Bioorganic & Medicinal Chemistry Letters 10 (2000) 1175±1179
Design, Synthesis and SAR of a Series of 2-Substituted 4-
Amino-quinazoline Neuropeptide Y Y5 Receptor Antagonists
Heinrich Rueeger, a,* Pascal Rigollier, a Yasuchika Yamaguchi, a Tibur Schmidlin, a
Walter Schilling, a Leoluca Criscione, a Steven Whitebread, a Michele Chiesi, a
Mary W. Walker, b Dale Dhanoa b,y, Imadul Islam b,{
Jack Zhang b and Charles Gluchowski b,x
,
aNovartis Pharma AG, Metabolic and Cardiovascular Diseases, CH-4002 Basel, Switzerland
bSynaptic Pharmaceutical Corporation, 215 College Road, Paramus, NJ, USA
Received 8 October 1999; accepted 16 March 2000
AbstractÐThe design of a novel series of NPY-Y5 receptor antagonists is described. Key elements for the design were the identi®-
cation of weak Y5 hits from a Y1 program, results from a combinatorial approach and database mining. This led to the discovery of
the quinazoline 4 and the aryl-sulphonamide moiety as major components of the pharmacophore for Y5 anity. The synthesis and
SAR towards CGP71683A is described. # 2000 Elsevier Science Ltd. All rights reserved.
Neuropeptide Y (NPY), a 36 amino acid peptide, has been
the focus of much attention since its discovery as the most
abundant peptide in the mammalian brain.1 It is present in
a highly conserved manner across species and is involved
in a number of physiological responses and implicated in
the pathophysiology of several disorders. Within the
hypothalamus, NPY is intimately involved in the regula-
tion of several aspects of neuroendocrine function and
behavior, in particular food intake.2 At least six receptor-
subtypes have been characterized to date by pharmacolo-
gical and molecular cloning techniques.3,4 However, their
speci®c involvement in NPY mediated food intake reg-
ulation remains to be fully validated.
tion that the NPY-Y1 receptor is also involved in the
control of NPY-induced food intake.8 10 Our ®ndings,
however, indicate that the Y5-subtype shows more
robust evidence for an involvement in the regulation of
food intake.12 Antagonists for the NPY-Y5-subtype are,
therefore, required and targeted.
Herein, we disclose a novel series of potent and selective
NPY-Y5 antagonists that demonstrate that the Y5-sub-
type plays a major role in mediating food intake induced
by NPY.
We used an integrated approach of selected screening
and combinatorial chemistry to identify Y5-subtype
selective compounds. Exploitation of weak Y5 hits from
a previous Y1 program and exploration of the internal
compound library by Y5 pharmacophore models gener-
ated with Catalyst1, revealed the 2-substituted 4-ami-
noquinazolines 1±3 with sub-micromolar anity and
some selectivity towards the Y5-subtype.
Recently, the hypothetical ``feeding'' receptor, named
Y5, was cloned and expressed by Synaptic Pharmaceu-
tical Corporation.5 In collaboration with Novartis, evi-
dence was generated indicating that the NPY-Y5
receptor is the primary mediator of NPY-induced feed-
ing.6,7 However, other investigators made the observa-
In parallel to the optimization of the quinazoline scaf-
fold 4 by traditional methodology, a small biased com-
binatorial library was prepared in solution12 and on
solid support,13 based on the weak Y5 hit 5, con-
taining at least two distal hydrophobic moieties
namely a basic nitrogen containing scaold and an
H-bond acceptor functionality. These eorts resulted in
the identi®cation of compounds 6 and 7 (SNAP6608A),
*Corresponding author. Fax:+41-61-6965966;
e-mail: heinrich.rueeger@pharma.novartis.com
yPresent address: 3-D Pharmaceuticals Inc., 665 Stockton Drive,
Exton, PA 9341, USA.
{Present address: Berlex Bioscience, 15049 San Pablo Avenue, Rich-
mond, CA 94804-0099, USA.
xPresent address: RiboGene Inc., 26118 Research Rd. Hayward, CA
94545, USA.
0960-894X/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(00)00177-3