title: A novel method for assessing inhibition of ibuprofen chiral inversion and its application in drug discovery.
abstract: An inhibition assay to assess the potential for chiral inversion of compounds was developed using R(-)-ibuprofen as the probe substrate. Inhibition of the chiral inversion of R(-)-ibuprofen by structurally similar compounds in cyropreserved rat hepatocytes was studied using chiral HPLC and LC/MS methods for the chromatographic separation and detection of enantiomers. Concept validation of this assay was performed with three commercially available compounds and four Pfizer compounds. The results of these studies demonstrated that compounds that are structurally similar to ibuprofen inhibited the formation of S(+)-ibuprofen, suggesting that they may undergo similar enzymatic chiral inversion pathways or compete for the same enzyme active sites. Additionally, an application of this assay in early drug discovery for a specific class of compounds was demonstrated. Thirty-three in-house compounds were screened for their chiral inversion potential utilizing this assay to investigate the structure activity relationship (SAR) for this class of compounds.
authors.affiliation: Preclinical Discovery-Development, Pfizer Global Research and Development, Ann Arbor Laboratories, Ann Arbor, MI 48105, USA. Electronic address: anita.reddy@pfizer.com.
authors.forename: Anita
authors.initials: A
authors.lastname: Reddy
authors.affiliation: Preclinical Discovery-Development, Pfizer Global Research and Development, Ann Arbor Laboratories, Ann Arbor, MI 48105, USA.
authors.forename: Muhammed
authors.initials: M
authors.lastname: Hashim
authors.affiliation: Chemistry, Pfizer Global Research and Development, Ann Arbor Laboratories, Ann Arbor, MI 48105, USA.
authors.forename: Ziqiang
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Bioanalytical Research, Pharmacokinetics, Dynamics and Metabolism, Pfizer Global Research and Development, Ann Arbor Laboratories, Ann Arbor, MI 48105, USA.
authors.forename: Lara
authors.initials: L
authors.lastname: Penn
authors.affiliation: Preclinical Discovery-Development, Pfizer Global Research and Development, Ann Arbor Laboratories, Ann Arbor, MI 48105, USA.
authors.forename: Charles J
authors.initials: CJ
authors.lastname: Stankovic
authors.affiliation: Preclinical Discovery-Development, Pfizer Global Research and Development, Ann Arbor Laboratories, Ann Arbor, MI 48105, USA.
authors.forename: Douglas
authors.initials: D
authors.lastname: Burdette
authors.affiliation: Preclinical Discovery-Development, Pfizer Global Research and Development, Ann Arbor Laboratories, Ann Arbor, MI 48105, USA.
authors.forename: Narayanan
authors.initials: N
authors.lastname: Surendran
authors.affiliation: Preclinical Discovery-Development, Pfizer Global Research and Development, Ann Arbor Laboratories, Ann Arbor, MI 48105, USA.
authors.forename: Hongliang
authors.initials: H
authors.lastname: Cai
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000378:metabolism*; D001667:Binding, Competitive; D002851:Chromatography, High Pressure Liquid / Q000379:methods*; D003066:Coenzyme A Ligases / Q000378:metabolism; D015925:Cryopreservation; D004285:Dogs; D015195:Drug Design; D022781:Hepatocytes / Q000187:drug effects* / Q000201:enzymology; D006867:Hydrolases / Q000037:antagonists & inhibitors / Q000378:metabolism; D007052:Ibuprofen / Q000737:chemistry / Q000378:metabolism*; D066298:In Vitro Techniques; D007275:Injections, Intravenous; D007700:Kinetics; D008252:Macaca fascicularis; D015394:Molecular Structure; D004364:Pharmaceutical Preparations / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism; D019998:Racemases and Epimerases / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015203:Reproducibility of Results; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D053719:Tandem Mass Spectrometry / Q000379:methods*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D004364:Pharmaceutical Preparations; D006867:Hydrolases; D019998:Racemases and Epimerases; D003066:Coenzyme A Ligases; D007052:Ibuprofen