SAR of the arylpiperazine moiety of obeline somatostatin sst1 receptor antagonists

Article abstract of DOI:10.1016/j.bmcl.2007.04.078

The SAR of over 50 derivatives of octahydrobenzo[g]quinoline (obeline)-type somatostatin sst₁ receptor antagonist 1 is presented, focusing on the modification of its arylpiperazine moiety. Sst₁ affinities in this series cover a range of five orders of magnitude with the best derivatives displaying subnanomolar sst₁ affinities and >10,000-fold selectivities over the sst₂ receptor subtype as well as promising pharmacokinetic properties.

Full text of DOI:10.1016/j.bmcl.2007.04.078

Bioorganic & Medicinal Chemistry Letters 17 (2007) 3988–3991
SAR of the arylpiperazine moiety of obeline
somatostatin sst1 receptor antagonists
Konstanze Hurth,* Albert Enz, Philipp Floersheim, Conrad Gentsch, Daniel Hoyer,
Daniel Langenegger, Peter Neumann, Paul Pfa¨ffli, Dieter Sorg, Robert Swoboda,
Annick Vassout and Thomas Troxler*
Novartis Institutes for BioMedical Research, CH-4002 Basel, Switzerland
Received 26 March 2007; revised 24 April 2007; accepted 25 April 2007
Available online 30 April 2007
Abstract—The SAR of over 50 derivatives of octahydrobenzo[g]quinoline (obeline)-type somatostatin sst1 receptor antagonist 1 is
presented, focusing on the modification of its arylpiperazine moiety. Sst1 affinities in this series cover a range of five orders of mag-
nitude with the best derivatives displaying subnanomolar sst1 affinities and >10,000-fold selectivities over the sst2 receptor subtype as
well as promising pharmacokinetic properties.
Ó 2007 Elsevier Ltd. All rights reserved.
O
O
The initial structure–activity relationship of highly ac-
tive, non-peptidic, obeline-type somatostatin sst1
receptor antagonists and their in vitro pharmacologi-
cal profile is presented in the preceding paper.1 The
focus of our medicinal chemistry derivatization pro-
gram was on the arylpiperazine moiety of lead mole-
cule 1 (example 2a in Ref. 1) with the goal to raise
the sst1 receptor affinities to a subnanomolar level
while improving on selectivities toward the somato-
statin sst2 receptor (a detailed rationale is given in
the preceding paper1) without compromising on the
favorable drug-like properties of 1 (no ‘rule-of-5’ vio-
lations, clogP 3.4, molecular weight 421, PSA 49 A ).
From our earlier work on structurally related somato-
statin ligands2 it was anticipated that an efficient fine-
tuning of somatostatin receptor binding properties is
achievable by introducing structurally and electroni-
cally diverse aryl piperazine moieties. In a second step,
additional criteria (e.g., in vitro or in vivo ADME
properties) served for selection among a subset of
highly active and selective compounds.
H
H
N
N
N
N
1
Representative examples for the derivatization of the
arylpiperazine moiety in 1 are shown in Tables 1–3. As
in the preceding paper,1 radioligand binding data to
rat somatostatin sst1 and sst2 receptors are given. The
assay is performed in rat cortex membranes using
2
˚
[
125I]SRIF-14 in the presence of 120 mM NaCl.3 The
synthesis of all compounds listed in Tables 1–3 is out-
lined in Supporting Information.
The optimization program started by replacement of the
2-pyridyl moiety in 1 (pKd sst1 = 7.76, selectivity over
sst2 ca. 600-fold) with other heteroaryl moieties: while
the regioisomeric 4-pyridyl compound and the corre-
sponding pyridazine and pyrimidine derivatives were
considerably less active and selective (Table 1, entries
2–4), introduction of a 4-cyano substituent gave a clear
gain in sst1 affinity (entry 5, pKd sst1 = 8.45); other sub-
stituents in 3-, 4- or 6-position were however less
favorable (entries 6–8). Going from the 2-pyridine to a
2-pyridone moiety led to an improved affinity, with the
N-methyl derivative 10 showing a superior profile (pKd
sst1 = 8.74, selectivity over sst2 > 6000-fold) over the
Keywords: Somatostatin sst1 receptor antagonist; Octahydro[g]quino-
line (obeline).
*
Corresponding authors. Tel.: +41 61 3244027; fax: +41 61 3246760
(K.H.); e-mail: konstanze.hurth@novartis.com
0960-894X/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2007.04.078

