Decahydroisoquinoline derivatives as novel non-peptidic, potent and subtype-selective somatostatin sst3 receptor antagonists

Article abstract of DOI:10.1016/j.bmcl.2010.01.063

Starting from non-peptidic sst₁-selective somatostatin receptor antagonists, first compounds with mixed sst₁/sst₃ affinity were identified by directed structural modifications. Systematic optimization of these initial leads afforded novel, enantiomerically pure, highly potent and sst₃-subtype selective somatostatin antagonists based on a (4S,4aS,8aR)-decahydroisoquinoline-4-carboxylic acid core moiety. These compounds can efficiently be synthesized and show promising PK properties in rodents.

Full text of DOI:10.1016/j.bmcl.2010.01.063

Bioorganic & Medicinal Chemistry Letters 20 (2010) 1728–1734
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Decahydroisoquinoline derivatives as novel non-peptidic, potent
and subtype-selective somatostatin sst3 receptor antagonists
a
a
b
b
Thomas Troxler a, , Konstanze Hurth , Karl-Heinrich Schuh , Philippe Schoeffter , Daniel Langenegger ,
*
Albert Enz b, Daniel Hoyer b
a Novartis Institutes for BioMedical Research, Global Discovery Chemistry—Neuroscience, CH-4002 Basel, Switzerland
b Novartis Institutes for BioMedical Research, Neuroscience Disease Area, CH-4002 Basel, Switzerland
a r t i c l e i n f o
a b s t r a c t
Article history:
Starting from non-peptidic sst1-selective somatostatin receptor antagonists, first compounds with mixed
sst1/sst3 affinity were identified by directed structural modifications. Systematic optimization of these
initial leads afforded novel, enantiomerically pure, highly potent and sst3-subtype selective somatostatin
Received 30 November 2009
Revised 6 January 2010
Accepted 7 January 2010
Available online 21 January 2010
antagonists based on
compounds can efficiently be synthesized and show promising PK properties in rodents.
Ó 2010 Elsevier Ltd. All rights reserved.
a (4S,4aS,8aR)-decahydroisoquinoline-4-carboxylic acid core moiety. These
Keywords:
Somatostatin
GPCR
Somatostatin sst3 receptor
Non-peptidic somatostatin receptor ligands
Subtype-selective sst3 receptor antagonists
Somatostatin (somatotropin release-inhibiting factor, SRIF) is a
cyclic peptide expressed throughout the CNS (central nervous sys-
tem), in endocrine tissues and in the gastrointestinal tract (GIT).
SRIF exerts a wide range of biological actions via five somatostatin
receptor subtypes (sst1 to sst5),1–3 including inhibition of secretion
of growth hormone, insulin, glucagon and gastrin as well as other
hormones secreted by the pituitary and the GIT.4 SRIF also acts as a
neuromodulator in the CNS and in addition has marked anti-prolif-
erative effects on a wide range of cancer cells.5 Clinically, SRIF
receptor modulation is targeted primarily in the endocrine and
gastro intestinal sphere, especially in a number of gastro-entero-
pancreatic cancers, although preclinical evidence points at a num-
ber of other diseases,4 such as inflammation, pain, migraine,
epilepsy,6 additional cancers,7 and neuropsychiatric disorders such
as depression and Alzheimer disease.5,8–11 These effects seem to be
mediated primarily through sst2 and sst5 receptors. The sst1 recep-
tor appears to play a role as autoreceptor in the brain and the eye,12
and sst4 may be involved in memory and epilepsy,13,14 whereas the
sst3 receptor is the least studied of the family. It is present in the
brain,15 apparently limited to neuronal cilia, and in the periphery,
primarily in tumors.16,17,7 It has been proposed to play a role in
epilepsy,18,19 depression20 and tumor growth.21
olines.22–25 In the course of our efforts towards non-peptidic,
subtype-selective somatostatin receptor antagonists, we initiated
a program aimed at the identification of novel, sst3 receptor selec-
tive and brain penetrable compounds.
