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In Vitro Activity and Pharmacologic Properties of Two Novel Series of HCV Protease Inhibitors
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Reported by Jules Levin
43rd EASL Conference, April 23-27, 2008, Milan Italy
D Standring, C Parsy, F-R Alexandre, M Derock, F Leroy, T Convard, M La Colla, L Lallos, A-G Loi, C Musui, T Marceddu, B Podessu, L Vargui, M Liuzzi, and D Surleraux
AUTHOR CONCLUSIONS
IDX Protease Inhibitors exhibit
Subnanomolar potency against purified enzyme (low doses needed for suppression of HCV)
Single nanomolar potency in the replicon model
No interaction with 8 human proteases
Differences in resistance profile versus other PIs
Favorable early PK profile (BID/QD) - expect to be dosed once or twice daily
Two clinical candidates selected for scale-up and further evaluation:
--More detailed PK
--Early toxicology
Preferred IDX Scaffold is IDX-B
More potent in vitro antiviral activity against the purified 1b NS3/4A HCV protease (subnanomolar)
Single nanomolar potency in CV 1b replicon model
O inhibition of cellular proteases
Slower metabolism in human microsomes
Favorable PK profile
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