A novel method for assessing inhibition of ibuprofen chiral inversion and its application in drug discovery.
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.
Reddy
Anita
A
Preclinical Discovery-Development, Pfizer Global Research and Development, Ann Arbor Laboratories, Ann Arbor, MI 48105, USA. Electronic address: anita.reddy@pfizer.com.
Hashim
Muhammed
M
Preclinical Discovery-Development, Pfizer Global Research and Development, Ann Arbor Laboratories, Ann Arbor, MI 48105, USA.
Wang
Ziqiang
Z
Chemistry, Pfizer Global Research and Development, Ann Arbor Laboratories, Ann Arbor, MI 48105, USA.
Penn
Lara
L
Bioanalytical Research, Pharmacokinetics, Dynamics and Metabolism, Pfizer Global Research and Development, Ann Arbor Laboratories, Ann Arbor, MI 48105, USA.
Stankovic
Charles J
CJ
Preclinical Discovery-Development, Pfizer Global Research and Development, Ann Arbor Laboratories, Ann Arbor, MI 48105, USA.
Burdette
Douglas
D
Preclinical Discovery-Development, Pfizer Global Research and Development, Ann Arbor Laboratories, Ann Arbor, MI 48105, USA.
Surendran
Narayanan
N
Preclinical Discovery-Development, Pfizer Global Research and Development, Ann Arbor Laboratories, Ann Arbor, MI 48105, USA.
Cai
Hongliang
H
Preclinical Discovery-Development, Pfizer Global Research and Development, Ann Arbor Laboratories, Ann Arbor, MI 48105, USA.
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*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D004364:Pharmaceutical Preparations; D006867:Hydrolases; D019998:Racemases and Epimerases; D003066:Coenzyme A Ligases; D007052:Ibuprofen