Synthesis of novel 1H-Pyrazolo[3,4-b]pyridine derivatives as DYRK 1A/1B inhibitors.

As DYRK1A and 1B inhibitors, 1H-pyrazolo[3,4-b]pyridine derivatives were synthesized. Mostly, 3-aryl-5-arylamino compounds (6) and 3,5-diaryl compounds (8 and 9) were prepared and especially, 3,5-diaryl compound 8 and 9 showed excellent DYRK1B inhibitory enzymatic activities with IC50 Values of 3-287 nM. Among them, 3-(4-hydroxyphenyl), 5-(3,4-dihydroxyphenyl)-1H-pyrazolo[3,4-b]pyridine (8h) exhibited the highest inhibitory enzymatic activity (IC50 = 3 nM) and cell proliferation inhibitory activity (IC50 = 1.6 µM) towards HCT116 colon cancer cells. Also compound 8h has excellent inhibitory activities in patient-derived colon cancer organoids model as well as in 3D spheroid assay model of SW480 and SW620. The docking study supported that we confirmed that compound 8h binds to DYRK1B through various hydrogen bonding interactions and hydrophobic interactions.

A Novel Selective 11ß-HSD1 Inhibitor, (E)-4-(2-(6-(2,6-Dichloro-4-(Trifluoromethyl)Phenyl)-4-Methyl-1,1-Dioxido-1,2,6-Thiadiazinan-2-yl)Acetamido)Adamantan-1-Carboxamide (KR-67607), Prevents BAC-Induced Dry Eye Syndrome.

Dry eye syndrome is the most common eye disease and it is caused by various reasons. As the balance of the tear film that protects the eyes is broken due to various causes, it becomes impossible to properly protect the eyes. In this study, the protective effects and underlying mechanisms of topical (E)-4-(2-(6-(2,6-dichloro-4-(trifluoromethyl)phenyl)-4-methyl-1,1-dioxido-1,2,6-thiadiazinan-2-yl)acetamido)adamantan-1-carboxamide (KR-67607), a novel selective 11ß-hydroxysteroid dehydrogenase 1 (11ß-HSD1) inhibitor, were investigated in benzalkonium chloride (BAC)-induced dry eye syndrome. BAC-treated rat eyes induced significant increases in ocular surface damage, decreased corneal thickness, corneal basement membrane destruction in the conjunctival epithelium, and expression of pro-inflammatory cytokines tumor necrosis factor-α and 11ß-HSD1. These effects of BAC were reversed by topical KR-67607 treatment. Furthermore, KR-67607 decreased 4-hydroxynonenal expression and increased antioxidant and mucus secretion in BAC-treated rat eyes. Taken together, a novel selective 11ß-HSD1 inhibitor can prevent BAC-induced dry eye syndrome by inhibiting pro-inflammatory cytokine and reactive oxygen species expression via the inhibition of both 11ß-HSD1 activity and expression.

Protective effect of a novel selective 11ß-HSD1 inhibitor on eye ischemia-reperfusion induced glaucoma.

Glaucoma is one of the leading causes of preventable blindness, affecting > 2 million people in the United States. Recently, 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) inhibitors were found to exert preventive effects against glaucoma. However, there is no evidence for the role of 11ß-HSD1 inhibitors against glaucoma. Here, we developed a novel 11ß-HSD1 inhibitor, (1R,2S,3S,5R,6S,7S)-6-(2-(6-(2,6-dichloro-4-(trifluoromethyl)phenyl)-4-methyl-1,1-dioxido-1,2,6-thiadiazinan-2-yl)acetamido)-adamantane-2-carboxamide (KR-67607) and showed its protective effects against ischemia-reperfusion-induced eye injury. We demonstrate that KR-67607 effectively reduced cortisol levels in mouse eyes and maintained the trabecular meshwork (TM) structure in the presence of transient ischemic stress. Furthermore, KR-67607 reversed the elevation of intra-ocular pressure (IOP), suggesting that the TM structure maintained by KR-67607 prevented the excessive rise in IOP that exacerbates glaucoma. KR-67607 was shown to have a higher specificity for 11ß-HSD1 than carbenoxolone (CBX) in vitro. Moreover, KR-67607 reduced apoptosis and the structural disruption of TM cells. Antioxidation was the major protective pathway of KR-67607 against chemically-induced ischemia-reperfusion in TM cells and the glucocorticoid receptor (GR) was closely associated with this pathway. When TM cells undergo ischemic stress, GR is activated and then translocates to the cell nucleus where it interferes with Nrf-2-mediated antioxidant gene expression. However, when KR-67607 inhibited GR translocation, Nrf-2 was able to induce antioxidant gene transcription, which consequently, enhanced the antioxidant capacity of the cells. In conclusion, our current work describes a novel selective 11ß-HSD1 inhibitor for glaucoma treatment and provides evidence of its physiological role in anti-oxidative pathways in the TM.