Recently, we have described non-peptidic somatostatin antago-
nists with exquisite selectivity for the sst1 receptor subtype, based
on
octahydrobenzo[g]quinoline
(obeline),26,27
octahydro-
indolo[4,3-fg]quinoline (ergoline)28 and b-alanine29 (e.g., 1, Fig. 1)
scaffolds. During optimization of the b-alanine series, we realized
that increasing the size of the small alkyl substituent at the tertiary
amine from methyl (1) to cyclopropylmethyl (2) reduced sst1 affin-
ity while increasing binding to the sst3 receptor (Table 1). We
decided to explore this trend further by increasing steric bulk even
more, and restrict conformational flexibility by cyclizing the b-ala-
nine amide core. Indeed, the resulting (racemic) nipecotic acid
amide derivative 3 showed further improved sst3 affinity and
was the first compound that was equipotent on sst1 and sst3. Initial
variation of the fluorenyl-ethyl moiety using parallel synthesis
techniques30 led to the identification of methylendioxyphenyl
derivative 4 (Fig. 1). Although 4 is still a mixture of four stereoiso-
mers, it showed promising sst3 affinity and a first hint of selectivity
over sst1 (Table 1), therefore it was chosen as novel lead towards
sst3-selective somatostatin ligands.
Up to now, only one class of non-peptidic sst3 receptor antago-
nists has been described, namely
D
-Trp derived imidazolyl-b-carb-
First, we evaluated whether the stereogenic center introduced
by the methyl group at the propyl linker of 4 could be avoided.
However, both the corresponding des-methyl as well as the
dimethyl derivative of 4 showed considerably reduced sst3 affinity
* Corresponding author. Tel.: +41 61 3246604; fax: +41 61 3246760.
E-mail address: thomas.troxler@novartis.com (T. Troxler).
0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2010.01.063

T. Troxler et al. / Bioorg. Med. Chem. Lett. 20 (2010) 1728–1734
1729
O
O
N
N
N
N
N
N
N
N
N
N
N
N
1
2
NO2
NO2
(RS)
O
O
O
(RS) O
(RS)
NO2
NO2
3
4
Figure 1. Evolution from sst1 receptor antagonist 1 to mixed sst3/sst1 ligand 4.
Table 1
carboxylic acid, respectively, followed by separation of diastereo-
isomers by chromatography or crystallization. While all three
decahydroquinoline derivatives (5–7) and one decahydroisoquin-
oline derivative (9) lost sst3 affinity to some or to a considerable
extent, the decahydroisoquinoline core of 8 (relative configura-
tion determined by NMR NOE experiments) turned out to confer
both increased affinity for sst3 and improved selectivity over sst1.
Although still a mixture of four stereoisomers, 8 binds to sst3
with an affinity of 10 nM and displays selectivity over sst1 by a
factor of nearly 100.
Binding affinities of somatostatin receptor ligands 1–4 to h rec. sst3 and sst1 receptors
Compound
1
2
3
4
a
pKD h sst3
pKD h sst1
5.98 0.02
8.12 0.04
6.52 0.02
7.11 0.03
6.93 0.02
6.92 0.10
7.07 0.05
6.99 0.04
a
a
Mean SEM. Number of experiments: n = 3–6.
(pKDs of 6.19 and 5.70 as compared to 7.07 for 4). Therefore, the
methyl group was retained at this position.
