Design and Synthesis of Benzimidazoles As Novel Corticotropin-Releasing Factor 1 Receptor Antagonists

Benzazole derivatives with a flexible aryl group bonded through a one-atom linker as a new scaffold for a corticotropin-releasing factor 1 (CRF₁) receptor antagonist were designed, synthesized, and evaluated. We expected that structural diversity could be expanded beyond that of reported CRF₁ receptor antagonists. In a structure–activity relationship study, 4-chloro-<i>N</i>²-(4-chloro-2-methoxy-6-methylphenyl)-1-methyl-<i>N</i>⁷,<i>N</i>⁷-dipropyl-1<i>H</i>-benzimidazole-2,7-diamine <b>29g</b> had the most potent binding activity against a human CRF₁ receptor and the antagonistic activity (IC₅₀ = 9.5 and 88 nM, respectively) without concerns regarding cytotoxicity at 30 μM. Potent CRF₁ receptor-binding activity in brain in an ex vivo test and suppression of stress-induced activation of the hypothalamus–pituitary–adrenocortical (HPA) axis were also observed at 138 μmol/kg of compound <b>29g</b> after oral administration in mice. Thus, the newly designed benzimidazole <b>29g</b> showed in vivo CRF₁ receptor antagonistic activity and good brain penetration, indicating that it is a promising lead for CRF₁ receptor antagonist drug discovery research

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