An atomic and molecular view of the depth dependence of the free energies of solute transfer from water into lipid bilayers.

Molecular interactions and orientations responsible for differences in 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) bilayer partitioning of three structurally related drug-like molecules (4-ethylphenol, phenethylamine, and tyramine) were investigated. This work is based on previously reported molecular dynamics (MD) simulations that determined their transverse free energy profiles across the bilayer. Previously, the location where the transfer free energy of the three solutes is highest, which defines the barrier domain for permeability, was found to be the bilayer center, while the interfacial region was found to be the preferred binding region.

Functional group dependence of solute partitioning to various locations within a DOPC bilayer: a comparison of molecular dynamics simulations with experiment.

Atomic-level molecular dynamics simulations of 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) bilayers containing small, amphiphilic, drug-like molecules were carried out to examine the influence of polar functionality on membrane partitioning and transport. Three related molecules (tyramine, phenethylamine, and 4-ethylphenol) were chosen to allow a detailed study of the isolated effects of the amine and hydroxyl functionalities on the preferred solute location, free energies of transfer, and the effect of combining both functional groups in a same molecule. Transfer free energy profiles (from water) generated from molecular dynamics (MD) simulations as a function of bilayer depth compared favorably to comparable experimental results.

Substituent effects on the ionization and partitioning of p-(aminoethyl)phenols and structurally related compounds: electrostatic effects dependent on conformation.

Computational methods to predict pK(a) values and partition coefficients of drug molecules based on linear free energy relationships (LFERs) rely largely on the principles of independence and additivity of the functional group contributions in each molecule to the overall free energy. Nonadditivities in functional group contributions are often seen when multiple polar functional groups are in close proximity and in cases where conformational flexibility allows widely separated polar functional groups to interact. The degree to which long-range interactions may alter group contributions in more conformationally constrained molecules such as p-(aminoethyl)phenol and structurally similar analogs is more difficult to predict.

Metabolism of 5-isopropyl-6-(5-methyl-1,3,4-oxadiazol-2-yl)-N-(2-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (BMS-645737): identification of an unusual N-acetylglucosamine conjugate in the cynomolgus monkey.

5-Isopropyl-6-(5-methyl-1,3,4-oxadiazol-2-yl)-N-(2-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (BMS-645737) is a potent and selective vascular endothelial growth factor receptor-2 antagonist. In this study, liquid chromatography/tandem mass spectrometry and NMR were used to investigate the biotransformation of BMS-645737 in vitro and in the cynomolgus monkey, dog, mouse, and rat. Metabolic pathways for BMS-645737 included multistep processes involving both oxidation and conjugation reactions.

Influence of intravesicular pH drift and membrane binding on the liposomal release of a model amine-containing permeant.

Accurate determination of intrinsic permeability coefficients is critical to the development of structure-permeability relationships and liposomal delivery systems. The apparent release rate of a drug from liposomes may reflect not only its intrinsic permeability coefficient and barrier properties but also a variety of underlying equilibria including drug ionization, membrane binding or complexation, and kinetic processes such as buffer exchange. Additionally, transport of ionizable drugs that are initially at high concentrations in liposomes can generate or dissipate pH gradients across the barrier causing deviations from classical pH-permeability profiles.

Discovery and development of 5-[(5S,9R)-9-(4-cyanophenyl)-3-(3,5-dichlorophenyl)-1-methyl-2,4-dioxo-1,3,7-triazaspiro[4.4]non-7-yl-methyl]-3-thiophenecarboxylic acid (BMS-587101)--a small molecule antagonist of leukocyte function associated antigen-1.

LFA-1 (leukocyte function-associated antigen-1), is a member of the beta2-integrin family and is expressed on all leukocytes. This letter describes the discovery and preliminary SAR of spirocyclic hydantoin based LFA-1 antagonists that culminated in the identification of analog 8 as a clinical candidate. We also report the first example of the efficacy of a small molecule LFA-1 antagonist in combination with CTLA-4Ig in an animal model of transplant rejection.

Bioavailability enhancement of a poorly water-soluble drug by solid dispersion in polyethylene glycol-polysorbate 80 mixture.

Oral bioavailability of a poorly water-soluble drug was greatly enhanced by using its solid dispersion in a surface-active carrier. The weakly basic drug (pK(a) approximately 5.5) had the highest solubility of 0.