Program Abstr Intersci Conf Antimicrob Agents Chemother. 1996 Sep
A rational drug design strategy using crystallographic information
generated from several HIV Protease-inhibitor complexes has led to the
discovery of a novel series of highly potent, non-peptidic and cyclic
inhibitors of the HIV protease. The new structure of these compounds
possesses a C(2) symmetric diol which resembles the transition state of
the enzyme-catalyzed reaction. In addition, the complete lack of the
amide functionality in the structure prevents these molecules from
proteolytic cleavage. The structural water in the active site was
displaced by the oxygen atom of the SO(2) group in the cyclic scaffold.
The side chains of the cyclic structure occupy only S(1)(S(1)) and
S(2)(S(2)) regions of the enzyme active site. Those structural features
are different from HIV protease inhibitors described previously. One
member of this class, GS 3333 (Ki less than 1 nM, IC(90)=40 nM in MT2
cells) was selected for further evaluation of pharmacokinetics and oral
bioavailability. A single 10 mg/kg oral dose of GS 3333 administered to
dogs (n=5/group) gave the following pharmacokinetic profiles: F=74%,
C(max)=3.3 micrograms/mL, t(1/2)=4.7h. The duration that the plasma drug
concentration remained 20 times above IC(90) exceeded 12 hours.
Preliminary structure activity relationships will also be presented.
*HIV Protease Inhibitors/CHEMICAL SYNTHESIS *Sulfones/CHEMISTRY