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Zhuo X, Cantone JL, Wang Y, et al. Phosphocholine conjugation: an unexpected in vivo conjugation pathway associated with hepatitis c ns5b inhibitors featuring a bicyclo[1.1.1]pentane. Drug Metab Dispos. 2016;44(8):1332-1340doi: 10.1124/dmd.115.069062.
Zhuo, X., Cantone, J. L., Wang, Y., Leet, J. E., Drexler, D. M., Yeung, K. S., Huang, X. S., Eastman, K. J., Parcella, K. E., Mosure, K. W., Soars, M. G., Kadow, J. F., & Johnson, B. M. (2016). Phosphocholine conjugation: an unexpected in vivo conjugation pathway associated with hepatitis c ns5b inhibitors featuring a bicyclo[1.1.1]pentane. Drug metabolism and disposition: the biological fate of chemicals, 44(8), 1332-1340. https://doi.org/10.1124/dmd.115.069062
Zhuo, Xiaoliang, et al. "Phosphocholine conjugation: an unexpected in vivo conjugation pathway associated with hepatitis c ns5b inhibitors featuring a bicyclo[1.1.1]pentane." Drug metabolism and disposition: the biological fate of chemicals vol. 44,8 (2016): 1332-1340. doi: https://doi.org/10.1124/dmd.115.069062
Zhuo X, Cantone JL, Wang Y, Leet JE, Drexler DM, Yeung KS, Huang XS, Eastman KJ, Parcella KE, Mosure KW, Soars MG, Kadow JF, Johnson BM. Phosphocholine conjugation: an unexpected in vivo conjugation pathway associated with hepatitis c ns5b inhibitors featuring a bicyclo[1.1.1]pentane. Drug Metab Dispos. 2016 Aug;44(8):1332-1340. doi: 10.1124/dmd.115.069062. Epub 2016 Mar 09. PMID: 26961241.
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Drug Metab Dispos. 2016 Aug;44(8):1332-1340. doi: 10.1124/dmd.115.069062. Epub 2016 Mar 09.

Phosphocholine conjugation: an unexpected in vivo conjugation pathway associated with hepatitis c ns5b inhibitors featuring a bicyclo[1.1.1]pentane.

Drug metabolism and disposition: the biological fate of chemicals

Xiaoliang Zhuo, Joseph L Cantone, Yingzi Wang, John E Leet, Dieter M Drexler, Kap-Sun Yeung, Xiaohua Stella Huang, Kyle J Eastman, Kyle E Parcella, Kathleen W Mosure, Matthew G Soars, John F Kadow, Benjamin M Johnson

Affiliations

  1. Bristol-Myers Squibb; [email protected].
  2. Bristol-Myers Squibb;
  3. Bristol-Myers Squibb Company.

PMID: 26961241 DOI: 10.1124/dmd.115.069062

Abstract

During a medicinal chemistry campaign to identify inhibitors of the hepatitis C virus nonstructural protein 5B (RNA-dependent RNA polymerase), a bicyclo[1.1.1]pentane was introduced into the chemical scaffold to improve metabolic stability. The inhibitors bearing this feature, 5-(3-(bicyclo[1.1.1]pentan-1-ylcarbamoyl)-4-fluorophenyl)-2-(4-fluorophenyl)-N-methyl-6-(3,3,3-trifluoropropyl)furo[2,3-b]pyridine-3-carboxamide (1) and 5-(3-(bicyclo[1.1.1]pentan-1-ylcarbamoyl)phenyl)-2-(4-fluorophenyl)-N-methyl-6-(3,3,3-trifluoropropyl)furo[2,3-b]pyridine-3-carboxamide (2), exhibited low turnover in incubations with liver S9 or hepatocytes (rat, human), with hydroxylation of the bicyclic moiety being the only metabolic pathway observed. In subsequent disposition studies using bile-duct-cannulated rats, the metabolite profiles of bile samples revealed, in addition to multiple products of bicyclopentane-oxidation, unexpected metabolites characterized by molecular masses that were 181 Da greater than those of 1 or 2. Further LC/MSn and NMR analysis of the isolated metabolite of 1 demonstrated the presence of a phosphocholine (POPC) moiety bound to the methine carbon of the bicyclic moiety through an ester bond. The POPC conjugate of the NS5B inhibitors was assumed to result from two sequential reactions: hydroxylation of the bicyclic methine to a tertiary alcohol and addition of POPC by CDP-choline: 1,2-diacylglycerol cholinephosphotransferase, an enzyme responsible for the final step in the biosynthesis of phosphatidylcholine. However, this pathway could not be recapitulated using CDP-choline-supplemented liver S9 or hepatocytes due to inadequate formation of the hydroxylation product in vitro. The observation of this unexpected pathway prompted concerns about the possibility that 1 and 2 might interfere with routine phospholipid synthesis. These results demonstrate the participation in xenobiotic metabolism of a process whose function is ordinarily limited to the synthesis of endogenous compounds.

The American Society for Pharmacology and Experimental Therapeutics.

Keywords: NMR; antivirals; drug design; mass spectrometry/MS; metabolite disposition; metabolite identification

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