National Center for
1HVR: RATIONAL DESIGN OF POTENT, BIOAVAILABLE, NONPEPTIDE CYCLIC UREAS AS HIV PROTEASE INHIBITORS
Science (1994) 263 p.380-384
Mechanistic information and structure-based design methods have been used to design a series of nonpeptide cyclic ureas that are potent inhibitors of human immunodeficiency virus (HIV) protease and HIV replication. A fundamental feature of these inhibitors is the cyclic urea carbonyl oxygen that mimics the hydrogen-bonding features of a key structural water molecule. The success of the design in both displacing and mimicking the structural water molecule was confirmed by x-ray crystallographic studies. Highly selective, preorganized inhibitors with relatively low molecular weight and high oral bioavailability were synthesized.