CYCLIC UREA AMIDES - HIV-1 PROTEASE INHIBITORS WITH LOW NANOMOLAR POTENCY AGAINST BOTH WILD-TYPE AND PROTEASE INHIBITOR RESISTANT MUTANTS OF HIV

Cyclic urea amides, a novel series of HIV-1 protease (HIV PR) inhibito rs, have increased activity against drug-resistant mutants of the HIV PR. The design strategy for these inhibitors is based on the hypothese s that (i) the hydrogen-bonding interactions between the inhibitor and the protease backbone will remain constant for wild-type and mutant e nzymes and (ii) inhibitors which are capable of forming many nonbonded interactions, distributed throughout the active site, will experience a lower percent change in binding energy as a result of mutation in t he target enzyme than those that form fewer interactions by partial oc cupation of the active site. The cyclic urea amide, SD146, forms 14 hy drogen bonds and 191 van der Waals contacts to HIV PR. SD146 is a very potent antiviral agent (IC90 = 5.1 nM) against wild-type HIV and pote ncy against a range of mutant strains of HIV with resistance to a wide variety of HIV protease inhibitors.