New sst4/5-selective somatostatin peptidomimetics based on a constrained tryptophan scaffold

Article abstract of DOI:10.1021/jm070246f

The synthesis and biological evaluation of four peptidomimetic analogs of somatostatin based on a constrained Trp residue, 3-amino-indolo[2,3-c]azepin-2- one (Aia), are reported. It is shown that dipeptidomimetics with a D-Aia-Lys sequence, functionalized

Full text of DOI:10.1021/jm070246f

J. Med. Chem. 2007, 50, 3397-3401
3397
New sst4/5-Selective Somatostatin Peptidomimetics Based on a Constrained Tryptophan Scaffold
Debby Feytens,† Renzo Cescato,‡ Jean Claude Reubi,‡ and Dirk Tourwe´*,†
Department of Organic Chemistry, Vrije UniVersiteit Brussel, Pleinlaan 2, B-1050, Brussels, Belgium, and DiVision of Cell Biology and
Experimental Cancer Research, Institute of Pathology, UniVersity of Berne, Berne, Switzerland
ReceiVed March 5, 2007
The synthesis and biological evaluation of four peptidomimetic analogs of somatostatin based on a constrained
Trp residue, 3-amino-indolo[2,3-c]azepin-2-one (Aia), are reported. It is shown that dipeptidomimetics with
a D-Aia-Lys sequence, functionalized with N- and C-terminal aromatic substituents, display a good selectivity
for both sst4 and sst5. This study allowed us to identify a new highly potent sst5 agonist with good selectivity
over the other receptors, except versus sst4.
Introduction
This lead structure was used to build further libraries that
were screened for affinity to all of the five SRIF receptor
subtypes.26 Selective peptidomimetics for each of the receptor
subtypes were found. Our attention was drawn by the series of
analogs containing a â-MeTrp residue. Whereas the (2R,3S)
isomer 10 was a potent and selective sst2 ligand, the (2R,3R)
isomer was much less potent.28 This is in agreement with the
requirement for a trans-conformation of ø1 of the Trp sidechain,
which is favored by the (3S) methyl substituent.27-29
We have recently developed a synthesis of a new type of
Trp analog in which the side chain conformation is fixed by
formation of a seven-membered ring (Figure 3).30 The resulting
3-amino-indolo[2,3-c]azepin-2-one (Aia) constrains ø1 to trans
and gauche(+), but ø2 is also fixed ((5° and (70°).
Somatostatin (SRIFa, H-Ala1-Gly2-[Cys3-Lys4-Asn5-Phe6-
Phe7-Trp8-Lys9-Thr10-Phe11-Thr12-Ser13-Cys14]-OH), 1, was orig-
inally isolated from mammalian hypothalamus as a potent
inhibitor of growth hormone secretion.1 It is now known that it
is widely distributed throughout the endocrine and central
nervous systems and peripheral tissues. SRIF has multiple
functions, such as modulation of growth hormone, insulin,
glucagon, and gastric acid secretion.2-4 The effects of SRIF are
mediated by five G protein-coupled receptors, termed sst1-5
5
.
Structure-activity relationship (SAR) studies on a large number
of SRIF analogs revealed that the Phe7-Trp8-Lys9 sequence is
critical for biological recognition.6,7 Several cyclic hexa- and
octapeptide analogs containing a D-Trp8-Lys9 sequence (num-
bering of the residues follows that of native SRIF) have been
developed,8,9 including octreotide 2 (Figure 1), which is
clinically used for the treatment of endocrine tumors and
acromegaly.10,11 Extensive structural studies by NMR6,12 and
also by X-ray diffraction13 indicated that a type-II′ â-turn
conformation with D-Trp8 and Lys9 at the i+1 and i+2 position,
respectively, was present. A close proximity of the D-Trp8 side
chain to that of Lys9, as indicated by a high field shift of the
Lys CγH2 in the NMR spectra, was a requisite for high
potency.14 Despite the successful clinical development of small
cyclic SRIF analogs such as octreotide, lanreotide, and vap-
reotide,15,16 extensive research toward nonpeptide analogs that
are selective for each receptor subtype was carried out over the
past decade.17-19 The critical side chains of the Phe7-Trp8-Lys9
sequence were displayed successfully on a variety of nonpeptide
scaffolds 3-8 (Figure 1).17,18,20-25
We now report the use of this new scaffold in the design of
novel receptor selective SRIF peptidomimetics.
