Antiviral InteliStrat Inc.

Benzothiadiazine cpnd, derived from A-782759;

Acts as non-nucleoside inhibitor of HCV RNA-dependent, RNA polymerase (NS5B gene)

Ref.: Lu L et al., Antiviral Res. 2007 Oct;76(1):93-7 (www.ncbi.nlm.nih.gov/pubmed/17561278)

In rats and dogs, A-837093 displayed an oral plasma half-life of greater than 7 h, and its bioavailability was >60%;

In monkeys it had a half-life of 1.9 h and 15% bioavailability

Ref.: Chen CM et al., Antimicrob Agents Chemother. 2007 Dec;51(12):4290-6 (www.ncbi.nlm.nih.gov/pubmed/17908950)

In vitro selection of variants with reduced susceptibility to A-837093 has given the following results (mutations in viral NS5B gene encoding RNA polymerase):

• Mutation S368A, inducing a 173- to 547-fold loss of drug susceptibility and some loss of replicative capacity
• Mutation Y448H, inducing a 19-fold loss of drug susceptibility and some loss of replicative capacity
• Mutation G554D, inducing a 244- to 918-fold loss of drug susceptibility and some loss of replicative capacity
• Mutation Y555C, inducing a 198-fold loss of drug susceptibility and a significant loss of replicative capacity
• Mutation D559G, inducing a 110- to 288-fold loss of drug susceptibility and a significant loss of replicative capacity
• Combined mutations Y448H/Y586C, inducing a 115-fold loss of drug susceptibility
• Combined mutations G554D/S121A, inducing a 798-fold loss of drug susceptibility
• Combined mutations K155R/D177D,Y/D559G, inducing a 203-fold loss of drug susceptibility

Mutants S368A, Y448H, G554D and D559G retained susceptibility to thiophene cpnd of Shire/Virochem

Ref.: Data presented at 57th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD), Oct. 27-31, 2006, Boston (Lu et al.); Lu L et al., Antiviral Res. 2007 Oct;76(1):93-7 (www.ncbi.nlm.nih.gov/pubmed/17561278)

Results of an animal proof-of-concept study were published by Chen CM et al., Antimicrob Agents Chemother. 2007 Dec;51(12):4290-6 (www.ncbi.nlm.nih.gov/pubmed/17908950), in which 2 chimpanzees infected with HCVGT1a and GT1b, respectively, were given an oral dosing of 30 mg/kg of body weight twice a day for 14 days, followed by a 14-day posttreatment observation:

• Maximum viral load reductions of 1.4 and 2.5 log10 copies RNA/mL for GT1a- and 1b-infected chimpanzees, respectively, were observed within 2 days after the initiation of treatment; After this initial drop in the viral load, a rebound of plasma HCV RNA was observed in the GT1b-infected chimpanzee, while the GT1a-infected chimpanzee experienced a partial rebound that lasted throughout the treatment period
• Mutations associated with resistance to A-837093, including Y448H, G554D, and D559G in the GT1a-infected chimpanzee and C316Y and G554D in the GT1b-infected chimpanzee were identified (some of them were previously identified in in vitro selection experiments, see Resistance data)

EC50: 6 nM (replicon system, viral genotype 1b)

EC50: 42 nM (replicon system, viral genotype 1b, with 40% human serum)

EC50: 6 nM (replicon system, viral genotype 1b)

EC50: 42 nM (replicon system, viral genotype 1b, with 40% human serum)

EC50: 11 nM (replicon system, viral genotype 1a)

EC50: 143 nM (replicon system, viral genotype 1a, with 40% human serum)

CCIC50: 32.2 μM

Ref.: Data presented at 57th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD), Oct. 27-31, 2006, Boston