Letters
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 11 2025
Ta ble 2. Binding Affinities of Compounds 11a -h , 15, 22 to
dicular conformation with respect to the uracil core,
which in turn, may be preferred for π-π interaction
with the GnRH receptor. Deletion of the 6-methyl group
obviously leads to unrestricted rotation of the 5-phenyl
ring and thus reduces its binding capacity. By contrast,
the 6-ethyl group of 22 could be too large and thus
causes a steric clash with the binding pocket on the
receptor.
the Human GnRH Receptor9
While the principle goal of this study was to establish
SAR of a simple monocyclic core with low molecular
weight, we also want to take a first look at the basic
pharmacokinetic profiles for possible orally active agents.
9a was then selected for mouse and human liver
microsome stability study and mouse pharmacokinetic
experiments. In vitro, 9a exhibited relatively poor
metabolic stability with intrinsic clearance of 347 mL/
min‚kg and 84 mL/min‚kg in the mouse and human
liver microsomes, respectively. The predicted hepatic
extraction was 79% for both mouse and human. In vivo,
upon oral administration (10 mg/kg) in the mice, 25%
of this compound made to the blood circulation, which
suggested 75% hepatic extraction. This compound had
high clearance (CL ) 120 mL/min‚ kg) in the mice with
and a Vd value of 4.2 l/kg and a half-life of 0.4 h. Oral
bioavailability was 1.6%. The high lipophilicity8 of this
compound may be associated with the poor metabolic
stability and thus low oral bioavailibility. Further
optimization of this series of compounds is required to
reduce lipophilicity and therefore increase metabolic
stability.
In conclusion, on the basis of the SAR of the bicyclic
analogues, we have successfully designed and synthe-
sized a series of novel and potent monocyclic uracil
GnRH antagonists. The initial work on this series
provided us with new directions for obtaining orally
active GnRH antagonists.
Ack n ow led gm en t. This work was supported, in
part, by National Institutes of Health grants 1-R43-
HD38625-01 and 2-R44-HD38625-02.
enantiomer (9e) was much preferred than the other one
(9f), and its affinity was within 5-fold of 9a . In the
meantime the impact of the substitution on the 5-phenyl
group was examined, and the results are shown in Table
2. The unsubstituted compound, 11a , was more than
10-fold less potent than 9a , indicating that the 3-meth-
oxy group may provide a productive H-bonding acceptor.
Replacement of the methoxy group by 3,4-methylene-
dioxy (11b) or 3,4-ethylenedioxy (11c) generated equally
potent molecules. However, replacement with the polar
3-hydroxyl group (11d , 480 nM) reduced the binding
affinity significantly, as did the trifluoromethoxy group
(11e, 4800 nM), again illustrating the need for a
hydrogen bond acceptor. This requirement was further
confirmed by 11f, where deletion of the oxygen led to
lower potency. Shifting the methoxy group from the 3-
to the 4-position also resulted in a substantial reduction
in potency (11g, 230 nM). Nevertheless, switch of the
4-methoxy to the 4-phenoxy fully regained the potency
(11h , 30 nM), implying possible hydrophobic interaction
of the extra phenyl group with the receptor. The
enhancement of binding by the 6-methyl group on the
uracil core was recognized by comparing the methyl
analogue 9a to hydrogen and ethyl analogues (15, 22)
on the 6-position, respectively; the latter two gave very
poor binding affinities. Our speculation is that the
6-methyl group forces the 5-phenyl ring into a perpen-
Su p p or tin g In for m a tion Ava ila ble: Description of the
binding assay, stepwise syntheses, and characterization of
compounds 9a and 11c. This material is available free of
Refer en ces
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