Piperazine ferulate protects against cardiac ischemia/reperfusion injury in rat via the suppression of NLRP3 inflammasome activation and pyroptosis.

Piperazine ferulate (PF) has been reported to protect cardiac from ischemia/reperfusion injury to achieve myocardial protection. NLRP3 inflammasome activation-mediated pyroptosis has been shown to the involvement in myocardial ischemia-reperfusion injury (MI/RI). Increasing evidence suggested that PF is used for cardiovascular diseases, whereas its protection of MI/RI and the mechanism are not fully understood. Rats' model of MI/RI was subjected by occlusion of the left anterior descending (LAD) coronary artery for 30 min followed by 120 min of reperfusion to investigate whether PF exhibited cardiac protection via modulating the NLRP3 inflammasome-mediated pyroptosis. Rats were intragastrically administrated with PF (100 mg/kg) for 7 consecutive days prior to I/R surgery. The results showed that PF remarkedly elevated left ventricular ejection fraction (LVEF), left ventricular fraction shortening (LVFS), and decrease mitral early diastolic flow velocity/late diastolic flow velocity (E/A) of I/R injury rats compared with the I/R group. Besides, MI/RI contributes to increasing the cardiac infarction size and aggravates the myocardial injury as well as causes inflammation, whereas these detrimental alterations were ameliorated by PF pretreatment. Mechanically, the protein and gene expression levels of NLRP3, ASC, GSDMD, IL-Iß and caspase-1 in the PF-treated group were lower than those of the I/R group, which indicates that PF can evidently suppress the I/R-triggered NLRP3 inflammasome activation and pyroptosis in the heart. These results indicated that PF could prevent I/R-induced cardiac damages and cardiac dysfunction in the rats induced by I/R challenge, and it might be a potential therapeutic strategy for the treatment of ischemic heart disease.

Discovery of a Candidate Containing an (S)-3,3-Difluoro-1-(4-methylpiperazin-1-yl)-2,3-dihydro-1H-inden Scaffold as a Highly Potent Pan-Inhibitor of the BCR-ABL Kinase Including the T315I-Resistant Mutant for the Treatment of Chronic Myeloid Leukemia.

BCR-ABL kinase inhibition is an effective strategy for the treatment of chronic myeloid leukemia (CML). Herein, we report compound 3a-P1, bearing a difluoro-indene scaffold, as a novel potent pan-inhibitor against BCR-ABL mutants, including the most refractory T315I mutant. As the privileged (S)-isomer compared to its (R)-isomer 3a-P2, 3a-P1 exhibited potent antiproliferative activities against K562 and Ku812 CML cells and BCR-ABL and BCR-ABLT315I BaF3 cells, with IC50 values of 0.4, 0.1, 2.1, and 4.7 nM, respectively. 3a-P1 displayed a good safety profile in a battery of assays, including single-dose toxicity, hERG K+, and genotoxicity. It also showed favorable mice pharmacokinetic properties with a good oral bioavailability (32%), a reasonable half-life (4.61 h), and a high exposure (1386 h·ng/mL). Importantly, 3a-P1 demonstrated a higher potency than ponatinib in a mice xenograft model of BaF3 harboring BCR-ABLT315I. Overall, the results indicate that 3a-P1 is a promising drug candidate for the treatment of CML to overcome the imatinib-resistant T315I BCR-ABL mutation.

Novel Piperazino-Enaminones Decrease Pro-inflammatory Cytokines Following Hemarthrosis in a Hemophilia Mouse Model.

Hemarthrosis is the primary cause of hemophiliac arthropathy (HA). Pro-inflammatory cytokines are thought to play an important role in the pathogenesis of HA, and thus, anti-cytokine approaches may be used as an adjuvant therapy. A novel series of enaminone compounds (JODI), that contain the N-aryl piperazino motif, have been shown in vitro to reduce pro-inflammatory cytokines and thus may be efficacious in vivo. In this report, we will assess whether JODI can suppress multiple cytokines which might be potentially responsible for joint inflammation in a mouse model of hemarthrosis. The results showed that JODI significantly improved the survival after LPS treatment, and most pro-inflammatory cytokines/chemokines were decreased significantly after JODI administration. In the hemophilia mouse model, hemarthrosis resulted in local cytokine/chemokine changes, represented by elevated pro-inflammatory (IL-6, MCP-1, MIP-1α, MIP-1ß) and pro-angiogenic (VEGF and IL-33) cytokines, and decreased anti-pro-inflammatory cytokines IL-4 and IL-10. The changes were reversed by administration of JODI, which can be used as a novel approach to manage hemophilia arthropathy.