Drug discovery method

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ABSTRACT:The application discloses a method for selecting Hepatitis C (HCV) inhibitors that form long-lived, tight complexes (EI complex) with their targets (eg NS3/4a protease). It also discloses the compound VX-950 which has such properties and its medical use for treating HCV infection and eliminating HCV contamination. The use of cellular viral replication assays for selecting viral inhibitors are equally claimed.

This invention addresses the above problems by providing novel drug discovery methods and compounds identified by those methods. Presently, it takes between three and five years to bring new potentially therapeutic compounds from the early discovery to preclinical development (in vivo animal testing). This lead time requires a tremendous commitment of company resources. Understandably, a technique that could predict the efficacy of the multitude compounds that arrive at or near the initial synthesis stage of drug discovery would have an enormous impact on the efficiency with which new drugs are identified by eliminating, early in the drug discovery process, compounds that have an unfavorable efficacy profile. An immediate expected benefit of more powerful, early stage in vitro effcicacy testing is the reduction of the number of these three to five year drug discovery cycles that result in failures, and thus reduce the average number of cycles required to develop successful new therapeutics. Related benefits include reduced costs for drug development and more rapid availability of new pharmaceuticals to the medical community. The present invention provides methods for prioritizing new chemical entities within a class for further development or for identifying such compounds as appropriate lead compounds that will be effective as therapeutic agents early in the drug development and discovery process. As such, these methods can be used to prioritize large numbers of new compounds for further drug development. In addition, the methods greatly increase the probability that an identified agent will be successful in preclinical efficacy testing. The adaptability of these in vitro methods for high-throughput analysis makes them an economical and cost-effective addition to a drug discovery program. In particular, the present invention relates to the kinetics of inhibitors of infectious agents and is directed to a drug discovery method comprising comparing a time a reversible inhibitor is bound to a target of an infectious agent; and a replication time of an infectious agent, or a life-cycle time of the infectious agent. Using such determinations, the present invention teaches methods for selecting a compound having activity against an infectious agent, comprising selecting a target in the agent; identifying a compound that binds reversibly with the target; determining the half life of the compound on the target; determining the half life of the replication cycle of the infectious agent; and selecting a compound that has a half life on the target of at least about 25% of the time of an average life cycle for the infectious agent. Other embodiments are directed to methods of selecting a compound having activity against an infectious agent, comprising selecting a target in the agent; identifying a compound that binds reversibly with the target; determining the half life of the compound on the target; determining the half life of the replication cycle of the infectious agent; and selecting a compound that has a half life on the target of at least about 25% of the half life of the replication cycle of the infectious agent. In still further embodiments, the selection methods described herein are directed to selecting a compound having activity against an infectious agent, comprising selecting a target in the agent; identifying a compound that binds reversibly with the target; determining the half life of the compound on the target; determining the half life of the replication cycle of the infectious agent; and selecting a compound that has a half life on the target of at least about 25% of the time of the target's turnover. Typically, the may be about 25%, about 50%, about 75%, about 100%, about 125%, about 150%, about 175%o, about 200%o, about 225%, about 250%, about 275% to about 300%. These are merely exemplary percentages and other integers in between any of these numbers are contemplated to be determinable and encompassed by the parameters set forth herein. The invention further is directed to a method for selecting a compound as an anti-infective agent against a target of the agent, wherein the half life of the compound bound to the target is from about 25% to about 300% of the half life of the infective agent, from about 25% to about 300% of the replication time of the infective agent, or from about 25% to about 300% of the half life of the target turnover. The methods described herein comprise performing an in vitro measurement of compound k0ff or enzyme-compound (i.e., enzyme-inhibitor) complex half life. In further embodiments, the invention involves a demonstration of a delayed maximal response in a viral replication system or a replicon system. In some aspects of the invention, the methods involve measuring sustained effects in inhibitor wash-out studies using a cellular replicon or replication system. The methods of the invention form an adjunct to drug discovery methods wherein the methods may involve performing a first determination of e.g., the half life on the target of the compound as compared to the time of an average life cycle for the infectious agent and a second method that determines the half-life vis a vis another parameter. Additional embodiments are directed to methods of selecting a viral inhibitor, comprising demonstrating a delayed maximal response in a viral replication system or a replicon system. Other methods involve assaying compounds for activity against an infectious agent, comprising determining a) a time a reversible inhibitor is bound to a target of the infectious agent; and b) a replication time of the infectious agent. In the methods of the invention, the infectious agent may be a virus having a fast replicating life cycle. An exemplary such virus is Hepatitis C virus. In specific embodiments, the target for the methods described herein is Hepatitis C virus NS3/4A protease.