Pentafluorosulfanyl-Substituted Benzopyran Analogues As New Cyclooxygenase‑2 Inhibitors with Excellent Pharmacokinetics and Efficacy in Blocking Inflammation

In this report, we disclose the design and synthesis of a series of pentafluorosulfanyl (SF₅) benzopyran derivatives as novel COX-2 inhibitors with improved pharmacokinetic and pharmacodynamic properties. The pentafluorosulfanyl compounds showed both potency and selectivity for COX-2 and demonstrated efficacy in several murine models of inflammation and pain. More interestingly, one of the compounds, <i>R</i>,<i>S</i>-<b>3a</b>, revealed exceptional efficacy in the adjuvant induced arthritis (AIA) model, achieving an ED₅₀ as low as 0.094 mg/kg. In addition, the pharmacokinetics of compound <i>R</i>,<i>S</i>-<b>3a</b> in rat revealed a half-life in excess of 12 h and plasma drug concentrations well above its IC₉₀ for up to 40 h. When <i>R</i>,<i>S</i>-<b>3a</b> was dosed just two times a week in the AIA model, efficacy was still maintained. Overall, drug <i>R</i>,<i>S</i>-<b>3a</b> and other analogues are suitable candidates that merit further investigation for the treatment of inflammation and pain as well as other diseases where COX-2 and PGE₂ play a role in their etiology

Identification of GZD824 as an Orally Bioavailable Inhibitor That Targets Phosphorylated and Nonphosphorylated Breakpoint Cluster Region–Abelson (Bcr-Abl) Kinase and Overcomes Clinically Acquired Mutation-Induced Resistance against Imatinib

Bcr-Abl^T315I mutation-induced imatinib resistance remains a major challenge for clinical management of chronic myelogenous leukemia (CML). Herein, we report GZD824 (<b>10a</b>) as a novel orally bioavailable inhibitor against a broad spectrum of Bcr-Abl mutants including T315I. It tightly bound to Bcr-Abl^WT and Bcr-Abl^T315I with <i>K</i>_d values of 0.32 and 0.71 nM, respectively, and strongly inhibited the kinase functions with nanomolar IC₅₀ values. The compound potently suppressed proliferation of Bcr-Abl-positive K562 and Ku812 human CML cells with IC₅₀ values of 0.2 and 0.13 nM, respectively. It also displayed good oral bioavailability (48.7%), a reasonable half-life (10.6 h), and promising in vivo antitumor efficacy. It induced tumor regression in mouse xenograft tumor models driven by Bcr-Abl^WT or the mutants and significantly improved the survival of mice bearing an allograft leukemia model with Ba/F3 cells harboring Bcr-Abl^T315I. GZD824 represents a promising lead candidate for development of Bcr-Abl inhibitors to overcome acquired imatinib resistance