PARACYCLOPHANES - A NOVEL CLASS OF WATER-SOLUBLE INHIBITORS OF HIV PROTEINASE

A versatile synthesis of functionalized para- and metacyclophanes (mac rocycles with one or more aromatic rings incorporated; ansa-compounds) has been developed. Cyclophanes constitute a novel building block for potent human immunodeficiency virus (HIV) protease inhibitors. The sy nthesis of the macrocyclic ring system was achieved by regio- and ster eospecific ring opening of N-protected 4-amino-2,3-epoxy-5-phenylpenta noates with appropriate alpha,omega-diamines and consecutive ring clos ure under high dilution conditions. The resulting macrocyclic building blocks enabled further broad and flexible derivation. Paracyclophanes , containing oxyethylene substructures, were found to dissolve in phos phate-buffered saline at concentrations as high as 3 mg/mL at physiolo gical pH. Several derivatives with K-i values lower than 10 nM and ant iviral activities in the range of 15-50 nM have been obtained. The inf luence of the ring size and of the substitution pattern of the cycloph ane moiety on enzyme inhibition, antiviral activity, and water solubil ity are discussed. Preliminary data on oral bioavailability in mice ar e given for selected compounds.