Design, synthesis and pharmacological investigation of isoindoline derivatives as 5-HT/NE double reuptake inhibitors / 药学学报

A series of isoindoline derivatives were designed, synthesized, and evaluated for their double inhibitory activities. All of them were new compounds, and their structures were confirmed by 1H NMR and HR-MS. Preliminary in vitro pharmacological tests showed that all compounds exhibited 5-HT or NE reuptake inhibition activity. Among the tested compounds, compound I-3 exhibited potent inhibitory activity against 5-HT and NE reuptake in vitro, and exhibited potent antidepressant activity in vivo. These compounds designed can be further optimized for finding more potent 5-HT/NE dual reuptake inhibitors and antidepressant candidates as well.

Synthesis and activity of some new histone deacetylases inhibitors / 药学学报

To explore novel histone deacetylase (HDAC) inhibitors with anti-tumor activity, twelve target compounds were synthesized, and their structures were confirmed by 1H NMR, MS and elemental analyses. Evaluation results in vitro showed that compound Ia exhibited potent inhibition against HDAC and is worth for further investigation. And compounds IIa, IIb, IIIa-IIIi possessed moderate HDAC inhibitory activity.

Design of multiple targeted drugs / 药学学报

Drugs designed to act on individual molecular targets usually can not combat multigenic diseases such as cancer, or diseases that affect multiple tissues or cell types such as diabetes. Increasingly, it is being recognised that a balanced modulation of several targets can provide a superior therapeutic effect and side effect profile compared to the action of a selective ligand. The multi-target drugs which impact multiple targets simultaneously are better at controlling complex disease systems and are less prone to drug resistance. Here, we compare the disadvantage of the selective ligands and the predominance of multi-targets drugs in detail and introduce the approaches of designing multiple ligands and the procedure of optimization particularly. A key challenge in the design of multiple ligands is attaining a balanced activity at each target of interest while simultaneously achieving a wider selectivity and a suitable pharmacokinetic profile. On this point, the multi-target approach represents a new challenge for medicinal chemists, pharmacologists, toxicologists, and biochemists.

Comparative pharmacophore analysis of dual dopamine D2/5-HT(2A) receptor antagonists / 药学学报

Dual dopamine D2/5-HT2A receptor antagonists have potent activity and are referred to atypical antipsychotics due to their lower propensity to elicit EPS and their moderate efficacy toward negative symptoms. However, an on-going challenge in developing atypical antipsychotics drugs is to maintain the favorable profiles and avoid of cardiovascular risk. In this paper, comparative pharmacophore analysis of dual dopamine D2/5-HT2A receptor antagonists, hERG K+ channel blockers, and alA adrenoceptor antagonists is carried out, and the results could give some insight into multi-target drug design.

Design, synthesis and activity evaluation of novel matrix metalloproteinases inhibitors based on the structure of enzyme / 药学学报

A novel inhibitor series for matrix metalloproteinases (MMPs) were designed and synthesized. Using succinate and malonate as zinc binding groups and long hydrophobic substituents to bind with S1' pockets, the compounds showed micromolar inhibition and selectivity for MMP-2 over others. And we found a better activity compound. It is a chance to find a better precursor of MMP-2 inhibitors with activity and bioavailability by further optimization of compounds.

Using distance comparison method to build pharmacophore model of epidermal growth factor receptor inhibitors / 中国医学科学院学报

<p><b>OBJECTIVE</b>To build 3D-pharmacophore model of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors using distance comparisons method and design novel EGFR inhibitors.</p><p><b>METHODS</b>Thirteen typical EGFR inhibitors were selected, and their biologically active conformations were obtained by using DOCK5.0 program, then 3D-pharmacophore model of EGFR inhibitors was built using distance comparisons method.</p><p><b>RESULTS</b>Validation of the 3D-pharmacophore model was carried out and novel structures with potential inhibitory activity were selected by means of 3D-searching and docking method.</p><p><b>CONCLUSION</b>This method can improve hit rate of lead compounds discovery and can be used to design novel EGFR inhibitors.</p>