Lead development: validation and application of high throughput screening for determination of pharmacokinetic parameters for enzyme inhibitors.
An approach utilizing robotics (automation) for the rapid and reliable determination of protease inhibitor concentration in rat plasma samples is described. The bioassay protocol using an immobilized peptide substrate allows high sample throughput, compatible with parallel synthesis/SAR development strategy.
Singh
J
J
Department of Medicinal Chemistry, Sterling Winthrop Pharmaceutical Research Division, Collegeville, PA 19426-0900, USA.
Soloweij
J
J
Allen
M
M
Killar
L
L
Ator
M
M
D000595:Amino Acid Sequence; D000818:Animals; D001681:Biological Assay / Q000379:methods*; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D004305:Dose-Response Relationship, Drug; D005109:Extracellular Matrix / Q000201:enzymology; D005453:Fluorescence; D006801:Humans; D006868:Hydrolysis; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000432:Methanol / Q000737:chemistry; D008969:Molecular Sequence Data; D011480:Protease Inhibitors / Q000097:blood / Q000493:pharmacokinetics*; D051381:Rats; D011994:Recombinant Proteins / Q000378:metabolism; D015203:Reproducibility of Results; D012371:Robotics / Q000379:methods*; D013329:Structure-Activity Relationship; D013997:Time Factors
D011480:Protease Inhibitors; D011994:Recombinant Proteins; D008666:Metalloendopeptidases; D000432:Methanol