Design, synthesis and biological evaluation of novel benzoxaborole derivatives as potent PDE4 inhibitors for topical treatment of atopic dermatitis.

In this work, a series of structurally novel benzoxaborole derivatives were designed, synthesized and biologically evaluated as PDE4 inhibitors for battling atopic dermatitis (AD). Among them, the majority exhibited superior PDE4B inhibitory activities to that of the lead compound Crisaborole, an approved PDE4 inhibitor. In particular, 72, the most potent PDE4B inhibitor throughout this series, displayed 136-fold improved enzymatic activity (IC50 = 0.42 nM) as compared to Crisaborole (IC50 = 57.20 nM), along with favorable isoform specificity. In the phorbol ester (PMA)-induced mouse ear oedema model, 72 exerted remarkably greater efficacy than Crisaborole at the same dosage (P < 0.05). Moreover, the ointment of 72 exerted dramatically enhanced therapeutic potency than the ointment of Crisaborole (P < 0.05) in the calcipotriol-induced mouse AD model. In addition to the potent in vitro and in vivo activity, 72 displayed favorable safety in the repeated oral dose toxicity study and did not exhibit phototoxicity. With the above attractive biological performance, 72 is worthy of further functional investigation as a novel anti-AD therapeutic agent.

YiQiFuMai Powder Injection attenuates coronary artery ligation-induced myocardial remodeling and heart failure through modulating MAPKs signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: YiQiFuMai Powder Injection (YQFM), a traditional Chinese medicine prescription re-developed based on Sheng-Mai-San, is a classical and traditional therapeutic for clinical heart failure (HF) and angina. However, its potential mechanism against HF remains unclear. AIM OF THE STUDY: The present study observes the therapeutic role of YQFM and mechanisms underlying its effects on coronary artery ligation (CAL)-induced myocardial remodeling (MR) and HF. METHODS: MR and HF were induced by permanent CAL for 2 weeks in ICR mice. Then mice were treated with YQFM (0.13g/kg, 0.26g/kg and 0.53g/kg) once a day until 2 weeks later. Cardiac structure and function were evaluated by echocardiography. Serum lactate dehydrogenase (LDH), creatine kinase (CK) and malondialdehyde (MDA) were measured by biochemical kits and cardiomyocyte morphology was assessed by hematoxylin-eosin (HE) staining. Myocardial hydroxyproline (HYP), serum amino-terminal pro-peptide of pro-collagen type III (PIIINP), and Masson's trichrome staining were employed to evaluate cardiac fibrosis. Circulating level of N-terminal pro-B-type natriuretic peptide (NT-proBNP) was tested by ELISA kit to predict prognosis of CAL-induced HF. Effects of YQFM on the mitogen-activated protein kinases (MAPKs) pathway after CAL operation was evaluated by Western blotting and immunohistochemistry assay. RESULTS: YQFM (0.53g/kg) improved the left ventricular (LV) function and structure impairment after 2 weeks in CAL mice. YQFM administration also decreased LDH and CK activities, circulating levels of MDA, PIIINP, NT-proBNP, and HYP contents. Moreover, YQFM ameliorated cardiac injury and fibrosis. Furthermore, YQFM (0.53g/kg) inhibited the myocardial phosphorylation of MAPKs in HF mice. CONCLUSION: Our findings suggest that YQFM attenuates CAL-induced HF via improving cardiac function, attenuating structure damage, oxidative stress, necrosis, collagen deposition, and fibrosis. In addition, YQFM ameliorates cardiac remodeling and HF, partially through inhibiting the MAPKs signaling pathways. These data provide insights and mechanisms into the widely application of YQFM in patients with HF, MI and other ischemic heart diseases.