Lipophilicity screening of novel drug-like compounds and comparison to clogP

Abstract

We determined the distribution coefficients of solutes between a polymer film phase (polyvinyl chloride (PVC) with 67% (w/w) dioctyl sebacate (DOS)) and an aqueous phase in a 96-well format. The parallel measurement approach is efficient and uses very little material. Polymer-water distribution coefficients (Dpw) at different pH values yield the pKa and polymer-water partition coefficient values (Ppw) of the solutes. Log Ppw of a prominent drug-like compound, 2H-1, 2, 6-thiadiazine, 3-methyl-5-phenyl-, 1, 1-dioxide, is in good agreement with cLogP, while the pKa value is substantially different from calculated values. This method has been also successfully applied to a library of novel drug-like compounds. Log Dpw values (at pH 4.0, 7.0, 10.0) of 24 novel drug-like compounds have been determined with good reproducibility with the 96-well plate approach. Differences between experimental values and a variety of available calculated values are significant. This emphasizes the need for laboratory separations-based measurements of logD.

Novel Pyrimidines as Multitarget Protein Tyrosine Kinase Inhibitors for the Treatment of Idiopathic Pulmonary Fibrosis (IPF)

“…46), showing its good overall capability to penetrate the cell membrane. [35,36] All these test results clearly indicated that these structural modifications, which were inspired by our previous structure and activity relationship (SAR) explorations are rational and effective. Moreover, this study further confirmed the benefit of 1-substitutedacetamide linker in the C-2 aniline, and revealed that the morpholine substituent (6 a,c,d,h) in the C-2 aniline side chain of the pyrimidine core is more favorable than the piperazine ring (6 b,e,f,g) at the same position.…”

“…Moreover, compound 6 a has low toxicity against the normal human bronchial epithelioid (HBE) cells at concentration lower than 2.78 μM. In addition, compound 6 a displayed a moderate cLog P value (4.46), showing its good overall capability to penetrate the cell membrane …”

Incorporating a Monofluoroalkene into the Backbones of Short Peptides: Evaluating the Impact on Local Hydrophobicity

“…The log P and log D values—representing the partition and the distribution coefficients, respectively, of a compound between H 2 O and octan‐1‐ol—are widely used . A computational approach to calculating the intrinsic hydrophobicity of an amino acid residue in a peptide has also been established …”

Fragmental Method KowWIN as the Powerful Tool for Prediction of Chromatographic Behavior of Novel Bioactive Urea Derivatives

“…It should be stressed that in some cases these relationships require corrections considering ionization of the analytes. 21,22 In recent years, several adsorbents imitating the biological membranes have been developed. The artificial biological membranes with immobilized phosphatidylcholine, ceramides, keratin, proved to be useful in drug design process, to compare lipophilicity, modeling bioavailability or anticipate the process of the cell membrane permeation.…”