Nicotinamide Phosphoribosyltransferase Inhibitors, Design, Preparation, and Structure–Activity Relationship

Existing pharmacological inhibitors for nicotinamide phosphoribosyltransferase (NAMPT) are promising therapeutics for treating cancer. By using medicinal and computational chemistry methods, the structure–activity relationship for novel classes of NAMPT inhibitors is described, and the compounds are optimized. Compounds are designed inspired by the NAMPT inhibitor APO866 and cyanoguanidine inhibitor scaffolds. In comparison with recently published derivatives, the new analogues exhibit an equally potent antiproliferative activity in vitro and comparable activity in vivo. The best performing compounds from these series showed subnanomolar antiproliferative activity toward a series of cancer cell lines (compound <b>15</b>: IC₅₀ 0.025 and 0.33 nM, in A2780 (ovarian carcinoma) and MCF-7 (breast), respectively) and potent antitumor in vivo activity in well-tolerated doses in a xenograft model. In an A2780 xenograft mouse model with large tumors (500 mm³), compound <b>15</b> reduced the tumor volume to one-fifth of the starting volume at a dose of 3 mg/kg administered ip, bid, days 1–9. Thus, compounds found in this study compared favorably with compounds already in the clinic and warrant further investigation as promising lead molecules for the inhibition of NAMPT

Training Load Monitoring in Team Sports: A Novel Framework Separating Physiological and Biomechanical Load-Adaptation Pathways

There have been considerable advances in monitoring training load in running-based team sports in recent years. Novel technologies nowadays offer ample opportunities to continuously monitor the activities of a player. These activities lead to internal biochemical stresses on the various physiological subsystems; however, they also cause internal mechanical stresses on the various musculoskeletal tissues. Based on the amount and periodization of these stresses, the subsystems and tissues adapt. Therefore, by monitoring external loads, one hopes to estimate internal loads to predict adaptation, through understanding the load-adaptation pathways. We propose a new theoretical framework in which physiological and biomechanical load-adaptation pathways are considered separately, shedding new light on some of the previously published evidence. We hope that it can help the various practitioners in this field (trainers, coaches, medical staff, sport scientists) to align their thoughts when considering the value of monitoring load, and that it can help researchers design experiments that can better rationalize training-load monitoring for improving performance while preventing injury.</p