Summary

Name:

A-837093

Synonyms:

A-837,093; A837093; A 837093

Sponsor:

Abbott / AbbVie (global presence)

Type of product:

Inhibitor

Viral family:

Flaviviridae

Status:

Preclinical
No further development

Structure

Structure A-837093  C24H27N3O6S2

Formula:

C24H27N3O6S2

Molecular weight:

517.62

A-837093 

Synonyms:A-837,093; A837093; A 837093       Sponsor:Abbott / AbbVie (global presence)       Type of product:Inhibitor       Mode of action:RNA Pol IN       Viral family:Flaviviridae       Virus:HCV (Hepatitis C virus)      

Details

Characteristics:

Benzothiadiazine cpnd, derived from A-782759;

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

 

Ref.: Lu et al., Antiviral Res. 2007 Oct;76(1):93-7

PK Data, Dosage or Route of Administration:

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 et al., Antimicrob Agents Chemother. 2007 Dec;51(12):4290-6

Resistance:

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

 

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 et al., Antiviral Res. 2007 Oct;76(1):93-7

In vivo and clinical data:

Results of an animal proof-of-concept study were published by Chen et al., Antimicrob Agents Chemother. 2007 Dec;51(12):4290-6, 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)

Activity in vitro

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

 

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

Development status

Preclinical
No further development

Remarks

Benzothiadiazine derivative developed as non-nucleoside inhibitor of HCV RNA polymerase;

 

Abbott's antiviral program focused on HCV



Formula: C24H27N3O6S2
Molecular weight: 517.62