Having identified this promising new core moiety, we set out to
determine the optimal absolute configurations at the linker stere-
ogenic center and the bicyclic core (synthesis discussed below, see
Scheme 1). For this assessment, the slightly more potent dimethyl
isophthalate derivative 10 (Table 3) was chosen. First, two deriva-
tives of 10 were prepared with enantiomerically pure core moie-
ties (11: (4R,4aR,8aS) and 12: (4S,4aS,8aR)) while the methyl
stereogenic center was kept racemic (therefore, 11 and 12 are mix-
tures of two diastereoisomers). Binding studies revealed that
nearly all sst3 affinity resided in the core with (SSR) configuration
(Table 3, compound 12). Next, this more active enantiomerically
pure core moiety was combined with both pure enantiomers at
the methyl propyl linker moiety (13: (R) and 14: (S)), which
showed that at this position, the (S) configuration is preferred both
with regard to sst3 affinity as well as sst1 selectivity. With the
enantiomerically pure (S) (SSR) derivative 14, a remarkably potent
sst3 ligand (KD = 1.2 nM) with good sst1 selectivity (760-fold) had
been identified.31
Next, we explored whether sst3 potency and selectivity could
be improved by further increasing steric bulk around the nipe-
cotic acid piperidine ring. To this end, the nipecotic acid core
of 4 was replaced with three different diastereoisomers of deca-
hydroquinoline-3-carboxylic acid (5–7, Table 2) and two diaste-
reoisomers of decahydroisoquinoline-4-carboxylic acid (8 and 9,
Table 2). For synthetic simplicity, these bicyclic core building
blocks were introduced as racemic mixtures; structures in Table
2 show relative configurations only. In combination with the
racemic stereogenic center at the methyl propyl linker, this leads
to mixtures of four stereoisomers (two racemic diastereoisomers)
for 5–9. Testing such mixtures carries some risk that initial SAR
obtained in this way does not fully translate to enantiomerically
pure compounds, however, this approach considerably simplified
initial synthetic efforts and allowed for a fast first assessment of
these new core moieties. Synthetically, the corresponding bicyclic
b-amino acids were obtained by exhaustive hydrogenation of the
ethyl esters of quinoline-3-carboxylic acid and isoquinoline-4-
Table 2
Evaluation of bicyclic core moieties: binding affinities to h rec. sst3 and sst1 receptors
O
O
(RS)
O
N
R
N
N
R
4-9
NO2
O
O
O
O
O
H
O
H
H
H
H
H
H
H
H
H
H
N
N
N
N
N
H
N
H
Core moietya
Compound
H
H
H
4
5
6
7
8
9
b
pKD h sst3
7.07 0.05
6.99 0.04
6.79 0.02
6.31 0.08
5.91 0.03
5.61 0.01
6.81 0.03
6.27 0.03
7.96 0.03
6.04 0.02
5.95 0.05
5.21 0.10
b
pKD h sst1
a
Drawings represent relative configurations only. Core moieties were 1:1 mixtures of the stereoisomer as drawn, and its enantiomer.
Mean SEM. Number of experiments: n = 3–6.
b

1730
T. Troxler et al. / Bioorg. Med. Chem. Lett. 20 (2010) 1728–1734
acrylic acids) was resolved into the pure enantiomers by fraction-
O
O
Br
ated crystallization of diastereoisomeric (S)-(ꢀ)-phenethylamine
salts.32 The enantiomerically pure carboxylic acid was then con-
verted to aldehyde 17 using mild conditions in order to prevent
racemization. Enantiomerically pure decahydroisoquinoline-4-car-
boxylic acid ethyl ester 19 was obtained from the corresponding
O
OEt
N
O
O
O
18
15
f,g
a,b
racemate by crystallization as [L]-di-p-toluoyl tartrate. The abso-
lute configuration of 19 was determined both by NMR and X-ray
crystallography after conversion to a Mosher’s acid amide. Abso-
lute configurations at all stereogenic centers were confirmed later
with X-ray structures of more advanced final compounds (vide
infra). Ester 19 was converted to piperazine amide 20 by Boc pro-
tection of the amine, ester hydrolysis, amide formation and amine
deprotection. A reductive amination reaction of 17 with 20 affor-
ded 14 which contained only <3% of any other diastereoisomer
or enantiomer as determined by HPLC on chiral stationary phase.
Although isophthalic acid dimethyl ester derivative 14 showed
promising initial results in somatostatin receptor binding assays,
we were concerned about (i) potential genotoxicity liabilities of
the p-nitrophenyl piperazine moiety, and (ii) issues with chemical
and metabolic stability of the methyl ester moieties. We therefore
set out to individually optimize the aryl piperazine moiety as well
as the aryl moiety at the propyl linker.
O
O
H
O
OEt
HN
H
H
OH
O
O
16
19
c-e
h-k
O
O
H
O
N
HN
H
H
O
N
O
O
17
NO2
20
l
In order to quickly assess potential alternatives for the p-nitro-
phenyl piperazine moiety, we reacted carboxylic acid 21 (racemic
mixtures of two diastereoisomers) with a set of 20 aryl pipera-
zines27 using parallel synthesis techniques (Scheme 2). Amide
bond formation in DCE using polymer supported dicyclohexyl car-
bodiimide, followed by filtration and evaporation of the solvent
afforded the desired piperazine amides in sufficient purity (>85%)
for testing in the sst3 binding assay. Affinity to the sst1 receptor
was not assessed at this point.
