c
*
a Medicinal Chemistry, Arena Pharmaceuticals, 6166 Nancy Ridge Drive, San Diego, CA 92121, USA
b Drug Metabolism and Pharmacokinetics, Arena Pharmaceuticals, 6166 Nancy Ridge Drive, San Diego, CA 92121, USA
c Discovery Biology, 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:
A new series of H3 antagonists derived from the natural product Conessine are presented. Several com-
pounds from these new series retain the potency and selectivity of earlier diamine based analogs while
exhibiting improved PK characteristics. One compound (3u) demonstrated functional antagonism of the
H3 receptor in an in vivo pharmacological model.
Received 14 April 2008
Revised 20 May 2008
Accepted 21 May 2008
Available online 24 May 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Histamine
H3 antagonist
The histamine H3 receptor is one of four members of the G-pro-
tein coupled receptor (GPCR) super-family which bind histamine.1
H3 receptors are expressed primarily on presynaptic neurons of the
central nervous system (CNS) where they regulate the synthesis
and release of several neurotransmitters including histamine, ace-
tylcholine, dopamine and serotonin.2 The central role of H3 recep-
tors in these signaling pathways has led to a significant effort to
develop H3 antagonists as potential treatments for a diverse collec-
tion of CNS related disorders.3 Several H3 antagonists are currently
being investigated in clinical trials,4 and preliminary results sug-
gest that an H3 antagonist can increase wakefulness in narcolepsy
patients.5
We recently reported early data from our effort to develop no-
vel H3 antagonists/inverse agonists as wake promoting agents.6
Utilizing the known H3 antagonist natural product Conessine (1)7
as a structural starting point, we prepared a series of simplified
diamines, exemplified by 2, which exhibited potent antagonism
and inverse agonism of the H3 receptor (Chart 1). While diamines
such as 2 were suitable for preliminary in vivo studies, they fre-
quently exhibited delayed absorption and long half-lives. We con-
sidered these characteristics less than ideal in a potential wake
promoter and sought to develop new compounds in this series
with pharmacokinetic (PK) profiles more consistent with our goal
of developing a rapidly absorbed, short-acting drug. We have pre-
viously demonstrated that the basic phenethylamine portion of
these compounds is required for activity at the H3 receptor,6 and
describe here the effect of changes in the bicyclic core on H3 recep-
tor binding, PK characteristics and in vivo activity.
Alteration of the bicyclic portion of these molecules was exam-
ined in analogs 3a–o (Scheme 1). Previously described single iso-
mer bicyclic ketone 46 was reacted with the lithium reagent
derived from 4-bromo-phenethylpyrrolidine 6a to give the alcohol
derivative 7a. Deprotection of the N-benzyl group of 7a followed
by dehydration with HCl provided diamine 8a. Subsequent reac-
tion of 8a with various acid chlorides, sulfonyl chlorides or isocya-
nates provided the amide, sulfonamide and urea analogs 3a–o,
which contained the preferred (3aR, 6aR) stereochemistry found
in our earlier studies.
Compounds 3a–o were tested in a rat cortex N-[3H]-methylhis-
tamine displacement assay,8 the results of which are shown in
Table 1. It was readily apparent that the new analogs were signif-
icantly less potent H3 antagonists than the diamines prepared in
our earlier study. For example, the urea derivatives 3a–d, whose
Ki’s ranged from 12 to 20 nM, and the sulfonamide analogs 3e–h
(Ki = 12–27 nM) were approximately 200-fold less potent than dia-
mine 2. With the exception of phenyl amide 3i (Ki = 21 nM), the
amide analogs 3j–o (Ki = 3–7 nM) were slightly more potent than
either the ureas or sulfonamides and approximately 70-times less
potent than diamine 2. Notwithstanding the differences observed
between various functional groups, no significant potency trends
were observed within the amide, urea or sulfonamide series.
In order to focus subsequent efforts on compounds with prom-
ising in vivo characteristics, the PK properties of several com-
* Corresponding author. Tel.: +1 858 453 7200; fax: +1 858 453 7210.
E-mail address: vsantora@arenapharm.com (V.J. Santora).
0960-894X/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2008.05.086

4134
V. J. Santora et al. / Bioorg. Med. Chem. Lett. 18 (2008) 4133–4136
Chart 1. Structure of conessine and representative H3 antagonists.
Scheme 1. Synthesis of target compounds 3. Reagents and conditions: (a) CH3SO2Cl, Et3N, CH2Cl2, 0 °C, 95%; (b) pyrrolidine or 2-R-methylpyrrolidine, K2CO3, CH3CN, 25 °C,
65–70%; (c) n-BuLi, THF, À78 °C, 60–64%; (d) ammonium formate, Pd(OH)2/C, MeOH, 96–98%; (e) HCl, i-PrOH, 60 °C, 98%; (f) i—R2NCO, CH2Cl2, 25 °C, 29–40%; or ii—RSO2Cl,
CH2Cl2, Et3N, 25 °C, 31–43%; or iii—RCOCl, CH2Cl2, Et3N, 25 °C, 32–46%.
Table 1
Binding affinities (Ki and pKi) of compounds 3a–r at rat H3 receptora
R1
R2
N
N
Compound
R1
R2
H
Rat H3Kib (nM)
Rat pKib
2
0.07 (h Antag. = 0.9, Inverse Ag. = 1.0)c
10.17 0.21
3a
H
20
7.69 0.15
O
NH
3b
3c
H
H
16
13
7.78 0.38
7.89 0.10
O
O
NH
N
O
3d
3e
H
H
12
27
7.91 0.13
7.56 0.16
O
O
N
O
S
S
3f
H
H
12
12
7.92 0.26
7.93 0.16
O
O
3g
O S O
3h
3i
H
H
H
17
21
6
7.77 0.03
7.67 0.26
8.21 0.04
O
O
S O
N
3j
O

