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This study investigated the oral bioavailability and efficacy of BILS 45 BS, a selective herpes simplex virus (HSV) helicase-primase inhibitor, against acyclovir (ACV)-resistant (ACV(r)) infections mediated by the HSV type 1 (HSV-1) dlsptk and PAA(r)5 mutant strains. In vitro, the compound was more potent than ACV against wild-type clinical and laboratory HSV-1 strains and ACV(r) HSV isolates, as determined by a standard plaque reduction assay, with a mean 50% effective concentration of about 0.15 microM. The oral bioavailability of BILS 45 BS in hairless mice was 49%, with a peak concentration in plasma of 31.5 microM after administration of a single dose of 25 mg/kg. Following cutaneous infection of nude mice, both the HSV-1 dlsptk and PAA(r)5 mutant strains induced significant, reproducible, and persistent cutaneous lesions that lasted for more than 2 weeks. Oral treatment with ACV (100 or 125 mg/kg/day, three times a day by gavage) did not affect either mutant-induced infection. In contrast, BILS 45 BS at an oral dose of 100 mg/kg/day almost completely abolished cutaneous lesions mediated by both ACV(r) HSV-1 mutants. The 50% effective doses of BILS 45 BS were 56.7 and 61 mg/kg/day against dlsptk- and PAA(r)5-induced infections, respectively. Taken together, our results demonstrate very effective oral therapy of experimental ACV(r) HSV-1 infections in nude mice and support the potential use of HSV helicase-primase inhibitors for the treatment of nucleoside-resistant HSV disease in humans.

Starting from palinavir (1), our lead HIV protease inhibitor, we have discovered a new series of truncated analogues in which the P(3)-P(2) quinaldic-valine portion of 1 was replaced by 2', 6'-dimethylphenoxyacetyl. With EC(50)'s in the 1-2 nM range, some of these compounds are among the most potent inhibitors of HIV replication in vitro, reported to date. One of the most promising members in this series (compound 27, BILA 2185 BS) exhibited a favorable overall pharmacokinetic profile, with 61% apparent oral bioavailability in rat. X-ray crystal structures and molecular modeling were used to rationalize the high potency resulting from incorporation of this structurally simple, achiral ligand into the P(3)-P(2) position of hydroxyethylamine-based HIV protease inhibitors.

A novel series of hydroxyethylamine-based inhibitors of HIV protease which contain a substituted pipecolinic amide were developed. After preliminary screening, a representative of this series, compound BILA 2185 BS, demonstrated an IC50 value of 3.3 nM in the enzymatic assay and an EC50 value of 2.0 nM in cell culture. The plasma profile and bioavailability values for BILA 2185 BS in the rat will be presented. The analyte was isolated from rat plasma using a liquid-liquid extraction procedure. The analytical technique used utilizes a high performance liquid chromatography system with photodiode array detector. The range of the standard curve was from 10 to 5000 nM. Recovery values averaged 72.4 +/- 8.6% (mean +/- S.D.). The limit of detection for BILA 2185 BS was 6-12 nM.