14
Scheme 1. Synthesis of enantiomerically pure decahydroisoquinoline sst3 antag-
onist 14. Reagents and conditions: (a) 2-methylacrylic acid, Pd(OAc)2, P(o-Tol)3,
Bu3N, DMF, microwave, 10 min (64%, cis and trans isomers combined); (b) H2, Pd/C,
EtOH (98%); (c) crystallization from Et2O as salt of (S)-(ꢀ)-phenethylamine,
recrystallization from i-PrOH (53% relative to pure enantiomer); (d) ClCOOEt,
Et3N, THF, then NaBH4, MeOH, ꢀ70 °C (45%, ½a D20
= ꢀ12.3 (EtOH, c = 1)); (e) Dess–
ꢁ
Martin periodinane, DCM, 0 °C to rt, 1 h (70%); (f) H2, 5% Rh/C, HOAc, 60 °C, 150 bar,
5 h (89% as mixture of diastereoisomers). Crystallization from EtOH/MTBE affords
As apparent from Figure 2, variation at this position has a strong
influence on sst3 affinity, with pKDs ranging from <6 (e.g., 23i, 23t)
to >7.5 (e.g., 23c, 23m, 23n) (pKDs SEM for all 20 derivatives
see33). The SAR is relatively steep; even small changes can have
considerable effects on sst3 affinity (e.g., 23p vs 23q). All aryl res-
idues leading to good sst3 affinity (e.g., 23c, 23m, 23n) had also
been found earlier to confer good sst1 affinity in combination with
the obeline, ergoline or b-alanine scaffolds.26–29 On the other hand,
some arly residues that were known to afford highly potent sst1 li-
pure racemic (4RS, 4aRS, 8aSR) isomer (61%); (g) crystallization from EtOH as [L]-di-
p-toluoyl tartrate (37% relative to pure enantiomer, ½a D20
= ꢀ2.8 (EtOH, c = 1)); (h)
ꢁ
Boc2O; (i) LiOH (88%); (j) hexachloroacetone, PPh3, DCM, 0 °C, then 4-nitrophenyl
piperazine, Et3N (82%); (k) TFA, DCM (82%); (l) NaBH(OAc)3, DCE, rt (90%).
Preparation of enantiomerically pure building blocks was
achieved as exemplified for derivative 14 (Scheme 1). Racemic 2-
methyl-3-aryl propionic acid 16 (obtained by a Heck reaction, fol-
lowed by hydrogenation of the resulting mixture of cis and trans
Table 3
Determination of preferred absolute configurations at methyl propyl linker and decahydroisoquinoline core: Binding affinities to h rec. sst3 and sst1 receptors
O
O
O
4
N
N
4a
N
O
O
8a
NO2
O
10-14
O
H
O
O
H
O
H
H
H
H
H
H
N
H
N
H
N
H
(RS)
(SR)
N
H
N
H
H
H
Core moiety
(RS)
Compound
Conf. at Me
10
(RS)
11
12
13
14
(RS)
(RS)
(R)
(S)
Conf. at core (4,4a,8a)
(RS,RS,SR)
0
(R,R,S)
+24.6
(S,S,R)
ꢀ25.4
8.87 0.03
6.40 0.06
(S,S,R)
ꢀ1.0
8.65 0.07
6.36 0.05
(S,S,R)
ꢀ48.2
8.91 0.05
6.03 0.11
½ ꢁ
a 2D0
a
b
b
pKD h sst3
pKD h sst1
8.54 0.08
6.00 0.03
6.97 0.10
5.63 0.03
a
EtOH, c = 1
b
Mean SEM. Number of experiments: n = 3–6.

T. Troxler et al. / Bioorg. Med. Chem. Lett. 20 (2010) 1728–1734
1731
O
O
O
O
O
O
HN
a
b
N
OH
N
N
N
Aryl
N
+
Aryl
21
22a-t
23a-t
Scheme 2. Parallel synthesis of racemic decahydroisoquinoline sst3 antagonists 23a–t. Configurations for 21 and 23a–t: (RS) at methyl group, (4RS,4aRS,8aSR) at
decahydroisoquinoline core. Reagents and conditions: (a) 21 (1.5 equiv), 22 (1 equiv), polymer supported DCC (3 equiv), DCE, rt, 18 h; (b) filter, evaporate solvent (77–98%
yield).
