Pye, Cameron R. published the artcileNonclassical Size Dependence of Permeation Defines Bounds for Passive Adsorption of Large Drug Molecules, Safety of (S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-phenylpropanoic acid, the publication is Journal of Medicinal Chemistry (2017), 60(5), 1665-1672, database is CAplus and MEDLINE.
There is a growing number of intracellular protein-protein interactions (PPI’s) with potential therapeutic importance that demand larger ligands than those that neatly fit into most common criteria for “drug-likeness”. Macrocyclic peptides pro-vide the large surface area required to inhibit PPIs and, in principle, avoid many of the pitfalls associated with peptides, including low stability and membrane permeability. However, the design of passively cell-permeable mols. in this space remains a great challenge due to the poorly understood roles of mol. size and lipophilicity in determining passive membrane permeability above MW â?00. Using split-pool combinatorial synthesis, we constructed a library of cyclic, per-N-methlyated peptides spanning a wide range of calculated lipohilicities (0 < AlogP < 8) and mol. weights (â?00 Da < MW < â?200 Da). Assaying mixtures of compounds using the Parallel Artificial Membrane Assay (PAMPA) revealed a steep drop-off in apparent passive permeability with increasing size and a bilinear relationship with lipophilicity. We observed a size dependence of permeability that is in stark disagreement with current permeation models. The lipophilicities required to overcome this size penalty led to poor aqueous solubility, effectively bounding the chem. space of likely passively permeable mols. This understanding provides a new set of design criteria for achieving permeability in larger mol. size regimes and suggests an operational cut-off beyond which passive permeability is constrained by a sharply increasing penalty on permeation through the system.
Journal of Medicinal Chemistry published new progress about 77128-73-5. 77128-73-5 belongs to ethers-buliding-blocks, auxiliary class Inhibitor, name is (S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-phenylpropanoic acid, and the molecular formula is C25H23NO4, Safety of (S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-phenylpropanoic acid.
Referemce:
https://en.wikipedia.org/wiki/Ether,
Ether | (C2H5)2O – PubChem