Discovery and Development of Cyclin-Dependent Kinase 8 Inhibitors.

Cyclin-dependent Kinase 8 (CDK8), a member of the CDKs family, has been widely focused owing to investigations of its critical roles in transcription and oncogenesis in recent years. Selective inhibition of CDK8 and its paralog CDK19 offers a novel therapeutic strategy for the treatment of some cancers. Up to now, though many small molecules against CDK8 have been discovered, most of them are discontinued in the preclinical trials due to the low selectivity and poor physicochemical properties. This review mainly summarizes the design strategies of selective CDK8 inhibitors having different chemical scaffolds with the aim to improve the inhibitory activity, selectivity, metabolic stability and solubility. Their corresponding Structure-activity Relationships (SAR) are also reviewed. On the basis of the discussion in this review, we hope more effective, selective and drug-like CDK8 inhibitors will be developed and demonstrate therapeutic values in the near future.

Discovery of novel 2,3-dihydro-1H-inden-1-amine derivatives as selective monoamine oxidase B inhibitors.

Inhibition of MAO-B has been an effective strategy for the treatment of Parkinson's disease. To find more potent and selective MAO-B inhibitors with novel chemical scaffold, we designed and synthesized a series of new 2,3-dihydro-1H-inden-1-amine derivatives on basis of our previous study. Furthermore, the corresponding structure-activity relationship (SAR) of these compounds is detailedly discussed. Compounds L4 (IC50 = 0.11 µM), L8 (IC50 = 0.18 µM), L16 (IC50 = 0.27 µM) and L17 (IC50 = 0.48 µM) showed similar MAO-B inhibitory activity as Selegiline. Moreover, L4, L16 and L17 also exhibited comparable selectivity with Selegiline, indicating that L4, L16 and L17 could be promising selective MAO-B inhibitors for further study.

The selectivity and bioavailability improvement of novel oral anticoagulants: An overview.

Anticoagulants have exhibited a critical role in the prevention and/or treatment of thrombotic diseases. Up to now, kinds of novel oral anticoagulants, inhibiting plasma serine proteases in the coagulation cascade, have been developed to overcome the clinical limitations of classical anticoagulants (like warfarin and heparins). Some of them, such as Apixaban, Rivaroxaban, Edoxaban, and Dabigatran, have been approved by FDA in recent years. This review summarizes the discovery and optimization of representative novel oral anticoagulants with the aim to improve selectivity and bioavailability of compounds. The impact of different targets in the cascade on bleeding risk also is discussed. We hope some more effective, selective, and safer anticoagulants can be developed in the future on the basis of these design experiences.