Isoxazole-tethered diarylheptanoid analogs: Discovery of a new drug-like PAR2 antagonist |
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Authors: | Debnath Bhuniya Sandeep Bhosale Satyanarayana B Reddy Sudharshan N Reddy |
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Institution: | 1. Drug Discovery Facility – Pune, Advinus Therapeutics Limited, Block No. 21 & 22, Phase II, Peenya Industrial Area, Bangalore 560058, India;2. Interdisciplinary Science and Technology Research Academy (ISTRA), Abeda Inamdar College, University of Pune, 2390-B, Hidayatullah Road, Pune 411001, India |
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Abstract: | 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 Ca2+]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. IC50 of 4a (SB70) has been determined as 6?μM which is in the same range of current benchmarks for PAR2 antagonists. |
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Keywords: | Diarylheptanoid Stereo-conserved synthesis Isoxazole tether Protease-activated receptor-2 (PAR2) antagonist |
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