K. Hurth et al. / Bioorg. Med. Chem. Lett. 17 (2007) 3988–3991
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K. Hurth et al. / Bioorg. Med. Chem. Lett. 17 (2007) 3988–3991
Table 2. Binding affinities of octahydrobenzo[g]quinoline derivatives
24–46 (phenylpiperazines) to rat sst1 and sst2 receptors
Table 3. Binding affinities of octahydrobenzo[g]quinoline derivatives
47–55 (cyclic tertiary amides, not piperazine derivatives) to rat sst1 and
sst2 receptors
OMe
O
H
H
OMe
O
N
H
H
R'
N
R''
N
N
a
a
Compound
R0
pKd r sst1
pKd r sst2
a
a
Compound
R00
pKd r sst1
pKd r sst2
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
2-F
3-F
4-F
7.75 0.11
8.48 0.05
8.47 0.05
8.70 0.19
8.09 0.05
8.89 0.11
8.88 0.02
9.15 0.31
7.63 0.07
6.56 0.03
6.20 0.04
6.82 0.01
6.79 0.12
5.82 0.11
5.77 0.13
4.09 0.17
6.20 0.02
6.23 0.17
9.13 0.04
8.55 0.06
8.49 0.08
6.96 0.04
8.76 0.06
4.73 0.04
4.67 0.06
4.58 0.10
5.13 0.01
5.00 0.11
4.96 0.03
5.17 0.06
5.11 0.01
4.88 0.10
5.29 0.12
4.61 0.05
5.06 0.02
4.83 0.12
4.78 0.03
4.70 0.05
3.60 0.26
5.06 0.03
5.04 0.10
4.78 0.06
4.78 0.03
5.36 0.05
5.31 0.07
5.28 0.08
47
6.68 0.04
4.46 0.39
N
N
N
N
N
2-CN
4-CN
48
49
50
51
52
53
54
55
6.58 0.07
7.09 0.06
7.52 0.05
6.31 0.03
6.31 0.01
7.15 0.04
6.34 0.04
4.98 0.04
4.65 0.23
5.60 0.04
5.63 0.04
5.62 0.06
5.69 0.03
5.21 0.00
5.04 0.08
4.36 0.10
NO2
2-NO2
3-NO2
4-NO2
3-CF3
N
N
Cl
4-CF3
4-OH
N
4-COMe
4-CO2Me
4-CONH2
4-CONEt2
4-CO2Na
4-SO2Me
4-SO2NH2
3,4-F2
N
N
N
O
N
N
NH
2-CN-3-F
2-CN-4-NO2
2-NO2-4-CF3
N
N
2-SO2Me-4-NO2
a Mean SEM. Number of experiments: n = 3–6.
H
N
N
N
CH2Ph
parent pyridone 9 (pKd sst1 = 8.12, selectivity over sst2
1550-fold). The introduction of annelated six-membered
rings (entries 11–17) revealed the narrow SAR within
this series: for example, isomeric pyridopyrazines 16
and 17 that differ only by the position of one nitrogen
atom show a difference in sst1 affinity by nearly two
orders of magnitude (pKd sst1 = 8.24 for 16 vs 6.45 for
17). Among the benzoxadiazole and benzothiadiazole
derivatives (entries 18–22) compound 22 displays high-
est affinity and selectivity (pKd sst1 = 8.91, selectivity
over sst2 > 4600-fold). The corresponding imidazopyrid-
azine derivative 23, however, proved less promising (pKd
sst1 = 7.06).
NH
a Mean SEM. Number of experiments: n = 2–4.
Derivatives that replace the arylpiperazine moiety by
other cyclic secondary amines are given in Table 3.
The piperazine ring itself was replaced by a homopipera-
zine (entries 47 and 48) or a tetrahydropyridine ring (en-
tries 49–51). The arylpiperazine moiety was substituted
by
1-piperidin-4-yl-1,3-dihydro-benzoimidazol-2-one
(entry 52), a popular moiety in the field of peptidic
and non-peptidic sst receptor ligands,5,6 b-carboline (en-
try 53), benzylpiperazine (entry 54) or unsubstituted
piperazine (entry 55). All these derivatizations led to a
dramatic loss in affinity and selectivity and were not fol-
lowed up any further.
Substituted phenylpiperazines are given in Table 2.
While a fluorine atom was best tolerated in the 3-or 4-
position, not in the 2-position (entries 24–26) and a
cyano group in the 2-position (entries 27 and 28), intro-
duction of a nitro group in all positions resulted in
highly active derivatives (entries 29–31) with the 4-nitro
derivative 31 being one of the best compounds of the
whole series (pKd sst1 = 9.15, selectivity over
sst2 > 10,000-fold). The detailed in vitro profile of this
compound is published elsewhere.1,4 Less favorable is
a CF3 group (in 3- or 4-position, entries 32 and 33) or
a 4-hydroxy, -carbonyl, -carboxyl, -sulfonyl or -sulfon-
amide substitution (34–41). Among the disubstituted
phenyl derivatives (42–46), the 3,4-difluoro derivative
42 showed affinity and selectivity comparable to 31
(pKd sst1 = 9.13, selectivity over sst2 > 22,000-fold).
Attempts to develop a QSAR understanding of these
results based on different molecular descriptors (dipole
moments, volumes, surfaces areas, hydrophilicities,
frontier orbital energies, etc., alone or in combinations)
and using pertinent methods7 were not successful so far.
A possible explanation could be that these compounds
bind to different parts of the receptor in varying orienta-
tions and receptor conformations in spite of their rather
high structural analogy, a fact that cannot be further
elaborated in absence of structural information on the
somatostatin sst1 receptor.

