Preparation of injectable clopidogrel loaded submicron emulsion for enhancing physicochemical stability and anti-thrombotic efficacy.

Due to the superior safety and therapeutic efficacy, clopidogrel (CLP) has been widely used to prevent postoperative thrombosis. However, limitations of delayed absorption and metabolic activation of clopidogrel after oral administration hinder its clinic use for acute thrombosis treatment in percutaneous coronary intervention (PCI). Although clopidogrel aqueous injection systems were designed and developed, chemical instability under physiological condition or vascular irritation remains to be solved. In this study, we aim to prepare an injectable clopidogrel loaded submicron emulsion to overcome the drawbacks of conventional clopidogrel aqueous formulation and improve the antiplatelet aggregation effects. Results showed that this delivery system exerted inspiring features including uniform particle size, higher drug loading capacity and sustained drug release behavior. It can dramatically upgrade the formulation stability and prevent the drug degradation under sterilization or higher pH environments. No remarkable droplet size increase or drug content decrease was observed during storage. Compared to CLP tablet, the peak drug concentration (Cmax) and area under the curve (AUC) of CLP emulsion increased by 12.01-fold and 4.69-fold, respectively. Most importantly, it exerted excellent in vivo anti-thrombotic effect on numerous designed animal models. Conclusively, submicron emulsion is a promising delivery system for improving clopidogrel stability and anti-thrombotic efficacy.

Design, synthesis and biological activity of deuterium-based FFA1 agonists with improved pharmacokinetic profiles.

The free fatty acid receptor 1 (FFA1) is considered as a promising anti-diabetic target based on its function of glucose-stimulated insulin secretion. The previously reported compound 2 is a highly potent FFA1 agonist, but it might be suffered from poor pharmacokinetic properties because the phenylpropanoic acid is vulnerable to ß-oxidation. To identify orally available analogs, we tried to block the route of ß-oxidation by incorporating deuterium at phenylpropionic acid moiety. As expected, the deuterium-based analogs 3 and 4 exhibited better pharmacokinetic properties than parent compound 2. Although the difference of potency between compound 2 and 3 is quite small, the glucose-lowering effect of deuterium analog 3 was better than that of compound 2. Meanwhile, compound 3 docked well into the same binding pocket of TAK-875, and formed almost identical interactions of TAK-875 in binding site. Different from glibenclamide, a lower risk of hypoglycemia was observed in compound 3 even at the high dose of 60 mg/kg.

Design, synthesis, and biological evaluation of novel pan agonists of FFA1, PPARγ and PPARδ.

The free fatty acid receptor 1 (FFA1) and peroxisome proliferator-activated receptors (PPARs) have attracted interest as potent targets for the treatment of metabolic syndrome such as type 2 diabetes. Based on the hypothesis that the dual agonists of PPARs and FFA1 would act as insulin sensitizers and secretagogues by simultaneous activation of PPARs and FFA1, we developed the design strategy to obtain dual PPARs/FFA1 agonist by hybrid FFA1 agonist 1 with PPARδ agonist 2 in consideration of their structural similarity. As expected, systematic exploration of structure-activity relationship and molecular modeling, results in the discovery of lead compound 15, a pan agonist with relative balanced activities between FFA1, PPARγ and PPARδ. The dose-response relationship studies suggested that the pan agonist 15 suppressed the excursion of blood glucose levels in a dose-dependent manner. During a 5-days treatment in ob/ob mice, the pan agonist 15 (100 mg/kg) revealed sustained hypoglycemic effect, even proximity to the most advanced FFA1 agonist (TAK-875, 40 mg/kg), which might be attributed to its pan PPARs/FFA1 activities to simultaneous regulate the mechanism of insulin secretion and resistance. These positive results suggest that the dual PPARs/FFA1 agonists such as lead compound 15 might be novel therapeutic strategy to modulate the complex pathological mechanisms of type 2 diabetes.

Nitric oxide donor-based FFA1 agonists: Design, synthesis and biological evaluation as potential anti-diabetic and anti-thrombotic agents.

The cardiovascular complications were highly prevalent in type 2 diabetes mellitus (T2DM), even at the early stage of T2DM or the state of intensive glycemic control. Thus, there is an urgent need for the intervention of cardiovascular complications in T2DM. Herein, the new hybrids of FFA1 agonist and NO donor were design to obtain dual effects of anti-hyperglycemic and anti-thrombosis. As expected, the induced-fit docking study suggested that it is feasible for our design strategy to hybrid NO donor with compound 1. These hybrids exhibited moderate FFA1 agonistic activities and anti-platelet aggregation activities, and their anti-platelet effects mediated by NO were also confirmed in the presence of NO scavenger. Moreover, compound 3 revealed significantly hypoglycemic effect and even stronger than that of TAK-875 during an oral glucose tolerance test in mice. Potent and multifunctional hybrid, such as compound 3, is expected as a potential candidate with additional cardiovascular benefits for the treatment of T2DM.