O
O
O
N
N
N
Aryl
23a-t
8
7.5
7
6.5
6
5.5
23a
23b 23c
23d
23e
23f
23g
CF3
23h
23i
23j
23k
23l 23m 23n
23o 23p
23q
23r
23s
N
23t
S
N
N
F
N
F
Cl
N
N
N
N
O
N
N
S
N
N
O
N
N
F
N
o
q
c
m
a
e
g
O
N
N
N
i
k
s
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
O
N
F
Cl
CN
b
d
f
h
j
l
n
p
r
t
Figure 2. Structures of aryl residues for 22a–t and 23a–t. Binding affinities to h rec. sst3 receptors for 23a–t. Full numerical data given in Ref. 32.
gands28 (e.g., 1-methyl-1H-pyridin-2-one of 23i) were not toler-
ated by the sst3 receptor (23i: pKD = 5.62). Of the three aryl piper-
azine moieties resulting in sst3 ligands with pKDs >7.5 (23c:
pKD = 7.68, 23m: pKD = 7.70 and 23n: pKD = 7.71), the 3,4-difluoro-
phenyl piperazine moiety of 23c was finally selected mainly due to
its good synthetic accessibility.
exchange34), followed by Pd catalyzed coupling with aryl bromides
24, afforded the corresponding enantiomerically pure 2-methyl-3-
aryl propionic acid methyl esters in acceptable yields. Conversion
of these esters to aldehydes 25, followed by reductive amination
with enantiomerically pure amine building block 26 afforded the
desired derivatives 27.
For optimization of the aryl moiety at the methyl propyl linker,
11 aryl bromides 24 were converted to the corresponding enanti-
omerically pure 3,4-difluorophenyl piperazine derivatives 27 as
outlined in Scheme 3. Reaction of commercial, enantiomerically
pure (R)-3-bromo-2-methyl propionic acid methyl ester with Et2Zn
to an alkylzinc reagent (Mn/Cu catalyzed bromine-zinc
For derivatives 27a–k, pKD values for sst3 and sst1 are depicted
in Figure 3 (full list of pKDs SEM see35). Most of the 11 derivatives
retained good sst3 affinity with pKDs >7. Considerable differences
in sst1 affinities were seen between closely related structures;
especially noteworthy is the comparison between 27e and 27g,
where the introduction of one additional nitrogen atom to the imi-
O
H
N
HN
H
O
H
Aryl
H
H
N
F
F
Br
N
N
H
COOMe
26
Aryl
N
F
F
Br
Aryl
a-c
O
d
24a-k
25a-k
27a-k
Scheme 3. Synthesis of enantiomerically pure decahydroisoquinoline sst3 antagonists 27a–k. Reagents and conditions: (a) (R)-3-bromo-2-methyl-propionic acid methyl
ester, Et2Zn, cat. MnBr2/CuCl, DMPU, rt 4 h, then 24, cat. Cl2Pd(dppf), microwave; (b) DIBAH, DCM, 0 °C, 1 h; (c) Dess–Martin periodane, DCM, rt, 2 h; (d) 26, NaBH(OAc)3, DCE,
rt, 2 h.

1732
T. Troxler et al. / Bioorg. Med. Chem. Lett. 20 (2010) 1728–1734
O
H
Aryl
H
N
N
H
N
F
F
27a-k
8.8
8.3
7.8
7.3
6.8
6.3
5.8
5.3
4.8
sst3
sst1
0.4x
107x
407x
200x
148x
245x
288x
166x
66x
263x
616x
27a
27b
27c
27d
27e
27f
27g
27h
27i
27j
27k
N
N
O
O
N
O
N
O
N
N
N
N
N
N
N
N
N
N
S
N
N
N
O
O
N
H
a
b
c
d
e
f
g
h
i
j
k
Figure 3. Structures of aryl residues for 24a–k, 25a–k and 27a–k. Binding affinities to h rec. sst1 and sst3 receptors for 27a–k. Full numerical data given in Ref. 34. Numbers
on columns indicate selectivity for sst3 over sst1.
dazo[1,2-a]pyridine system of 27e boosts selectivity for sst3 over
sst1 from 0.4-fold to 620-fold. Of these 11 derivatives, 27c, 27d
and 27i were chosen for further assessment based on their good
sst3 potency (pKD >8) and selectivity over sst1 (>100-fold).