K. Hurth et al. / Bioorg. Med. Chem. Lett. 17 (2007) 3988–3991
3991
2. Pfaeffli, P.; Neumann, P.; Swoboda, R.; Stutz, P. PCT Int.
¨
Appl. WO 9854183, 1998; Chem. Abstr. 1998, 130, 25220.
The derivatives in Tables 1–3 have calculated molecular
properties that are in line with oral bioavailability
according to the ‘rule of 5’. Indeed, compounds 21, 22,
and 42 show good absorption and brain penetration in
mice (brain plasma ratios of 4.8, 1.8 and 7.5, respec-
tively, 1 h after 10 mg/kg oral administration). Com-
pound 31 was analyzed in more detail in rats: it shows
an oral bioavailability of ca. 35% and a moderate
clearance rate and tissue distribution (CL ca. 5 ml/min,
Vss 3–6 l/kg). Brain plasma ratios are 10–15 (90 min
after oral administration of 10, 30, and 100 mg/kg); at
doses of 1–10 mg/kg po, concentrations in the rat brain
are sufficient to fully occupy sst1 receptors for at least
4 h. Details as well as pharmacological in vivo data will
be published elsewhere in due course.
3. Hoyer, D.; Perez, J.; Schoeffter, P.; Langenegger, D.;
Schupbach, E.; Kaupmann, K.; Lubbert, H.; Bruns, C.;
¨
¨
Reubi, J. C. Eur. J. Pharmacol. 1995, 289, 151.
4. Hoyer, D.; Nunn, C.; Hannon, J.; Schoeffter, P.; Feuer-
bach, D.; Schuepbach, E.; Langenegger, D.; Bouhelal, R.;
Hurth, K.; Neumann, P.; Troxler, T.; Pfaeffli, P. Neurosci.
Lett. 2004, 361, 132.
5. Hannon, J. P.; Nunn, C.; Stolz, B.; Bruns, C.; Weckbecker,
G.; Lewis, I.; Troxler, T.; Hurth, K.; Hoyer, D. J. Mol.
Neurosci. 2002, 18, 15.
6. Selected recent examples: (a) Moinet, C; Sackur, C.;
Thurieau, C. PCT Int. Appl. WO 2002055510, 2002; Chem.
Abstr. 2002, 137, 93746; (b) Hay, B. A.; Cole, B. M.;
Ricketts, A. P. US Patent Appl. US 2002091125, 2002;
Chem. Abstr. 2002, 137, 94010; (c) Cole, B. M.; Ricketts, A.
P.; Hay, B. A. US Patent Appl. US2002091090, 2002;
Chem. Abstr. 2002, 137, 94001; (d) Thurieau, C. A.;
Poitout, L. F.; Galcera, M.-O.; Gordon, T. D.; Morgan,
B. A.; Moinet, C. P.; Bigg, D. PCT Int. Appl. WO
2002010140, 2002; Chem. Abstr. 2002, 136, 167373; (e) Hay,
B. A.; Cole, B. M.; DiCapua, F. M.; Kirk, G. W.; Murray,
M. C.; Nardone, R. A.; Pelletier, D. J.; Ricketts, A. P.;
Robertson, A. S.; Siegel, T. W. Bioorg. Med. Chem. Lett.
2001, 11, 2731; (f) Nunn, C.; Langenegger, D.; Hurth, K.;
Schmidt, K.; Fehlmann, D.; Hoyer, D. Eur. J. Pharmacol.
2003, 465, 211; (g) Kato, K.; Terauchi, J.; Suzuki, N.;
Takekawa, S. PCT Int. Appl. WO 2001025228, 2001; Chem.
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Abstr. 2001, 134, 147596.
In conclusion, we have established the SAR of the aryl-
piperazine moiety of obeline-type somatostatin sst1
receptor antagonist 1, leading to compounds with sub-
nanomolar sst1 affinities, >10,000-fold selectivities over
the sst2 receptor subtype and promising initial PK
properties.
Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/
j.bmcl.2007.04.078.
7. QSAR methods used: (a) Stewart, J. J. P. MOPAC93: A
General Molecular Orbital Package; Stewart Computa-
tional Chemistry; Colorado Springs; (b) Connolly, M. L. J.
Appl. Cryst. 1983, 16, 548; (c) Walkinshaw, M. D.;
Floersheim, P. J. Mol. Struct. 1990, 237, 63; (d) Goodford,
P. J. J. Med. Chem. 1985, 28, 849; (e) Geladi, P.; Kowalski,
B. R. Anal. Chim. Acta 1986, 185, 1.
References and notes
1. Troxler, T.; Hoyer, D.; Langenegger, D.; Neumann, P.;
Pfa¨ffli, P.; Schoeffter, P.; Sorg, D.; Swoboda, R.; Hurth, K.
Bioorg. Med. Chem. Lett. 2007 doi:10.1016/j.bmcl.2007.
04.086.