Results
Synthesis. The conformationally constrained D-Trp-Lys
analogs were prepared as shown in Scheme 1.
Boc-2′-formyl-D-tryptophan 11 was prepared by SeO2 oxida-
tion of 2-(tert-butoxycarbonyl)-2,3,4,9-tetrahydro-1H-beta-car-
boline-3-carboxylic acid (Boc-D-Tcc).30 Reductive amination
with mono-Fmoc-protected diaminopentane and NaBH3CN,
immediately followed by cyclization using EDC/pyridine,
yielded 14. Although the cyclization reaction was very slow
(2-3 weeks), no side compounds were formed and the final
compounds were obtained in very pure form. After Boc-
deprotection, a coupling with phenylacetic acid or 3,3′-diphe-
nylpropionic acid was performed leading to 16 and 17. Final
removal of the Fmoc protecting group with 1% 1,8-diazabicyclo-
[5.4.0]undec-7-ene (DBU) in DMF in the presence of dithio-
threitol (DTT)31 gave the SRIF mimetics 20 and 21, which were
purified by semipreparative HPLC. Similarly, aldehyde 11 was
reacted with Lys(Cbz)NHBn and NaBH3CN to yield 13, which
was cyclized to the dipeptide mimetic Boc-D-Aia-Lys(Cbz)-
NHBn 15 in 30% overall yield. The latter was transformed into
the phenylacetyl and diphenylpropionyl amides, as described
above, and the resulting compounds 22 and 23 were also purified
by HPLC.
The Merck group used the SRIF pharmacophore model to
select members of a library that was obtained by derivatizing
privileged structures with capped amino acids. Screening of a
library of only seventy-five members identified L-264,930 9
(Figure 2), which was further optimized by using the D-Trp
stereochemistry and extending the amine chain length to
that of Lys, which resulted in a potent and sst2 selective
ligand.26-28
* To whom correspondence should be addressed. Tel.: 32-2-629-3295.
Fax: 32-2-629-3304. E-mail: datourwe@vub.ac.be.
Determination of Somatostatin Receptor Affinity Profiles.
The compounds were tested for their ability to bind to the five
human sst receptor subtypes in complete displacement experi-
ments using the universal SRIF radioligand [125I]-[Leu8, D-Trp22,
Tyr25]-SRIF-28. CHO-K1 and CCL39 cells stably expressing
the human sst1-sst5 receptors were grown as described
† Vrije Universiteit Brussel.
‡ University of Berne.
a Abbreviations: SRIF, somatostatin; Aia, 3-amino-indolo[2,3-c]azepin-
2-one; DTT, dithiothreitol; EDC, 1-(3-dimethylaminopropyl)-3-ethylcar-
bodiimide; DBU, 1,8-diazabicyclo[5.4.0]undec-7-ene; NMM, N-methyl-
morpholine; IBMX, 3-isobutyl-1-methylxanthine; Boc-D-Tcc, 2-(tert-
butoxycarbonyl)-2,3,4,9-tetrahydro-1H-beta-carboline-3-carboxylic acid
10.1021/jm070246f CCC: $37.00 © 2007 American Chemical Society
Published on Web 06/09/2007

3398 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 14
Brief Articles
Figure 1. Structure of octreotide and of various SRIF mimetics.
percentages of stimulation over the nonstimulated level. The
EC50 value of 13.0 ( 4.2 nM was derived from concentration-
response curves of three independent experiments.33,34
NMR Study. The two most potent analogs 22 and 23 were
1
studied by H NMR and 13C NMR spectroscopy. All signals
were assigned using DEPT, HMQC, HMBC, and COSY spectra
and NOEs were detected using NOESY spectra. The temperature
dependence of the amide NH signals was studied in DMSO
solution, and NH signals in CDCl3 and DMSO were compared
for compounds 22 and 23. The obtained data are collected in
Table 2.
