Somatostatin (SS14) is a 14-amino acid peptide produced by a
wide variety of cell types in the CNS
stage to enable versatile variations to this part of the molecule.
Alternatively, azide II can react with an iso-nitrile with R4 group
pre-installed to generate intermediate VII, which was treated with
methyldiphenylphosphine to give 3,4-dihydroquinazoline-4-
carboxylic amide VIII. Alkylation of this compound gave bromo-
and gut and has pleiotropic effects.1 SS14 acts through both
endocrine, paracrine, and nerve pathways to affect its target cells
via a family of five receptors: sst1, sst2, sst3, sst4, and sst5.2, 3
Many of these effects result in the regulation of other hormones,
such as growth hormone (GH), glucagon, and insulin. SS14
inhibits the secretion of GH from the pituitary mainly via
activation of the sst2 and sst5 receptors.4
substituted
3,4-dihydroquinazoline-4-carboxamide
VI.
Subsequent Suzuki coupling followed by removal of protecting
group ultimately produced final compound IX.
The activation of sst2 by an agonist results in the decrease of
intracellular cyclic adenosine monophosphate (cAMP) in
functional cell-based assays.17 Breifly, Chinese hamster ovary
(CHO-K1) cells stably expressing the human sst2 receptor were
treated with NKH477, a soluble analog of forskolin, to induce the
production of cAMP. Upon agonist activation, the level of
intracellular cAMP is decreased in a concentration-dependent
manner, which allows the measurement of the potency of the
compound (EC50) to guide the study of structure activity
relationships (SAR).
Acromegaly is a rare disease in which a pituitary adenoma
results in the over-production of GH and subsequent elevation of
6
insulin-like growth factor 1 (IGF-1) levels.5, This loss of
homeostasis in the GH axis results in excess tissue growth and
other adverse metabolic effects throughout the body. If
transsphenoidal surgery to remove the adenoma is unsuccessful or
only partially successful, the first-in-line medical treatment for
acromegaly is the use of injectable somatostatin peptide analogs
(SSAs). Octreotide, lanreotide, and pasireotide are SSAs approved
by the FDA for the treatment of acromegaly, carcinoid tumor
As illustrated in Table 1, the initial hit 4 showed an EC50 of 38
nM in the functional assay, however, removing the N-methyl
group on the amide completely suppressed its ability to reduce
cAMP production (5). Deletion of the chloro-substitution on the 7
8
symptom control, or neuroendocrine tumors.7, They are most
commonly delivered monthly by intramuscular or deep
subcutaneous injections which require office visits and often lead
to injection site discomfort or pain.9 In addition to the burden on
the patient, SSAs like octreotide have undesirable properties and
side effects: octreotide is known to induce receptor
NH2
NH2
OH
O
phosphorylation, internalization, and desensitization responses,
N
S
11
limiting their therapeutic benefits.10,
Pasierotide suppresses
N
HN
N N
insulin secretion in the pancreas and results in hyperglycemia.12
Furthermore, many acromegaly patients under SSA treatment fail
to achieve normalization of IGF-1 levels and/or experience a
return of symptoms near the end of their injection cycle.
Consequently, an orally bioavailable and selective sst2 agonist that
could reduce counter-regulatory activities to improve efficacy is
highly desirable.
Cl
N
1
2
sst2/5 agonist
sst2 agonist
NH2
NH2
(S)
Cl
OH
CF3
N
O
N
Cl
N
N
3
Cl
N
Figure 1. Selected examples of nonpeptide sst2 agonists
4
sst2 agonist
initial hit
sst2 agonist
The search for nonpeptide sst2 agonists have been attempted by
many groups, and the representative examples are illustrated in
Figure 1. For instance, the triazole analog 1 was found to be a
potent sst2 and sst5 dual agonist.13 Compound 2 represents another
class of molecules reported to be selective sst2 agonists.14 Most
recently, an aminopyridine analog 3 was revealed to be a sst2
agonist.15 Based on chemical series reported in the literature, we
designed and synthesized a small but focused library featuring
diverse chemical structures, which led to the discovery of several
novel hits. Among them, the 3,4-dihydroquinazoline
pharmacophore as exemplified by compound 4 exhibited good
potency for sst2. In comparison to literature compound 2, which
contains lipophilic quinoline scaffold substituted with ether linker,
the 3,4-dihydroquinazoline carboxamide scaffold appears to be
more hydrophilic itself, thus allowed us to have more leeway to
use relatively hydrophobic side chains if necessary, maintaining
the balance of hydrophobicity and hydrophilicity.
position of the 3,4-dihydroquinazoline core also decreased agonist
activity more than 10-fold (6). Extending the length of the alkyl
group adjacent to the top primary amine enhanced sst2 potency
about 3-fold (EC50=11 nM) (7). Interestingly, agonist potency was
further improved when the 7-chloro group was replaced by a
methyl group (8). In an effort to reduce the total number of proton
donors and flexible bonds, the top primary amine was replaced
with a pyrrolidine fragment, resulting in compound 9, which also
improved potency to 1.3 nM. We subsequently carried out a rapid
SAR campaign on substituent R6 and found that halogens are well
tolerated and that Cl is preferred (compound 10-11).
With these results, we examined the impact of a 6-aryl
substituent to 3,4-dihydroquinazoline pharmacophore. The
original phenol group pharmacophore could potentially pose a
safety risk in development, although many approved drugs contain
phenol motifs.18 These results are summarized in Table 2. Initially,
it was revealed that truncating the hydroxyl group significantly
diminished sst2 agonist activity (12). Our SAR efforts then mainly
became focused on identifying suitable alternatives. We attempted
to use a substituted phenyl without hydrogen bond donors
(compounds 13-16), however, only nitrile (13, EC50=5.4 nM) was
tolerated whereas Cl and CF3 groups dramatically reduced agonist
potency. Introducing heterocycles, i.e. pyrazole, substantially
reduced potency as well (17). Notably, a fluoro-substitution to the
meta position of the cyano group boosted agonist potency to 1.3
nM (18). Replacing the cyano group with fluoro or methoxy group
did not further improve sst2 activity (19-20). We next examined
whether the phenol group could be replaced by its isosteric groups,
The synthesis of 3,4-dihydroquinazoline-4-carboxamides is
illustrated in Scheme 1. In this sequence, nucleophilic replacement
to fluoro-benzaldehyde I generated azide intermediate II which
underwent
dimethoxyethyl)-2-isocyanobenzene
a
multi-component Ugi reaction with 1-(2,2-
to afford 3,4-
dihydroquinazoline precursor III.16 The azide group was
subsequently reduced with methyldiphenylphosphine followed by
an acid-mediated cyclization to yield IV. Removal of the indole
protecting group furnished 3,4-dihydroquinazoline-4-carboxylic
acid V. This compound can either directly couple with a protected
secondary amine or a primary amine followed by alkylation to
produce amide VI. The top amide bond was constructed at the final
Betz, Stephen F.
