| Autor: |
Kumar, Kunal, Wang, Peng, Wilson, Jessica, Zlatanic, Viktor, Berrouet, Cecilia, Khamrui, Susmita, Secor, Cody, Swartz, Ethan A., Lazarus, Michael, Sanchez, Roberto, Stewart, Andrew F., Garcia-Ocana, Adolfo, DeVita, Robert J. |
| Zdroj: |
Journal of Medicinal Chemistry; March 2020, Vol. 63 Issue: 6 p2986-3003, 18p |
| Abstrakt: |
Recently, our group identified that harmine is able to induce β-cell proliferation both in vitro and in vivo, mediated via the DYRK1A-NFAT pathway. Since, harmine suffers from a lack of selectivity, both against other kinases and CNS off-targets, we therefore sought to expand structure–activity relationships for harmine’s DYRK1A activity, to enhance selectivity for off-targets while retaining human β-cell proliferation activity. We carried out optimization of the 9-N-position of harmine to synthesize 29 harmine-based analogs. Several novel inhibitors showed excellent DYRK1A inhibition and human β-cell proliferation capability. An optimized DYRK1A inhibitor, 2-2c, was identified as a novel, efficacious in vivo lead candidate. 2-2calso demonstrates improved selectivity for kinases and CNS off-targets, as well as in vivo efficacy for β-cell proliferation and regeneration at lower doses than harmine. Collectively, these findings demonstrate that 2-2cis a much improved in vivo lead candidate as compared to harmine for the treatment of diabetes. |
| Databáze: |
Supplemental Index |
| Externí odkaz: |
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