Isomeric thiazole derivatives as ligands for the neuropeptide Y5 receptor

Article abstract of DOI:10.1016/j.bmcl.2005.05.009

Sets of isomeric thiazole derivatives 1 and 2 have been synthesised in a parallel iterative solution-phase synthesis approach guided by the SAR analysis derived from biological results and computer-aided design and analysis. This synergistic and streamlined working procedure led to highly active isomeric NPY5 receptor ligands. However, a 10-fold difference at least in their respective binding affinities was consistently found for all isomeric pairs 1 and 2. The analysis of conformational differences due to heteroatom interactions in 1 and 2 revealed a favourable C=O...S interaction in 1, whereas thiazoles 2 showed a repulsive C=O...N interaction.

Full text of DOI:10.1016/j.bmcl.2005.05.009

Bioorganic & Medicinal Chemistry Letters 15 (2005) 3446–3449
Isomeric thiazole derivatives as ligands
for the neuropeptide Y5 receptor
Matthias Nettekoven,* Wolfgang Guba, Werner Neidhart, Patrizio Mattei,
Philippe Pflieger, Olivier Roche and Sven Taylor
F. Hoffmann-La Roche Ltd, Pharmaceutical Research Basel, Discovery Chemistry, CH-4070 Basel, Switzerland
Received 7 March 2005; revised 26 April 2005; accepted 2 May 2005
Abstract—Sets of isomeric thiazole derivatives 1 and 2 have been synthesised in a parallel iterative solution-phase synthesis
approach guided by the SAR analysis derived from biological results and computer-aided design and analysis. This synergistic
and streamlined working procedure led to highly active isomeric NPY5 receptor ligands. However, a 10-fold difference at least
in their respective binding affinities was consistently found for all isomeric pairs 1 and 2. The analysis of conformational differences
due to heteroatom interactions in 1 and 2 revealed a favourable C@OÁ Á ÁS interaction in 1, whereas thiazoles 2 showed a repulsive
C@OÁ Á ÁN interaction.
Ó 2005 Elsevier Ltd. All rights reserved.
Neuropeptide Y is a 36 amino acid peptide that is widely
distributed in the central and peripheral nervous sys-
tems. This peptide mediates a number of physiological
effects through its various receptor subtypes. Studies
on animals have shown that neuropeptide Y is a power-
ful stimulus of food intake, and it has been demon-
strated that activation of neuropeptide Y Y5 receptors
results in hyperphagia and decreased thermogenesis.
Therefore, the compounds that antagonise neuropeptide
Y at the Y5 receptor subtype represent an approach to
the treatment of eating disorders such as obesity and
hyperphagia.1–3 In the course of a medicinal chemistry
programme aimed towards the identification of novel
NPY5 receptor ligands, thiazole derivatives have been
previously described as interesting scaffolds.4,5 A versa-
tile procedure was developed towards the synthesis of
isomeric aminothiazole derivatives 1 and 2, thus allow-
ing for maximum flexibility in the design of new
NPY5 ligands having three main vectors of diversity.
The parallel iterative solution-phase synthesis of the ser-
ies of compounds of 1 and 2 demonstrates a streamlined
working procedure in which the latest biological results
were combined with the results from modelling activi-
ties. Any derived SAR was synergistically integrated
into the design and synthesis of new thiazole derivatives
in new synthetic rounds.6 Both synthetic routes started
from the common thiourea intermediate 3, which al-
ready defines the first vector of diversity. Pursuing the
first synthetic route, four subsequent steps were required
to arrive at the desired aminothiazole derivatives 1. The
C1 elongation of thiourea 3 by the reaction with N,N-
dimethylamino dimethylformamide gave access to the
iminourea 4 in 90% yield. The thiazole ring was formed
from the reaction of 4 with a-bromoketones, in this par-
ticular case 2-methylphenacyl bromide, in acceptable
77% yield.7 Obviously, this vector of diversity may easily
be altered by use of various a-bromoketones to arrive at
a structure activity relationship with respect to substitu-
tion patterns and electronic properties. Deprotection of
the amino functionality in 4 was followed by derivatisa-
tion with electrophiles (sulfonylchlorides, acid chlorides
and isocyanates) to add a third vector of diversity. In to-
tal, 50 thiazoles 1 with this particular sub-structure were
synthesised in synthetically useful yields depending on
the reactivity of the respective electrophile (Scheme 1).
twenty-nine sulfonamide thiazole derivatives 1 were ob-
tained, from which a preliminary SAR was derived.
However, to further improve our knowledge about re-
lated thiazoles, the isomeric counterparts of 1 seemed
to be interesting. Aminothiazole derivatives 2 were
obtained from a similarly versatile synthetic sequence.
The common starting thiourea 3 was reacted with 3-bro-
mo-1-o-tolyl-propane-1,2-dione8 to access the N-Boc
protected thiazole derivative 5 in 71% yield. Again, a
Keywords: Conformational analysis; Neuropeptide Y5; Iterative
parallel solution-phase chemistry; SAR; Thiazoles.
*
Corresponding author. Tel.: +41 61 6886227; fax: +41 61 6886459;
e-mail: matthias.nettekoven@roche.com
0960-894X/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2005.05.009

