Metabolic Soft Spot and Pharmacokinetics: Functionalization of C-3 Position of an Eph-Ephrin Antagonist Featuring a Bile Acid Core as an Effective Strategy to Obtain Oral Bioavailability in Mice.
Eph–ephrin system
UniPR129
UniPR500
high-resolution mass spectrometry (HR-MS)
in vivo PK
metabolite ID
Journal
Pharmaceuticals (Basel, Switzerland)
ISSN: 1424-8247
Titre abrégé: Pharmaceuticals (Basel)
Pays: Switzerland
ID NLM: 101238453
Informations de publication
Date de publication:
28 Dec 2021
28 Dec 2021
Historique:
received:
29
11
2021
revised:
23
12
2021
accepted:
24
12
2021
entrez:
21
1
2022
pubmed:
22
1
2022
medline:
22
1
2022
Statut:
epublish
Résumé
UniPR129, an L-β-homotryptophan conjugate of the secondary bile acid lithocholic acid (LCA), acts as an effective protein-protein interaction (PPI) inhibitor of the Eph-ephrin system but suffers from a poor oral bioavailability in mice. To improve UniPR129 bioavailability, a metabolic soft spot, i.e., the 3α-hydroxyl group on the LCA steroidal ring, was functionalized to 3-hydroxyimine. In vitro metabolism of UniPR129 and 3-hydroxyimine derivative UniPR500 was compared in mouse liver subcellular fractions, and main metabolites were profiled by high resolution (HR-MS) and tandem (MS/MS) mass spectrometry. In mouse liver microsomes (MLM), UniPR129 was converted into several metabolites: M1 derived from the oxidation of the 3-hydroxy group to 3-oxo, M2-M7, mono-hydroxylated metabolites, M8-M10, di-hydroxylated metabolites, and M11, a mono-hydroxylated metabolite of M1. Phase II reactions were only minor routes of in vitro biotransformation. UniPR500 shared several metabolic pathways with parent UniPR129, but it showed higher stability in MLM, with a half-life (
Identifiants
pubmed: 35056098
pii: ph15010041
doi: 10.3390/ph15010041
pmc: PMC8779995
pii:
doi:
Types de publication
Journal Article
Langues
eng
Subventions
Organisme : Italian Association for Cancer Research
ID : IG15211
Références
J Biol Chem. 1964 Jan;239:102-5
pubmed: 14114827
J Lipid Res. 2015 Jun;56(6):1085-99
pubmed: 25210150
Drug Metab Dispos. 2008 Feb;36(2):442-51
pubmed: 18039809
Biochemistry. 1998 Dec 8;37(49):17179-91
pubmed: 9860831
J Pharm Biomed Anal. 2020 Feb 20;180:113067
pubmed: 31891876
Eur J Med Chem. 2020 Mar 1;189:112083
pubmed: 32000051
Drug Metab Dispos. 2013 Jul;41(7):1295-9
pubmed: 23571428
Steroids. 1986 Apr-May;47(4-5):221-47
pubmed: 3473753
Eur J Pharm Sci. 2020 Dec 1;155:105544
pubmed: 32927068
Biochim Biophys Acta. 1999 Apr 19;1438(1):47-54
pubmed: 10216279
Biochem Pharmacol. 2018 Jan;147:21-29
pubmed: 29129483
Cell. 2008 Apr 4;133(1):38-52
pubmed: 18394988
J Lipid Res. 1989 Jun;30(6):907-18
pubmed: 2794781
Elife. 2016 Jun 28;5:
pubmed: 27350048
J Biol Chem. 1968 Jun 25;243(12):3493-9
pubmed: 4385344
Cell. 2007 Apr 20;129(2):359-70
pubmed: 17448994
Rapid Commun Mass Spectrom. 2010 Nov 15;24(21):3157-62
pubmed: 20941763
J Med Chem. 2006 Feb 9;49(3):1207-11
pubmed: 16451086
J Biol Chem. 2003 May 16;278(20):17838-44
pubmed: 12637555
Br J Pharmacol. 2014 Dec;171(23):5195-208
pubmed: 24597515
Biochem Pharmacol. 1994 Apr 29;47(9):1469-79
pubmed: 8185657
Drug Metab Dispos. 2013 Sep;41(9):1616-20
pubmed: 23756265
J Pharm Biomed Anal. 2011 Jul 15;55(5):1111-9
pubmed: 21530128
Proc Natl Acad Sci U S A. 2001 Mar 13;98(6):3375-80
pubmed: 11248086
Drug Metab Dispos. 1999 Nov;27(11):1350-9
pubmed: 10534321
Eur J Med Chem. 2015 Oct 20;103:312-24
pubmed: 26363867
Curr Opin Cell Biol. 2007 Oct;19(5):534-42
pubmed: 17928214
J Med Chem. 2017 Jan 26;60(2):787-796
pubmed: 28005388
Int J Mol Sci. 2021 Mar 01;22(5):
pubmed: 33804570
J Med Chem. 2013 Apr 11;56(7):2936-47
pubmed: 23489211
Expert Opin Ther Targets. 2020 May;24(5):403-415
pubmed: 32197575
Cell Mol Life Sci. 2008 Aug;65(16):2461-83
pubmed: 18488143
Drug Metab Rev. 2004 Oct;36(3-4):703-22
pubmed: 15554243
Biochim Biophys Acta. 2005 Feb 21;1687(1-3):84-93
pubmed: 15708356