Isoxazole-tethered diarylheptanoid analogs: Discovery of a new drug-like PAR2 antagonist.

A new class of isoxazole-tethered diarylheptanoids having characteristic 1,3- syn -diol and 1,3- anti -diol chemophoric moieties, e.g. 4a – d and 5a – c respectively, have been designed and synthesized starting from d -glucose following a stereo-conserved general synthetic strategy. The isoxazole heterocycle was installed using our recently elaborated methodology deploying Magtrieve™ as a selective oxidizing agent. Two of these new analogs 4a and 5a exhibited significantly improved in vitro drug-like properties including solubility, metabolic stability, cell permeability and lack of nonspecific cytotoxicity when compared with curcumin-I. In a HEK293 cell-based intracellular calcium [Ca 2+ ] i release assay, 4a and 5a , when tested at 30 μM, inhibited the trypsin agonist induced protease-activated receptor-2 (PAR2) activity by 80% and 70% respectively. IC 50 of 4a (SB70) has been determined as 6 μM which is in the same range of current benchmarks for PAR2 antagonists. [ABSTRACT FROM AUTHOR]