Synthesis and optimization of novel (3S,5R)-5-(2,2-dimethyl-5-oxo-4-phenylpiperazin-1-yl)piperidine-3-carboxamides as orally active renin inhibitors

We report synthesis and optimization of a series of (3S,5R)-5-(2,2-dimethyl-5-oxo-4-phenylpiperazin-1-yl)piperidine-3-carboxamides as renin inhibitors. Chemical modification of ${{\text{P}}_1}^{\prime }$, ${{\text{P}}_2}^{\prime }$ and P₃ portions led to a promising 3,5-disubstituted piperidine 32o showing high renin inhibitory activity and favorable oral exposure in both rats and cynomolgus monkeys with acceptable CYP and hERG current inhibition. Compound 32o exhibited a significant blood pressure lowering effect by oral administration in two hypertensive animal models, double transgenic rats and furosemide pretreated cynomolgus monkeys.     

Photosynthetic adaptation of soybean due to varying effectiveness of N2 fixation by two distinct Bradyrhizobium japonicum strains

Rhizobial N₂ fixation is a costly biochemical process, which takes 6–14% of current photosynthate (C) from legumes, without compromising grain productivity. In addition to the effects of leaf N nutrition, rhizobial symbiosis could stimulate photosynthesis due to the removal of C sink limitation by nodule activity. To test that hypothesis, we compared the photosynthetic capacity of soybean plants inoculated with two different strains of Bradyrhizobium japonicum (CPAC 390 or CPAC 7), varying in the effectiveness to fix N₂, with plants fertilized with NO₃⁻. Nodulated plants had 14–31% higher rates of photosynthesis and accumulated less starch in the leaves than N-fertilized plants. There was evidence that B. japonicum CPAC 390 had higher carbon costs of N₂ fixation compared with CPAC 7, but the increases in carbon costs were accompanied by higher rates of photosynthesis. By applying a biochemical model of leaf photosynthesis, including the limitations of Rubisco activity $(V_{{\text{C}}_{\text{max}}})$, electron transport rates (J) and triose-P utilization (TPU), we show that soybean plants adapt their photosynthetic capacity to support the stronger carbon sink created by faster rates of N₂ fixation. We observed that plants associated with CPAC 7 (of low effectiveness to fix N₂) increased their photosynthesis by removing sink limitation solely (with a constant $V_{{\text{C}}_{\text{max}}}$) whereas plants associated with CPAC 390 (of high effectiveness to fix N₂) increased their photosynthesis by sink stimulation. Based on the model, we propose that sink stimulation is governed by a positive feedback between TPU and Rubisco activation, resulting in an increased $V_{{\text{C}}_{\text{max}}}$.