Lipophilicity Of Inhibitors Research Articles

Modulation of the lipophilicity and molecular size of thiosemicarbazone inhibitors to regulate tyrosinase activity

A group of 5-methylsalicylaldehyde thiosemicarbazone derivatives (HMTs) bearing different lipophilic and steric substituents attached at the 3-position of cresol ring were synthesized and investigated as mushroom tyrosinase (TYR) inhibitors. The ability of HMTs to inhibit the diphenolase activity of TYR was evaluated with L-DOPA as substrate by determining IC50 values in relation to their structure modifications. HMTs displayed distinct inhibitory competencies towards TYR activity with IC50 values in the range of 1.02–143.56 μM. A close correlation between their inhibition potency and both lipophilicity and molecular size was observed. The inhibitory effect of the hydroxyethyl-containing derivatives was much higher than the hydroxyethyl-free ones overall. Among them, HMT-NBO exhibited the most potent effect with IC50 of 5.85 μM, which was nearly 25-fold and 3.8-fold lower than its parent HMT-NBE and the control kojic acid, respectively. The hydroxyethyl clearly benefited the improvement of the inhibitory competences and acted as a regulating group of lipophilicity of the inhibitors. The kinetic analyses showed that HMTs were reversible and mixed type inhibitors against mushroom TYR. The inhibition mechanism was studied by means of fluorescence spectroscopy, FT-IR, ESI-MS and molecular docking analysis. The results indicated that the observed inhibitory effect of HMTs was accomplished by acting on the amino acid residues rather than by chelating the centre copper ions of TYR. Each of HMTs can insert the hydrophobic pocket and interact with the residues of TYR through Van der Waals forces and hydrogen bonds, with additional electrostatic interactions for HMT-NEE and HMT-NEO further strengthening the affinity. Meanwhile, the inhibitors were observed to bind with L-DOPA or/and L-DOPAquinone forming 1:1 stoichiometric complexes, probably exerting indirect inhibition against TYR activity.

Structure-activity relationships of rationally designed AMACR 1A inhibitors

α-Methylacyl-CoA racemase (AMACR; P504S) is a promising novel drug target for prostate and other cancers. Assaying enzyme activity is difficult due to the reversibility of the ‘racemisation’ reaction and the difficulties in the separation of epimeric products; consequently few inhibitors have been described and no structure–activity relationship study has been performed. This paper describes the first structure–activity relationship study, in which a series of 23 known and potential rational AMACR inhibitors were evaluated. AMACR was potently inhibited (IC50 = 400–750 nM) by ibuprofenoyl-CoA and derivatives. Potency was positively correlated with inhibitor lipophilicity. AMACR was also inhibited by straight-chain and branched-chain acyl-CoA esters, with potency positively correlating with inhibitor lipophilicity. 2-Methyldecanoyl-CoAs were ca. 3-fold more potent inhibitors than decanoyl-CoA, demonstrating the importance of the 2-methyl group for effective inhibition. Elimination substrates and compounds with modified acyl-CoA cores were also investigated, and shown to be potent inhibitors. These results are the first to demonstrate structure–activity relationships of rational AMACR inhibitors and that potency can be predicted by acyl-CoA lipophilicity. The study also demonstrates the utility of the colorimetric assay for thorough inhibitor characterisation.

2-Aminoquinazolin-4(3H)-one based plasmepsin inhibitors with improved hydrophilicity and selectivity

2-Aminoquinazolin-4(3H)-ones were previously discovered as perspective leads for antimalarial drug development targeting the plasmepsins. Here we report the lead optimization studies with the aim to reduce inhibitor lipophilicity and increase selectivity versus the human aspartic protease Cathepsin D. Exploiting the solvent exposed area of the enzyme provides an option to install polar groups (R1) the 5-position of 2-aminoquinazolin-4(3H)-one to inhibitors such as carboxylic acid without scarifying enzymatic potency. Moreover, introduction of R1 substituents increased selectivity factors of compounds in this series up to 100-fold for Plm II, IV vs CatD inhibition. The introduction of flap pocket substituent (R2) at 7-postion of 2-aminoquinazolin-4(3H)-one allows to remove Ph group from THF ring without notably impairing Plm inhibitory potency. Based on these findings, inhibitors were developed, which show Plm II and IV inhibitory potency in low nanomolar range and remarkable selectivity against Cathepsin D along with decreased lipophilicity and increased solubility.

