ITMN-5489 AASLD
Identification of Novel Non-Macrocyclic Inhibitors of HCV NS3/4A Serine Protease Activity
B. O. Buckman1; L. Pan1; L. Huang1; K. Kossen1; R. Rajagopalan1; S. Misialek1; S. K. Stevens1; H. Tan1; D. Ruhrmund1; V. Serebryany1; J. Matulik-Adamic1; A. Stoycheva1; S. Ammons1; D. K. Fuhrer1; L. M. Blatt1; L. Beigelman1; S. Seiwert1
1. Intermune, Inc, Brisbane, CA, USA.
Background: Agents that target the serine protease activity of NS3/4A have emerged as potentially significant components of therapies targeting the HCV virus. An agent’s dosing convenience, side effect profile, and efficacy all bear on its clinical utility. Here we describe a non-macrocyclic compound that has emerged from our ongoing drug discovery efforts involving macrocyclic and non-macrocyclic protease inhibitors. The performance characteristics of this compound, ITMN-5489, compare favorably with ITMN-191, the latter compound having recently demonstrated robust antiviral activity and promising safety in initial clinical studies.
Methods: Structure guided drug design was used in a campaign to refine potency, ADME properties and exposure in animals.
Results: Ongoing discovery efforts have identified a series of non-macrocylic compounds with favorable in-vitro and pharmacokinetic characteristics. Among these, ITMN-5489 displays an EC50 of ~1 nM against a genotype 1b replicon and 81 nM provides HCV replicon clearance in 14 day antiviral assays. The profile of inhibition against of a panel of 79 proteases and other cellular proteins suggests that off-target effects would compare favorably to several NS3/4A inhibitors currently in clinical development. ITMN-5489 exhibits significant stability in hepatocytes derived from rat, monkey and human, and plasma protein binding is uniform across these species. In primates, plasma exposure of ITMN-5489 compares favorably to that of ITMN-191. ITMN-5489 plasma concentrations 24 hours after dosing are higher than the 12 hr post dose concentration of ITMN-191 and overall AUC is 5 to 10 fold higher for ITMN-5489. Primate liver exposure of ITMN-5489 is > 7 fold higher than that of ITMN-191, and its liver to plasma ratio is approximately 60.
Conclusions: In short duration clinical studies, administration of ITMN-191 under both q12h and q8h schedules has shown very favorable virologic response and safety profiles. Here, we report a novel inhibitor of NS3/4A with in-vitro and pharmacokinetics characteristics, including exposure in primate that compare favorably to ITMN-191. ITMN-5489, like ITMN-191, shows a significantly higher concentration in liver as compared to plasma. Both plasma and liver exposure of ITMN-5489 are higher than those of ITMN-191, suggesting lower doses of this agent may achieve similar antiviral effect. The significant concentrations present 24 hours post dosing suggest once daily regimens may be possible with ITMN-5489.
