We report our discovery of a novel series of potent and selective dipeptidyl peptidase IV (DPP-4) inhibitors. Starting from a lead identified by scaffold-hopping approach, our discovery and development efforts were focused on exploring structure−activity relationships, optimizing pharmacokinetic profile, improving in vitro and in vivo efficacy, and evaluating safety profile. The selected candidate, Imigliptin, is now undergoing clinical trial.
This study presents a process of developing a novel PI3K–mTOR inhibitor through the prodrug of a metabolite. The lead compound (compound 1) was identified with similar efficacy as that of NVP-BEZ235 in a tumor xenograft model, but the exposure of compound 1 was much lower than that of NVP-BEZ235. After reanalysis of the blood sample, a major metabolite (compound 2) was identified. Compound 2 exerted similar in vitro activity as compound 1, which indicated that compound 2 was an active metabolite and that the in vivo efficacy in the animal model came from compound 2 instead of compound 1. However, compound 1 was metabolized into compound 2 predominantly in the liver microsomes of mouse, but not in the liver microsomes of rat, dog, or human. In order to translate the efficacy in the animal model into clinical development or predict the pharmacokinetic/pharmacodynamic parameters in the clinical study using a preclinical model, we developed the metabolite (compound 2) instead of compound 1. Due to the low bioavailability of compound 2, its prodrug (compound 3) was designed and synthesized to improve the solubility. The prodrug was quickly converted to compound 2 through both intravenous and oral administrations. Because the prodrug (compound 3) did not improve the oral exposure of compound 2, developing compound 3 as an intravenous drug was considered by our team, and the latest results will be reported in the future.
Solid‐state polymer electrolytes (SPEs) have attracted significant attention owing to their improvement in high energy density and high safety performance. However, the low lithium‐ion conductivity of SPEs at room temperature restricts their further application in lithium‐ion batteries (LIBs). Herein, we propose a novel poly (ethylene oxide) (PEO)‐based nanocomposite polymer electrolytes by blending boron‐containing nanoparticles (BNs) in the PEO matrix (abbreviated as: PEO/BNs NPEs). The boron atom of BNs is sp2‐hybridized and contains an empty p‐orbital that can interact with the anion of lithium salt, promoting the dissociation of the lithium salts. In addition, the introduction of the BNs could reduce the crystallinity of PEO. And thus, the ionic conductivity of PEO/BNs NPEs could reach as high as 1.19 × 10−3 S cm−1 at 60°C. Compared to the pure PEO solid polymer electrolyte (PEO SPEs), the PEO/BNs NPEs showed a wider electrochemical window (5.5 V) and larger lithium‐ion migration number (0.43). In addition, the cells assembled with PEO/BNs NPEs exhibited good cycle performance with an initial discharge capacity of 142.5 mA h g−1 and capacity retention of 87.7% after 200 cycles at 2 C (60°C).
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