Synthesis and Activity of Putative Small-Molecule Inhibitors of the F-Box Protein SKP2

The tetrahydropyran 4-(((3-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-4-phenylbutyl)amino)methyl)-N,N-dimethylaniline was reported to disrupt the SCFSKP2 E3 ligase complex. Efficient syntheses of this tetrahydropyran derivative and analogues, including the des-dimethyl derivative 4-(((3-(tetrahydro-2H-pyran-4-yl)-4-phenylbutyl)amino)methyl)-N,N-dimethylaniline, are described. The enantiomers of the des-dimethyl compound were obtained using Evans’ chiral auxiliaries. Structure–activity relationships for these tetrahydropyrans and analogues have been determined by measurement of growth-inhibitory activities in HeLa cells, which indicated a non-specific mechanism of action that correlates with inhibitor lipophilicity. However, preliminary data with (R)- and (S)-4-(((3-(tetrahydro-2H-pyran-4-yl)-4-phenylbutyl)amino)methyl)-N,N-dimethylaniline showed enantioselective inhibition of the degradation of p27 in a cell-based assay that acts as a reporter of SKP2 activity.

Propranolol Transport Across the Inner Blood–Retinal Barrier: Potential Involvement of a Novel Organic Cation Transporter

The influx transport of propranolol across the inner blood-retinal barrier (BRB) was investigated. In the in vivo analysis of carotid artery single-injection method, [(3) H]propranolol uptake by the retina was greater than that of an internal reference compound, and was reduced by several organic cations. In the in vitro uptake study, TR-iBRB2 cells, an in vitro model of the inner BRB, showed a time-, concentration-, pH- and temperature-dependent [(3) H]propranolol uptake, suggesting the involvement of a carrier-mediated transport process in the influx of propranolol across the inner BRB. In the inhibition study, various organic cations, including drugs and candidates for the treatment of the retinal diseases, inhibited the [(3) H]propranolol uptake by TR-iBRB2 cells with no significant effects by the substrates and inhibitors of well-characterized organic cation transporters, suggesting that the influx transport of propranolol is performed by a novel transporter at the inner BRB. An analysis of the relationship between the inhibitory effect and the lipophilicity of inhibitors suggests a lipophilicity-dependent inhibitory effect of amines on the [(3) H]propranolol uptake by TR-iBRB2 cells. These results showed that influx transport of propranolol across the inner BRB is performed by a carrier-mediated transport process, suggesting the involvement of a novel organic cation transporter.

Discovery of GSK2656157: An Optimized PERK Inhibitor Selected for Preclinical Development.

We recently reported the discovery of GSK2606414 (1), a selective first in class inhibitor of protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK), which inhibited PERK activation in cells and demonstrated tumor growth inhibition in a human tumor xenograft in mice. In continuation of our drug discovery program, we applied a strategy to decrease inhibitor lipophilicity as a means to improve physical properties and pharmacokinetics. This report describes our medicinal chemistry optimization culminating in the discovery of the PERK inhibitor GSK2656157 (6), which was selected for advancement to preclinical development.

SAR studies of non-zinc-chelating MMP-13 inhibitors: Improving selectivity and metabolic stability

SAR studies to improve the selectivity and metabolic stability of a class of recently discovered MMP-13 inhibitors are reported. Improved selectivity was achieved by modifying interactions with the S1′ pocket. Metabolic stability was improved through reduction of inhibitor lipophilicity. This translated into lower in vivo clearance for the preferred compound.