RATIONAL DESIGN OF POTENT, BIOAVAILABLE, NONPEPTIDE CYCLIC UREAS AS HIV PROTEASE INHIBITORS

Mechanistic information and structure-based design methods have been u sed to design a series of nonpeptide cyclic ureas that are potent inhi bitors of human immunodeficiency virus (HIV) protease and HIV replicat ion. A fundamental feature of these inhibitors is the cyclic urea carb onyl oxygen that mimics the hydrogen-bonding features of a key structu ral water molecule. The success of the design in both displacing and m imicking the structural water molecule was confirmed by x-ray crystall ographic studies. Highly selective, preorganized inhibitors with relat ively low molecular weight and high oral bioavailability were synthesi zed.