The large temperature and solvent dependence of the amide
protons does not support the formation of a â-turn, which is
stabilized by the presence of an intramolecular hydrogen bond.
The Lys CγH2s are found at δ ) 0.59 and 1.05 ppm for 18
and at δ ) 0.57 and 0.96 ppm for 19, which are upfield
compared to the normal value (1.38 ppm for an inactive
analog35).
Figure 2. Structure of SRIF mimetics developed by Merck.
Discussion. The fixation of the tryptophan side chain in the
D-Trp-Lys sequence by formation of an indolo[2,3-c]azepin-2-
one ring system and attachment of aromatic substituents at the
N- and C-terminus provided new SRIF mimetics with a high
affinity for sst4 and sst5. These compounds also have moderate
affinity for sst2. Compounds lacking the lysine carboxylic amide
were less potent and displayed a slight selectivity for sst4,
whereas compound 22 containing the lysine benzylamide
displayed low nM affinity for both sst4 and sst5. Analog 23 is
less potent than 22 but has a better sst5 selectivity. The 1,5-
diaminopentane chain was selected because it has the same
length as the lysine side chain and it was shown to provide the
optimal distance between the amino groups for sst2 affinity.27
Potency was better for the phenylacetyl N-terminal analogs than
for the diphenylpropionyl analogs. These aromatic substituents
were introduced to target the receptor pockets occupied by Phe6
and Phe10 of the native ligand. The most potent analog 22 has
Figure 3. Constraining the tryptophan residue by cyclization.
previously.32 Cell membrane pellets were prepared and receptor
autoradiography was done as described in detail previously.32
SRIF-28 was run in parallel as control. IC50 values were
calculated after quantification of the data using a computer-
assisted image processing system. The data are shown in
Table 1.
Effect on cAMP Formation. The effect of the sst5 selective
analog 22 on forskolin-stimulated cAMP formation was per-
formed on sst5-transfected CHO-K1 cells, as described previ-
ously.33,34 cAMP formation was determined using a scintillation
proximity assay (SPA) system. cAMP data were expressed as

Brief Articles
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 14 3399
Scheme 1. Synthesis of 20-23a
but also of ø2, is a basis for differentiation between sst receptor
subtypes and is particularly effective for the sst5 and sst4. This
allowed us to identify analog 22 as a highly potent sst5 agonist
with good selectivity over the other receptors, except versus
sst4. The potential therapeutic utility of selective agonists for
sst4, which is expressed in the lung, or for sst5, which is
expressed in the lymphoid system, in pancreatic beta cells, and
in corticotroph adenoma cells has been mentioned.19 The
efficient synthetic method allows easy modifications of the
metabolically stable peptidomimetic. Thus, further improvement
can be expected for modifications of the N- and C-terminal
substituents. Work along these lines is currently in progress.
