Discovery of Benzofuran Derivatives that Collaborate with Insulin-Like Growth Factor 1 (IGF-1) to Promote Neuroprotection

A series of benzofuran derivatives with neuroprotective activity in collaboration with IGF-1 was discovered using a newly developed cell-based assay involving primary neural cells prepared from rat hippocampal and cerebral cortical tissues. A structure–activity relationship study identified compound <b>8</b> as exhibiting potent activity and brain penetrability. An in vitro pharmacological study demonstrated that although IGF-1 and <b>8</b> individually exhibited the neuroprotective effect, the latter acted in collaboration with IGF-1 to enhance neuroprotective activity

Structure-Based Design and Synthesis of 3‑Amino-1,5-dihydro‑4<i>H</i>‑pyrazolopyridin-4-one Derivatives as Tyrosine Kinase 2 Inhibitors

We report herein the discovery and optimization of 3-amino-1,5-dihydro-4<i>H</i>-pyrazolopyridin-4-one TYK2 inhibitors. High-throughput screening against TYK2 and JAK1–3 provided aminoindazole derivative <b>1</b> as a hit compound. Scaffold hopping of the aminoindazole core led to the discovery of 3-amino-1,5-dihydro-4<i>H</i>-pyrazolopyridin-4-one derivative <b>3</b> as a novel chemotype of TYK2 inhibitors. Interestingly, initial SAR study suggested that this scaffold could have a vertically flipped binding mode, which prompted us to introduce a substituent at the 7-position as a moiety directed toward the solvent-exposed region. Introduction of a 1-methyl-3-pyrazolyl moiety at the 7-position resulted in a dramatic increase in TYK2 inhibitory activity, and further optimization led to the discovery of <b>20</b>. Compound <b>20</b> inhibited IL-23-induced IL-22 production in a rat PD assay, as well as inhibited IL-23 signaling in human PBMC. Furthermore, <b>20</b> showed selectivity for IL-23 signaling inhibition against GM-CSF, demonstrating the unique cytokine selectivity of the novel TYK2 inhibitor