Compounds 27c, 27d and 27i as well as the enantiomer of 27i
(ent-27i) were profiled in a panel of somatostatin radioligand
binding assays performed either in rat cortex membranes (r sst1
and r sst2)36 or cell lines expressing the five human receptor sub-
types (h sst1–h sst5)37 (Table 4).
As indicated already in Scheme 3, 27c, 27d and 27i bind to the h
sst3 receptor with affinities below 10 nM. Selectivities over h sst1, h
sst2 and h sst5 are excellent (>150-fold), whereas some modest
affinity to h sst4 is retained (selectivity factors 120, 130 and 21,
respectively). Affinities for the rat sst1 and sst2 receptors are some-
what higher than for the corresponding human receptors for all
three compounds, but KD values remain above 100 nM. As ex-
pected, the enantiomer of 27i displays no appreciable affinity to
any of the measured somatostatin receptors.
Since there were no major differences in the binding profile for
27c, 27d and 27i, the methoxypyridine derivative 27i (ACQ090)
was selected for further profiling, mainly due to superior physico-
chemical properties and promising initial PK data in rodents.
The high affinity of ACQ090 for somatostatin sst3 receptors was
confirmed in a radioligand binding assay with recombinant mouse
sst3 receptors, using 125I-SRIF28 as radioligand, with a pKD of
8.31 0.03 (n = 3).
Radioligand binding affinities of ACQ090 were tested for a panel
of 70 monoamine or peptide receptors, ion channels and transport-
Table 4
Compounds 27c, 27d, 27i (ACQ090) and ent-27i: comparison of physicochemical parameters and affinities for somatostatin receptor subtypes
N
O
N
N
O
H
O
H
O
H
O
H
N
N
H
H
H
H
S
N
N
N
N
N
H
N
H
N
H
N
H
O
O
N
F
F
N
F
F
N
F
F
N
F
F
27c
27d
27i (ACQ090)
ent-27i
a
½ ꢁ
a 2D0
b
Compound
Mp (°C)
pKD
r sst1
r sst2
h sst1
h sst2
h sst3
h sst4
h sst5
27cc
n.d.
58–62
6.34 0.07
5.93 0.08
6.23 0.05
6.09 0.01
6.64 0.02
6.82 0.07
6.94 0.02
4.68 0.04
5.86 0.03
5.81 0.05
5.69 0.01
6.14 0.02
5.26 0.04
5.45 0.08
5.34 0.03
4.42 0.09
8.47 0.02
8.11 0.03
8.15 0.02
5.44 0.01
6.38 0.01
5.99 0.04
6.83 0.02
5.21 0.02
5.96 0.02
5.78 0.06
5.95 0.02
4.04 0.10
27dd
ꢀ3.4
ꢀ0.2
+0.2
152–155
119–121
116–120
27id
ent-27id
a
b
c
Mean SEM. Number of experiments: n = 3–6.
EtOH, c = 0.5.
Free base.
d
Fumarate.

T. Troxler et al. / Bioorg. Med. Chem. Lett. 20 (2010) 1728–1734
1733
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Enz, A.; Hoyer, D. Bioorg. Med. Chem. Lett. 2009, 19, 1305.
30. The 4-nitrophenyl piperazine amide of racemic nipecotic acid was reacted
under reductive amination conditions as described before29 with a number of
commercial or custom-made aldehydes, among the former being 3-
benzo[1,3]dioxol-5-yl-2-methyl-propionaldehyde (Helional).
31. Subsequently it was shown for several compounds in addition to 10 that this
SAR trend applies in general to this series. In all cases, the (S) (SSR) isomers
displayed best sst3 affinity and selectivity over sst1.
Figure 4. X-ray crystal structure of ACQ090 fumarate.
ers.37 Only very modest affinities were found for few of these
receptors (5-HT2C: pKD = 6.37 0.17,
a1: pKD = 6.16 0.03, Dopa-
mine D2: pKD = 6.13 0.12), suggesting that ACQ090 is indeed very
selective for sst3 somatostatin receptors.
In a cAMP-based functional assay using human recombinant
sst3 receptors expressed in CHO cells, ACQ090 behaves as a silent
and competitive antagonist of SRIF-14 (pKB = 7.88 0.18, n = 6).
