SBIR-STTR Award

A large number of pharmacologically-active compounds synthesized in the Discovery phase of pharmaceutical R&D are rejected either because of unsuitable pharmacokinetics, or because of interactions with existing therapeutic drugs. In many cases this is because the compounds are either substrates or inhibitors of one or more cytochrome P450 enzyme isoforms. Our goal is to develop methodologies that will provide information about drug candidate interactions with cytochrome P450 enzymes early in drug discovery. We propose to develop fluorescence based assays sensitive enough to test in a cost-effective manner all discrete compounds in the repositories of large pharmaceutical companies for interactions with the major human cytochrome P450 enzymes involved in drug metabolism. Existing fluorogenic substrates either have poor kinetics, or the enzyme needed to novel that would make large scale screening affordable. We proposed to synthesize substrates that are efficiently metabolized by human cytochrome P450 enzymes to yield highly fluorescent products. Assays utilizing these novel substrates will be validates with known cytochrome 450 inhibitors and licensed to pharmaceutical companies for use in high throughput profiling of their entire compound libraries for interactions with cytochrome P450 isozymes. PROPOSED COMMERCIAL APPLICATIONS: A shorter discovery cycle due to improved pharmacokinetic information is estimated to save at least one year and $4M per discovery program. More rapid progression to market for a top-selling drug could be worth >$100M per year saved. Products and services for sale will include Fluorogenic CYP450 substrates, CYP450-inhibition screening kits; Screening services; Licensing of screening technologies, Access to SAR-data from Aurora's in- house CYP450 inhibition screens.

A large number of pharmacologically-active compounds synthesized in the Discovery phase of pharmaceutical R&D are rejected either because of unsuitable pharmacokinetics, or because of interactions with existing therapeutic drugs. In many cases this is because the compounds are either substrates or inhibitors of one or more cytochrome P450 enzyme isoforms. Our goal is to develop methodologies, which will provide information about drug candidate interactions with cytochrome P450 enzymes early in drug discovery. We propose to develop screens both for standard 384 well microtiter plate formats and also for Aurora's proprietary ultra-high throughput, highly miniaturized 3,456 well NanoPlateTM format based on fluorogenic substrates developed and validated in Phase 1. We will screen Aurora Biosciences Corporation's entire compound collection (approximately 500,000 compounds by 3Q 2000), and generate SAR relationships using state of the art computational tools. The information gained from screening will permit CYP450 interaction screens to become an integral part of Aurora's screen portfolio. The results of the SAR analysis will further our understanding of drug metabolism by cytochrome P450 enzymes and allow early elimination of unsuitable compounds and chemical series from further development. PROPOSED COMMERCIAL APPLICATIONS: A shorter discovery cycle due to improved pharmacokinetic information is estimated to save at least one year and $4M per discovery program. More rapid progression to market for a top-selling drug could be worth >$100M per year saved. Products and services for sale will include: Fluorogenic CYP450 substrates; CYP450-inhibition screening kits; Screening services; Licensing of screening technologies, Access to SAR- data from Aurora's in-house CYP450 inhibition screens.