Experimental Section
General. Mono-Fmoc-protected diaminopentane and Boc-Lys-
(ꢀ-Cbz)OH were purchased from Fluka (Bornem, Belgium). Lys-
(ꢀ-Cbz)NHBzl was prepared using the standard procedures for
amide formation and Boc-deprotection.37 Boc-2′-formyl tryptophan
11 was synthesized as described previously.30
Thin layer chromatography (TLC) was performed on plastic sheet
precoated with silica gel 60F254 (Merck, Darmstadt, Germany) using
specified solvent systems. Mass Spectrometry (MS) was recorded
on a VG Quattro II spectrometer using electrospray (ESP) ionization
(positive or negative ion mode). Data collection was done with
Masslynx software. Analytical RP-HPLC was performed using an
Agilent 1100 Series system (Waldbronn, Germany) with a Supelco
Discovery BIO Wide Pore (Bellefonte, PA) RP C-18 column (25
cm × 4.6 mm, 5 µm) using UV detection at 215 nm. The mobile
phase (system 1, water/acetonitrile; system 2, water/methanol)
contained 0.1% TFA. The standard gradient consisted of a 20 min
run from 3 to 97% acetonitrile (system 1) or methanol (system 2)
at a flow rate of 1 mL/min. Preparative HPLC was performed on
a Gilson apparatus and controlled with the software package
Unipoint. The reverse phase C18-column (Discovery BIO Wide
Pore 25 cm × 21.2 mm, 10 µm) was used under the same conditions
as the analytical RP-HPLC, but with a flow rate of 20 mL min-1
.
Nuclear magnetic resonance (NMR): 1H NMR and 13C NMR
spectra were recorded at 250 and 63 MHz, respectively, on a Bruker
Avance 250 spectrometer or at 500 and 125 MHz on a Bruker
Avance II 500. Calibration was done with TMS (tetramethylsilane)
or residual solvent signals as an internal standard. The solvent used
is mentioned in all cases and the abbreviations used are s (singlet),
d (doublet), dd (double doublet), t (triplet), q (quadruplet), br s
(broad singlet), m (multiplet), cad (diaminopentane protons), Lys
(Lysine protons), azep (azepinone protons), arom (aromatic protons).
Optical rotations were measured on a Perkin-Elmer 241 polarimeter.
Infrared spectral data were obtained using an Avatar 370 FT-IR.
All culture reagents were supplied by Gibco BRL, Life Tech-
nologies (Grand Island, NY). Tissue standards (autoradiographic
a Reagents and conditions: (a) RNH2, CH2Cl2, NMM, pH 6, MgSO4,
NaBH3CN, 2 h; (b) EDC, pyridine, CH3CN/H2O 1:1, high dilution, 2 to 3
weeks; (c) (i) 0.5% H2O in TFA/CH3CN 2:1, 1 h; (ii) RCOOH, EDC,
CH2Cl2, NEt3, 18 h; (d) 1% DBU in DMF, DTT, THF, 2 h; (e) H2, Pd/C,
EtOH, 18 h.
an IC50 value of 1.2 nM for the sst5 and behaves as a full agonist
in the forskolin-stimulated cAMP assay with an EC50 value of
13.0 nM.
[
125I] microscales) were purchased from GE Healthcare, Little
Chalfont, Buckinghamshire, U.K. cAMP accumulation was deter-
mined using a commercially available cAMP scintillation proximity
assay (SPA) system (RPA538, GE Healthcare, Little Chalfont,
Buckinghamshire, U.K.) The EC50 values were calculated using
GraphPad Prism, version 4.0, by nonlinear regression analysis of
dose response curves.
Synthesis of 12 and 13. Procedure for the Reductive Ami-
nation of 11. Aldehyde 11 (0.332 g, 1 mmol) was suspended in
CH2Cl2 (puriss. p.a. 15 mL) and amine (hydrobromic or trifluoro-
acetic acid salt, 1.05 mmol, 1.05 equiv) was added. The pH was
adjusted to 6 with N-methyl-morpholine, followed by the addition
of MgSO4 (20 wt %) and NaCNBH3 (2.5 mmol, 2.5 equiv). The
reaction was monitored with HPLC or TLC. When the reaction
was completed (typically 2 h), the solvent was evaporated and the
crude product was used in the cyclization reaction.
