Objectives

  • Profiling of a representative set of 560 macrolides on several PhysChem properties and their comparison with 29000 small molecules
  • Investigating the link to cellular and in vivo PK properties with a rationally designed subset of macrolides

 

R3 – R6 = various hydrophilic and hydrophobic, aliphatic, alicyclic, aromatic and heteroaromatic substituents

Methodology

  • HPLC based bio-mimetic binding data were measured – automated platform for high-throughput measurements of physico-chemical properties
    • Lipophilicity determination – ChromLogD
    •  Acid/base (pKa) estimation
    •  Human serum albumin binding
    •  Alpha – 1-acidglycoprotein binfding
    •  Immobilised Artificial Membrane partition
  • Mimic biological systems – dynamic equilibrium processes on large surfaces
  • Cellular accumulation = accumulation in NCI-H292 cells in 3h, expressed relative to azithromycin
  • Cellular retention and in vivo PK parameters (rat) ranged from low-high clearance (CL); moderate-high Vdss, moderate-long t1/2, low-moderate oral bioavailability were also measured and used for developing QSAR models
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