M. Nettekoven et al. / Bioorg. Med. Chem. Lett. 15 (2005) 3446–3449
3447
Scheme 1. Synthetic route towards isomeric thiazole derivatives 1 and 2.
variation of the bromo propanedione led to the intro-
duction of further diversity. Further manipulation
through cleavage of the Boc group with HCl and subse-
quent reaction with electrophiles gave access to 35 amino
thiazoles 2 in synthetically useful yields. A set of 11 sulfon-
amide thiazole derivatives 2 was synthesised and could be
conveniently compared to their isomeric counterparts 1.
All compounds synthesised were tested for their bind-
ing affinity at the mouse NPY5 receptor. Ureas and
amide derivatives 1 and 2 were, in general, less potent
than the sulfonamide derivatives 1 and 2. In Table 1,
the IC50 values and, respectively, the % inhibition
data at 1 lM are shown for some pairs of isomeric
sulfonamide derivatives 1 and 2. With these sets of
Table 1. Inhibition data of selected sulfonamide derivatives 1 and 2 at the mNPY5 receptor
No
mNPY5 IC50 or inhibition at 1 lM
R
mNPY5 IC50 or inhibition at 1 lM
No
1a
5.5 nM
64 nM
2a
1b
1c
1d
1e
1f
9.9 nM
11 nM
16%
2b
2c
2d
2e
2f
12%
0.71 nM
1.6 nM
0.85 nM
1.0 nM
6 nM
17 nM
9 nM
11 nM
1g
2g

3448
M. Nettekoven et al. / Bioorg. Med. Chem. Lett. 15 (2005) 3446–3449
Figure 1. Conformations corresponding to the minimum energies for the thiazole isomers 1 and 2. The arrows represent the torsional angles sampled
in both isomers.
compounds the general SAR trend is nicely
illustrated.
carbonyl oxygen. The potential energy difference be-
tween the bent minimum and the extended conforma-
tion of thiazole 2 is 10 kJ/mol with the CDIE model
and 7 kJ/mol with the GB/SA model, which is in agree-
ment with the 10-fold IC50 shift, corresponding to a free
energy difference of 5.7 kJ/mol. Of course, the change in
potential energies is only a fraction of the observed free
energy difference, which also includes the interaction en-
ergy and entropy. Nevertheless, this comparison clearly
shows that an extended conformation is preferred for
the binding to the NPY5 receptor. The results of this
analysis will be further pursued and integrated in the de-
sign of new NPY5 receptor ligands.
In general, thiazoles 1 show low nanomolar binding
affinities for the mouse receptor. The nature of the sub-
stituents influenced the inhibition potential. Electron
withdrawing and pushing (e.g., 1a–1c) substituents show
similar IC50 values and also the positioning of the sub-
stituents seemed to have a minor influence. The combi-
nation of two substituents led to thiazoles (e.g., 1d–1f)
with IC50 values in the picomolar range. In general, het-
eroaromatic substitution is allowed as well (e.g., 1g).
The isomeric counterparts 2 showed, in general, at least
a 10-fold lower binding affinity, however, still producing
compounds in the nanomolar range. The SAR trends
for thiazoles 1 and 2 are very similar (e.g., 2a–2g).
In conclusion, sets of isomeric thiazole derivatives 1 and
2 have been synthesised in a parallel iterative solution-
phase synthesis approach guided by the SAR analysis
derived from biological results and computer-aided de-
sign and analysis. This synergistic and streamlined
working procedure led to highly active isomeric ligands
for the NPY5 receptor. However, a 10-fold difference at
least in their respective binding affinities was consis-
tently found for all isomeric pairs 1 and 2. The analysis
of conformational differences due to heteroatom interac-
tions in 1 and 2 revealed a favourable C@OÁ Á ÁS interac-
tion in 1, whereas thiazoles 2 showed a repulsive
C@OÁ Á ÁN interaction. In the design of new NPY5 recep-
tor ligands, this result will be incorporated in the quest
towards new compounds with preferable biological
and pharmacokinetic profiles. The variation of the bis-
amino linker moiety needs to be further explored. This
is currently under investigation in our laboratories and
will be reported in due course.
To understand the origin of the 10-fold shift of the bind-
ing affinity between thiazoles 1 and 2, a conformational
analysis was performed using MacroModel 8.6.9 For
this analysis, thiazole isomers have been reduced to their
core scaffolds since the shift is consistent over the whole
sulfonamide SAR (see Fig. 1). Three torsional angles
have been sampled with 5000 steps of Monte Carlo
search (MCMM), followed by 1000 steps of energy
minimization (PRCG). The solvent effect has been mod-
elled either with a dielectric constant (CDIE) of 4 or
with a Generalized Born/Surface Area (GB/SA) water
model. The results are similar in both models.
Figure 1 displays the energy minima for the thiazole iso-
mers 1 and 2. They both have in common a rotation of
the phenyl ring with respect to the carbonyl function of
58° induced by the methyl substituent, but the two
structures differ in the torsional angle between the car-
bonyl function and the heterocycle. On the one hand,
the more potent thiazole 1 series displayed a favourable
interaction between the carbonyl oxygen and the sulfur
stabilising an extended conformation. This type of
C@OÁ Á ÁS interaction, with a distance significantly below
Acknowledgments
It is with real pleasure that we wish to thank all our col-
laborators whose contributions made the described
work possible and so enjoyable, especially Dr. F. Daut-
zenberg, Dr. A. Bourson-Sleight, Dr. M. Klug and Dr.
M. Stahl.
˚
the sum of van der Waals radii (<3.3 A), is highly
favourable as explored both statistically and theoreti-
cally by Iwaoka et al.10 This is further corroborated
by more than 100 molecules with a similar atom
arrangement, which can be found in the Cambridge
Structural Database.11 On the other hand, the thiazole
2 series favours a bent conformation due to the repulsive
interaction between the thiazole nitrogen and the
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