A type II′ â-turn conformation around the D-Trp-Lys residues
is present in most sst2-5 subtype selective peptide analogs. An
NMR study of 22 and 23 indicated that these compounds do
not adopt a type-II′ â-turn conformation. This observation is in
agreement with previous findings that this type of amino-
azepinones do not adopt turn conformations but rather prefer
an extended conformation.36 However, the upfield position of
the Lys CγH2 (0.59 and 0.57 ppm), which is ascribed to a close
proximity of the Trp and Lys side chains in the peptidic analogs
and which correlates with high receptor affinity, is also observed
here. The corresponding chemical shift of the γ-methylene in
L-054,522 10 is 0.7 ppm.28
Conclusions. The conformational constraint of the D-Trp
residue in the Aia ring system has proven to be a successful
approach to obtain higly potent sst4/sst5 selective peptidomi-
metics. Apparently this type of conformational constraint of ø1,
Synthesis of 14 and 15. General Procedure for the Cyclization
of 12 and 13. Crude 12 or 13 was dissolved in acetonitrile/water
1:1 (80 mL). Pyridine (2 mmol, 2 equiv) was added, and the reaction
mixture was cooled to 0 °C for 10 min and EDC (1.1 mmol, 1.1

3400 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 14
Table 1. Receptor Affinities of the SRIF Peptide Mimetics
Brief Articles
IC50a (nM)
sst3
No
sst1
sst2
sst4
sst5
SS-28
20
21
22
23
2.4 ( 0.4 (4)
>1000 (2)
2.5 ( 0.2 (4)
>1000 (2)
357 ( 96
83 ( 2 (3)
103 ( 12 (3)
2.8 ( 0.3 (4)
>1000 (2)
2.3 ( 0.2 (4)
75 ( 2 (2)
129 ( 12 (2)
3.3 ( 0.2 (3)
73 ( 8 (3)
2.8 ( 0.4 (4)
245 ( 124 (2)
318 ( 177 (2)
1.2 ( 0.15 (3)
8 ( 0.87 (3)
>1000 (2)
>1000 (2)
233 ( 74 (3)
89 ( 2 (3)
251 ( 16 (3)
694 ( 19 (3)
a The number of independent repetitions to obtain the mean values ( SEM are indicated between brackets.
described in detail previously.32 For each of the tested compounds,
complete displacement experiments were done with the universal
SRIF radioligand [125I]-[Leu8, D-Trp22, Tyr25]-SRIF-28 using in-
creasing concentrations of the unlabeled compounds ranging from
0.1 to 1000 nmol/L. SRIF-28 was run in parallel as control using
the same increasing concentrations. IC50 values were calculated after
quantification of the data using a computer-assisted image process-
ing system. Tissue standards containing known amounts of isotopes,
cross-calibrated to tissue-equivalent ligand concentrations, were
used for quantification.32
Table 2. Solvent and Temperature Dependence of the Amide Protons in
22 and 23
No
∆δ CDCl3 f DMSO (ppm)
∆δ/∆T (ppb/K)
22
NHBzl
NHCOR
NHBzl
1.54
1.33
1.83
1.53
-5.7
-5.6
-5.5
-6.2
23
NHCOR
equiv) was added. After 1 h of stirring at 0 °C, the reaction was
continued at rt. The reaction was monitored using HPLC, and 1 to
5 equiv of EDC and pyridine were added until the reaction was
complete (2 to 3 weeks). Acetonitrile was evaporated and EtOAc
(100 mL) was added. The layers were separated and the organic
phase was then washed with 1 M HCl (3 × 30 mL), saturated
aqueous NaHCO3 (3 × 30 mL), and brine (3 × 20 mL). The organic
layer was dried over MgSO4. After filtration and evaporation, the
crude product was purified by flash column chromatography (CH2-
Cl2-EtOAc). Yield (14 from 11) ) 46%. Yield (15 from 11) )
30%.
Procedure for the Boc-Deprotection of 14 and 15. Boc-
protected cyclic product (1.0 mmol) was dissolved in a solution of
5% water in TFA (10 mL) and acetonitrile was added (5 mL). The
reaction was stirred for 1 h at room temperature. After completion
of the reaction, the mixture was evaporated and the crude TFA-
salt was used in the coupling reaction.
