768395-84-2Relevant academic research and scientific papers
Dipeptidomimetic ketomethylene isosteres as pro-moieties for drug transport via the human intestinal di-/tripeptide transporter hPEPT1: Design, synthesis, stability, and biological investigations
V?ben?, Jon,Nielsen, Carsten Uhd,Ingebrigtsen, Truls,Lejon, Tore,Steffansen, Bente,Luthman, Kristina
, p. 4755 - 4765 (2007/10/03)
Five dipeptidomimetic-based model prodrugs containing ketomethylene amide bond replacements were synthesized from readily available α,β- unsaturated γ-ketoesters. The model drug (BnOH) was attached to the C-terminus or to one of the side chain positions of the dipeptidomimetic. The stability, the affinity for the di-/tripeptide transporter hPEPT1, and the transepithelial transport properties of the model prodrugs were investigated. ValΨ[COCH2]-Asp(OBn) was the compound with highest chemical stability in buffers at pH 6.0 and 7.4, with half-lives of 190 and 43 h, respectively. All five compounds showed high affinity for hPEPT1 (Ki values 2]Asp(OBn) and ValΨ[COCH 2]Asp(OBn) had the highest affinities with Ki values of 68 and 19 μM, respectively. An hPEPT1-mediated transport component was demonstrated for the transepithelial transport of three compounds, a finding that was corroborated by hPEPT1-mediated intracellular uptake. The results indicate that the stabilized Phe-Asp and Val-Asp derivatives are promising pro-moieties in a prodrug approach targeting hPEPT1.
