Hydrazonil Cathepsin K Inhibitor Using Trifluoroethylamine as P2-P3 Linking Group and Its Application

Abstract

The invention belongs to the technical field of cathepsin K inhibitors, and particularly relates to novel nitrile cathepsin K inhibitors using cathepsin K as target protein and trifluoroethylamino groups as P2-P3 linkers and having different P3 position structures. The P2-P3 linkers are trifluoroethylamino groups, P3 positions are aryl groups comprising a bromophenyl group, a p-biphenyl group, a p-terphenyl group and a p-methyl biphenyl group. The nitrile inhibitors have the advantages that the structures are simple relatively, the synthesis is convenient, and the yield is high; inhibition constants (Ki) of the compounds (the inhibitors) to cathepsin K are in the picomole level, so that the effective inhibiting ability to the cathepsin K is reflected; when the P3 position is the P-terphenyl group, the inhibiting ability and the selectivity of the inhibitor to the Cat K (the cathepsin K) are better than those of corresponding amide inhibitors. In vitro cytotoxicity tests show that the inhibitors are free of cytotoxicity, and have the possibility of being applied to clinical trials and being used as potential anti-osteoporosis drug.

Description

technical field [0001] The invention belongs to the technical field of cathepsin K inhibitors, in particular to a hydrazinonitrile inhibitor for cathepsin K with trifluoroethylamine as the P2-P3 linking group and different P3-position groups and its use in Application in the preparation of anti-osteoporosis drugs. Background technique [0002] The components of human bones mainly include bone mineral and bone matrix. The bone mineral is mainly hydroxyapatite, and the bone matrix includes type I collagen, osteopontin and osteonectin, among which more than 95% of the bone matrix is ​​composed. Type I collagen is predominant. Skeleton is an important organ of the human body, which has the functions of movement, support and protection of the body. Normal bone metabolism maintains the bone health of the human body, while abnormal bone metabolism brings disease and pain to people. The bone metabolism process is usually regulated by two opposing and unified processes of bone for...

AI Technical Summary

Problems solved by technology

However, this type of inhibitor also has some disadvantages: the selection of inhibitors for Cat K relative to Cathepsin L (Cathepsin L, Cat L), Cathepsin B (Cathepsin B, Cat B) and Cathepsin S (Cathepsin S, Cat S) Low selectivity (about 1-10 times), especially poor selectivity to Cat L

Basic amino groups are prone to form ammonium ions (NH 2 + , ammoniumion), but ammonium ions need to go through desolvation (desolvation) to enter the active site of the enzyme. This process needs to consume part of the binding energy of the inhibitor and the enzyme, which is not good for the combination of the inhibitor and the enzyme. [13]

In addition, alkaline inhibitors have lysosome effect (lysosomotropism), that is, inhibitors tend to be in acidic lysosomes, enrich in lysosomes, and have higher inhibition on non-target enzymes in lysosomes effect, so the inhibitor with strong basicity is not conducive to improving the selectivity of the inhibitor [14]

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