SYNTHESIS AND PHARMACOLOGICAL EVALUATION OF CGP-57813 AND CGP-61755, HIV-1 PROTEASE INHIBITORS FROM THE PHE-C-PHE PEPTIDOMIMETIC CLASS

In this report we describe the enzyme inhibitory, antiviral and pharma cokinetic properties of CGP 57813 and CGP 61755, structural analogues of CGP 53437 that were synthesized in an attempt to obtain human immun odeficiency virus type 1 (HIV-1) protease inhibitors with improved sel ectivity and oral bioavailability. CGP 57813 inhibited HIV-1 protease with an IC50 of 11 nM (similar to CGP 53437), CGP 61755, on the other hand, was c.a. 10-fold more potent (IC50 = 1 nM; similar to saquinavir and indinavir). The selectivity profile of CGP 57813 was comparable t o that of CGP 53437 while CGP 61755 clearly had improved selectivity f or HIV-1 protease over human aspartic proteases, All three compounds h ad similar antiviral activity in HIV-1/MN infected MT-2 cells; ED(50)s were c.a. 5 nM and ED(90)s were 30 nM. Compared to CGP 53437, both CG P 57813 and CGP 61755 had markedly better bioavailability in mice afte r oral administration in a DMSO-hydroxypropyl-beta-cyclodextrin formul ation, However, when CGP 57813 was administered in a sesame oil-based formulation to either mice or dogs no useful plasma concentrations cou ld be measured. In contrast, CGP 61755 was clearly bioavailable in dog s after oral administration of the compound in the same formulation; 1 .2 g per dog resulted in a mean AUC(0-8 h) = 21.06 +/- 3.53 mu M . h, a mean C-max = 4.8 +/- 0.52 mu M and compound was detectable for at le ast 8 h after administration. The potent antiviral activity of CGP 617 55 together with improved selectivity and oral bioavailability holds p romise for efficacy in AIDS therapy.