Synthesis of 16, 17, 18, and 19. General Procedure for the
Amide Formation. To a solution of TFA-salt (0.35 mmol) in CH2-
Cl2 (10 mL) were added phenyl acetic acid (53 mg, 0.39 mmol,
1.1 equiv) or 3,3′-diphenyl propionic acid (88 mg, 0.39 mmol, 1.1
equiv), NEt3 (54 µL, 0.39 mmol, 1.1 equiv), and EDC‚HCl (74
mg, 0.39, 1.1 equiv). The reaction was stirred at room temperature
overnight and then washed with HCl (1 M, 3 × 10 mL), saturated
NaHCO3 (3 × 10 mL), and brine (3 × 10 mL). The organic layers
were combined and dried over MgSO4. After filtration and
evaporation, the crude compounds were purified by flash column
chromatography (CH2Cl2-EtOAc). Yield (16 from 14) ) 71%.
Yield (17 from 14) ) 76%. Yield (18 from 15) ) 62%. Yield (19
from 15) ) 52%.
Effect on cAMP Formation. The effect of 22 on forskolin-
stimulated cAMP formation was performed on CHO-K1 cells stably
expressing sst5, as described previously.33,34 sst5-Expressing cells
were subcultured in 96-well culture plates at 2 × 104 cells per well
and grown for 24 h. Culture medium was removed from the wells
and fresh medium (100 µL) containing 0.5 mM 3-isobutyl-1-
methylxanthine (IBMX) was added to each well. Cells were
incubated for 30 min at 37 °C. Medium was then removed and
replaced with fresh medium containing 0.5 mM IBMX, with or
without 10 µM forskolin and various concentrations of compounds.
Cells were incubated for 30 min at 37 °C. After removal of the
medium, cells were lysed and cAMP formation was determined
using a commercially available cAMP scintillation proximity assay
(SPA) system, according to the instructions of the manufacturer
(RTA538, GE Healthcare, Little Chalfont, U.K.). cAMP data were
expressed as percentages of stimulation over the nonstimulated
level. The EC50 values (the agonist concentration causing 50% of
its maximal effect) were determined using GraphPad Prism, version
4.0, by nonlinear regression analysis of dose response curves.33,34
The experiment was performed three times. Each concentration
point represents the mean of triplicate wells.
Acknowledgment. D. F. is a Research Assistant of the Fund
for Scientific Research-Flanders (Belgium). We would like to
thank Dr. Ingrid Verbruggen for taking the NMR spectra. We
also thank Ve´ronique Eltschinger for technical assistance.
Synthesis of 20 and 21. General Procedure for the Fmoc-
Deprotection. Fmoc-protected product (0.23 mmol) was dissolved
in THF (25 mL). DTT (0.35 g, 2.3 mmol, 10 equiv) and DBU in
DMF (1% solution, 100 µL, 0.007 mmol, 0.03 equiv) were added,
and the mixture was stirred at room temperature for 4 h. The
reaction mixture was evaporated and the crude compound was
purified by semipreparative RP-HPLC. Yield (20) ) 35%. Yield
(21) ) 76%.
Synthesis of 22 and 23. General Procedure for the Cbz-
Deprotection. Cbz-protected product (0.17 mmol) was dissolved
in EtOH (15 mL) and Pd/C (30 wt %) and HCl (17 µL, 0.17 mmol,
1 equiv) were added. The mixture was hydrogenated in a Parr
apparatus at 30 psi of H2 overnight. The catalyst was filtered off
and the mixture was evaporated. The crude product was purified
by semipreparative RP-HPLC. Yield (22) ) 50%. Yield (23) )
55%.
Supporting Information Available: Characterizations of com-
pounds 14-23. HPLC spectra of compounds 20-23. This material
is available free of charge via the Internet at http://pubs.acs.org.
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