As expected, its enantiomer shows only very weak antagonistic po-
tency with a pKB of 5.10.
The pharmacokinetics and brain penetration of ACQ090 were
studied in mice and rats after oral (3 mg/kg) and intravenous
(1 mg/kg) doses of unlabelled ACQ090. Plasma and brain samples
were analyzed with an LC–MS-based method (LOQ 0.4 ng/ml for
plasma and 2 ng/g for brain). ACQ090 was reasonably well ab-
sorbed after oral administration in both species, with an absolute
bioavailability estimated as 15% and 21% for mice and rats, respec-
tively. Apparent terminal half-lives in plasma after intravenous
administration were determined as 1.5 h for mice and 5.6 h for
rats. ACQ090 penetrates readily and significantly into the brain,
leading to brain/plasma ratios of 2.4 and 0.4 for mice and rats,
respectively, 1 h after oral administration.
ACQ090 was screened for inhibition of the five principal human
cytochrome P450 isoenzymes using a microplate-based, direct
fluorometric assay. IC50s for CYP450 inhibition were >10
lM for
all isoforms with the exception of CYP2D6 (IC50 = 6.5 M). There-
l
fore, ACQ090 is considered to be uncritical with regard to potential
drug–drug interaction. In an initial genotoxicity assessment,
ACQ090 was found to be negative in the Ames test as well as the
micronucleus test in V79 Chinese hamster cells.
A highly efficient and convergent synthesis of enantiomerically
pure ACQ090 has been published elsewhere.38 Using this route,
ACQ090 was prepared in 12 chemical steps starting from isoquin-
oline-4-carboxylic acid ethyl ester in an overall yield of 8.5%. The
structure of ACQ090 was unambiguously confirmed by X-ray anal-
ysis of fumarate salt crystals (Fig. 4).
In summary, we have developed a novel class of non-peptidic,
enantiomerically pure, highly potent and selective somatostatin
sst3 receptor antagonists that show promising PK properties in ro-
dents, are not genotoxic in vitro, and can effectively be synthe-
sized. Further details and results of in vivo studies with these
compounds will be published elsewhere in due course.
32. The absolute configuration of the pure enantiomer of 16 was determined by
comparison of the optical rotation with a sample of the same compound
prepared by a different route, starting from a commercial building block with
known absolute configuration. Commercial, enantiomerically pure (R)-3-
bromo-2-methyl propionic acid methyl ester was converted to an alkylzinc
reagent (Mn/Cu catalyzed bromine–zinc exchange33), followed by Pd catalyzed
coupling with 5-bromo-isophthalic acid dimethyl ester as outlined in
Scheme 3. Hydrolysis of the resulting methyl ester afforded an
enantiomerically pure sample of 16 with known absolute configuration.
33. Compound: pKD
h sst3 SEM; 23a: 6.70 0.05; 23b: 7.24 0.03; 23c:
7.68 0.04; 23d: 6.48 0.13; 23e: 6.39 0.04; 23f: 7.04 0.15; 23g: 6.13
0.03; 23h: 7.1 0.17; 23i: 5.62 0.06; 23j: 7.04 0.04; 23k: 6.72 0.04; 23l:
5.87 0.06; 23m: 7.7 0.1; 23n: 7.71 0.06; 23o: 7.02 0.05; 23p:
6.97 0.07; 23q: 5.8 0.13; 23r: 6.62 0.16; 23s: 5.9 0.08; 23t: 5.57 0.1.
34. Klement, I.; Knochel, P.; Chau, K.; Cahiez, G. Tetrahedron Lett. 1994, 35, 1177.
35. Compound: pKD h sst1 SEM, pKD h sst3 SEM; 27a: 6.04 0.07, 8.07 0.12;
27b: 5.79 0.02, 7.96 0.04; 27c: 5.86 0.03, 8.47 0.02; 27d: 5.81 0.05,
8.11 0.03; 27e: 7.4 0.02, 6.97 0.02; 27f: 5.04 0.01, 7.46 0.01; 27g:
5.02 0.06, 7.81 0.07; 27h: 5.58 0.05, 7.97 0.06; 27i: 5.69 0.01,
8.15 0.02; 27j: 5.63 0.04, 7.85 0.06; 27k: 5.72 0.04, 7.54 0.04.
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