title: Synthesis, stability and pharmacological evaluation of a novel codrug consisting of lamivudine and ursolic acid.
abstract: A novel codrug (LMX) was obtained from lamivudine (LMV) and ursolic acid (UA) coupled with ethyl chloroacetate through an amide and ester linkage. The structure of LMX was confirmed by ¹H NMR, ¹³C NMR, IR and HRMS. Herein, the in vitro non-enzymatic and enzymatic hydrolysis and in vivo pharmacological activities of LMX were studied. The kinetics of hydrolysis of LMX was studied in aqueous solution of pH 1-10, 80% buffered human plasma and in the presence of lipase from Porcine pancreas (EC 3.1.1.3) at 37°C. It is found that LMX hydrolysis rate was significantly faster in lipase with half-life of 1.4h compared to pH 7.4 phosphate buffer (t(1/2) 11.2h) and buffered human plasma (t(1/2) 5.4h). The decomposition rates in aqueous solution (pH 1-10) showed a U-shaped curve. LMX was comparatively stable between pH 3 and 6 (half-life >40 h). Pharmacological studies indicated that LMX had the dual action of anti-hepatitis B virus activity and hepatoprotective effects against acute liver injury. These findings suggest that LMX could be a promising candidate agent for the treatment of hepatitis.
authors.affiliation: School of Chemistry and Chemical Engineering, Southeast University, Nanjing 210096, PR China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhong
authors.forename: ZhaoHui
authors.initials: Z
authors.lastname: Dai
authors.forename: Yi
authors.initials: Y
authors.lastname: Xu
authors.forename: YanBo
authors.initials: Y
authors.lastname: Teng
authors.forename: Bin
authors.initials: B
authors.lastname: Wu
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D056486:Chemical and Drug Induced Liver Injury / Q000517:prevention & control; D004338:Drug Combinations; D004355:Drug Stability; D004372:Ducks; D006207:Half-Life; D018347:Hepadnaviridae Infections / Q000188:drug therapy; D015611:Hepatitis B Virus, Duck / Q000187:drug effects; D006524:Hepatitis, Viral, Animal / Q000188:drug therapy; D006801:Humans; D006863:Hydrogen-Ion Concentration; D006868:Hydrolysis; D019259:Lamivudine / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D008049:Lipase / Q000378:metabolism; D051379:Mice; D008813:Mice, Inbred ICR; D010949:Plasma / Q000737:chemistry / Q000201:enzymology; D011355:Prodrugs / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D020011:Protective Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D011897:Random Allocation; D014315:Triterpenes / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D000097245:Ursolic Acid
chemical_list: D000998:Antiviral Agents; D004338:Drug Combinations; D019259:Lamivudine; D008049:Lipase; D011355:Prodrugs; D020011:Protective Agents; D014315:Triterpenes; D000097245:Ursolic Acid