Automated high throughput ADME assays for metabolic stability and cytochrome P450 inhibition profiling of combinatorial libraries

Drug–Drug Interactions: Screening for Liability and Assessment of Risk

“…Typically concentrations in the 1-5 mM range are used [27,28]. Test compounds and vehicle control are incubated with the probe substrate and the amount of metabolite formation from the probe substrate determined.…”

Fast and Reliable CYP Inhibition Assays

“…Their advantages, limitations, and current applications are discussed. The main focus of this chapter is the methodology for in vitro assessment of CYP inhibitory potency, which is currently employed in the CYP inhibition assays using selective probe substrates and HLM followed by liquid chromatographymass spectrometry (LC -MS) analysis of metabolites of the probe substrates have been developed and validated for the defi nitive evaluation of drug candidates for their inhibitory effects in late discovery and drug development (Jenkins et al, 2004 ;Walsky and Obach, 2004 ;Yao et al, 2007 ). Results from HLM -LC -MS assays provide some key drug metabolism and pharmacokinetic (DMPK) information affecting the selection of clinical candidates, the design of clinical DDI studies, and regulatory fi lings for new drugs.…”

Enantiomeric separation and determination of absolute stereochemistry of asymmetric molecules in drug discovery—Building chiral technology toolboxes

“…[104][105][106][107][108][109][110][111][112][113][114] In the past, discovering a potential drug candidate focused ideally on finding a compound with nanomolar or better activity and exquisite selectivity toward the target receptor or enzyme. Now, the quality of compounds coming from drug discovery and entering development must also be dramatically improved with respect to their druglike properties, [115][116][117][118][119][120][121][122][123][124][125][126][127][128][129][130][131][132][133] i.e., physicochemical, pharmacokinetic, and safety (or toxicity and drug-drug interaction) properties, to reduce the attrition rate of drug candidates later in clinical trials. Structure-activity-relationship (SAR) studies are now carried out in parallel with structure-property-relationship (SPR) studies during lead optimization from the early exploratory phase all the way through the discovery phase into the predevelopment phase.…”