Isoxazole-tethered diarylheptanoid analogs: Discovery of a new drug-like PAR2 antagonist
| Autor: | Debnath Bhuniya, Sandeep Bhosale, Satyanarayana Reddy, Sudharshan N. Reddy |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Agonist medicine.drug_class Stereochemistry Clinical Biochemistry Pharmaceutical Science Stereoisomerism 01 natural sciences Biochemistry 03 medical and health sciences chemistry.chemical_compound Diarylheptanoids Drug Discovery medicine Humans Receptor PAR-2 Isoxazole Cytotoxicity Molecular Biology IC50 010405 organic chemistry Chemistry Organic Chemistry Diarylheptanoid Hep G2 Cells Isoxazoles Trypsin 0104 chemical sciences HEK293 Cells 030104 developmental biology Microsomes Liver GTP-Binding Protein alpha Subunits Gq-G11 Molecular Medicine Calcium medicine.drug |
| Zdroj: | Bioorganic & Medicinal Chemistry Letters. 28:2285-2288 |
| ISSN: | 0960-894X |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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