Song, Min Lee, Doohyun Kim, Sun Bae, Jong-Sup Lee, Jaeick Gong, Young-Dae Lee, Taeho Lee, Sangkyu 2024-01-20T09:04:56Z 2024-01-20T09:04:56Z 2021-09-05 2014-08 0090-9556 https://pubs.kist.re.kr/handle/201004/126542 KRO-105714 [ N-(5-benzoyl-2-(4-(2-methoxyphenyl)perazin-1-yl)thiazol-4-yl)pivalamide] is a 2,4,5-trisubstituted 1,3-thiazole derivative that exerts anti-atopic dermatitis activity via robust suppression of the sphingosylphosphorylcholine receptor. This study used high-resolution/high-accuracy tandem mass spectroscopy (HRMS) and recombinant cDNA-expressed cytochrome P450 (P450) iso-forms to identify the metabolic pathway and metabolites of KRO-105714 in human liver microsomes (HLMs) as therapeutic agents for inflammation. The incubation of KRO-105714 with pooled HLMs in the presence of NADPH generated four metabolites (M1-M4). The metabolites were identified using HRMS and confirmed using synthetic standards for M2 and M4. M1 and M2 were identified as monohydroxylated metabolites, and M3 and M4 were identified as O-demethyl KRO-105714 and C-demethyl KRO-105714, respectively. In the inhibition study with selective CYP3A4 inhibitors and incubation in recombinant cDNA-expressed P450 enzymes, all the metabolites of KRO-105714 were formed by CYP3A4 in HLMs. The CYP3A4-mediated formation of M4 from M2 was confirmed via incubation of M2 in HLMs. These results showed that the unusual C-demethylated metabolite M4 was generated from mono-hydroxyl metabolite M2 via a CYP3A4-mediated enzymatic reaction in HLMs. English AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS N-ACYL LINKAGE IN-VITRO RAT-LIVER O-DEALKYLATION SPHINGOSYLPHOSPHORYLCHOLINE SPECTROMETRY GLUCOSYLCERAMIDE SPHINGOMYELIN SPECIFICITIES INHIBITION Identification of Metabolites of N-(5-Benzoyl-2-(4-(2-Methoxyphenyl)piperazin-1-yl)thiazol-4-yl)pivalamid e Including CYP3A4-Mediated C-Demethylation in Human Liver Microsomes with High-Resolution/High-Accuracy Tandem Masss Article 10.1124/dmd.114.057570 1 DRUG METABOLISM AND DISPOSITION, v.42, no.8, pp.1252 - 1260 DRUG METABOLISM AND DISPOSITION 42 8 1252 1260 scie scopus 000339241400003 2-s2.0-84904188155 Pharmacology & Pharmacy Pharmacology & Pharmacy Article N-ACYL LINKAGE IN-VITRO RAT-LIVER O-DEALKYLATION SPHINGOSYLPHOSPHORYLCHOLINE SPECTROMETRY GLUCOSYLCERAMIDE SPHINGOMYELIN SPECIFICITIES INHIBITION