V. J. Santora et al. / Bioorg. Med. Chem. Lett. 18 (2008) 4133–4136
4135
Table 1 (continued)
Compound
R1
R2
H
Rat H3Kib (nM)
Rat pKib
3k
7
8.15 0.08
O
O
3l
H
H
H
5
3
4
8.26 0.16
8.49 0.17
8.42 0.10
O
O
3m
3n
O
OH
3o
3p
H
6
8.20 0.22
9.42 0.21
O
O
CH3
0.4
O
O
3q
3r
3s
CH3
CH3
CH3
0.4
3
9.46 0.19
8.57 0.13
8.97 0.18
N
1
O
3t
CH3
CH3
0.3
9.53 0.14
9.13 0.23
O
O
O
3u
0.7 (h Antag. = 2, Inverse Ag. = 4)c
a
Displacement of N-[3H]-methylhistamine from rat cortex membranes.6
b
c
Values are reported as average of n P 3 independent measurements for all compounds. Errors are logSD.
Antagonism determined by displacement of [3H] R(À)-
a-methylhistamine from recombinant CHO–K1 cells expressing the human H3 receptor (n = 1). Inverse agonism
determined by GTPc
S binding in CHO–K1 cells expressing the human H3 receptor in the absence of agonist (n = 1).10
Table 2
PK characteristics of selected compounds in the rat
pounds from the initial series (3a–o) were examined in rats (Table
2). Unfortunately, selected examples from the urea series exhibited
many of the same shortcomings we observed with the diamine ser-
ies. For example, although compound 3a was rapidly absorbed
(Tmax = 0.3 h), its long half-life (7.3 h) and modest oral bioavailabil-
ity (F = 22%) offered no improvement over diamine analog 2. The
PK characteristics of the sulfonamides were also disappointing.
This is demonstrated for isopropyl sulfonamide 3f, which had a
half-life that was similar to 3a and exhibited very low bioavailabil-
ity (F = 3%). We were gratified to find that some, though not all, of
the amide analogs possessed desirable PK characteristics. For
example, compound 3o exhibited a short half-life (1.8 h), rapid
absorption (Tmax = 0.6 h) and good bioavailability (F = 39%).
Having identified the promising PK characteristics of com-
pounds from the amide series, we sought to improve the potency
of these compounds prior to selecting a compound for in vivo phar-
macology studies. To this end, a new series of amides (3p–u),
which incorporated a distal R-2-methylpyrrolidine group, were
prepared starting from compound 6b (Scheme 1). We were grati-
fied to find that the inclusion of this group afforded compounds
with binding affinities six to 23 times greater than their respective
R1
R2
N
N
R1
R2
H
t1/2 (h)
Tmax (h)
%Fa
a
a
Compound
2
6
6
78
3a
H
7.3
0.3
22
O
NH
3f
H
H
5
0.2
0.6
3
O
O
S
O
OH
3o
1.8
39
O
3u
CH3
2.5
0.3
66
O
a
After PO dose (10 mg/kg, n = 3).

4136
V. J. Santora et al. / Bioorg. Med. Chem. Lett. 18 (2008) 4133–4136
Figure 1. (a) Inhibition of (R)-
a-methylhistamine induced drinking 0.5 h after oral administration of compound 3u (0.1, 0.3, 1 and 3 mg/kg). (b) Inhibition of (R)-a-
methylhistamine induced drinking 0.5 h, 3 h and 6 h after oral administration of compound 3u (3 mg/kg).
pyrrolidine analogs (Table 1). The R-2-methylpyrrolidine group has
been reported to enhance H3 potency in vitro in other series.6,9
Among several new analogs in this series was THP-amide analog
3u, which displayed sub-nanomolar potency against the rat H3
receptor (Ki = 0.7 nM). Further examination of 3u demonstrated
high affinity (Ki = 2 nM) and potent inverse agonist activity
(Ki = 4 nM) at the human H3 receptor. This compound also showed
>1000-fold selectivity for the H3 receptor versus a panel of over
100 human GPCRs, including H1, H2 and H4.10 Compound 3u was
ultimately chosen for in vivo pharmacological testing after rat PK
experiments demonstrated that it was rapidly absorbed, had a rel-
atively short half-life and excellent bioavailability (Table 2).
Compound 3u demonstrated functional antagonism of the H3
receptor in vivo in a rat dipsogenia model, in which an acute drink-
ing response induced by an H3 agonist is attenuated by pre-admin-
istration of an H3 antagonist.11 Specifically, 3u (0.1, 0.3, 1 and
3 mg/kg) or vehicle were administered orally to rats 0.5 hour prior
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