Synthesis and Biological Validation of a Harmine-Based, Central Nervous System (CNS)-Avoidant, Selective, Human β-Cell Regenerative Dual-Specificity Tyrosine Phosphorylation-Regulated Kinase A (DYRK1A) Inhibitor

Abstract

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-<i>N</i>-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, <b>2-2c</b>, was identified as a novel, efficacious in vivo lead candidate. <b>2-2c</b> also 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 <b>2-2c</b> is a much improved in vivo lead candidate as compared to harmine for the treatment of diabetes.