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Application of Asymmetric Catalysis to the Synthesis of Peptide Mimics
Published in John R. Kosak, Thomas A. Johnson, Catalysis of Organic Reactions, 2020
John J. Talley, Cathleen E. Hanau, Gary A. DeCrescenzo, Michelle A. Schmidt
Chiral 2-substituted succinic acid derivatives have been shown to be useful isosteric replacements of α-amino acids in certain enzyme inhibitors. Embodiment of this structural feature in both aspartic and metalloproteinase inhibitor candidates has proven to be a worthwhile strategy. Chiral succinate derivatives Kelatorphan (9) [10] and SC-44463 (10) [11] are potent and selective inhibitors of the metalloproteinase enzymes enkephalin-degrading enzyme and collagenase respectively. Aspartyl proteinases, particularly the blood-pressure-regulating enzyme renin, have been targets for therapeutic intervention. Renin holds potential for the treatment of human hypertension. Incorporation of chiral succinates into inhibitors of renin, particularly into the P3 site, has been reported by a number of groups [12]. Typical of these molecules is 11, a compound that is reported to have appreciable oral bioavailability [13]. Chiral 2-substituted succinate derivatives serve as key building blocks for the total synthesis of certain lignan natural products [14].
Osmotic and Ionic Regulation
Published in Alan G. Heath, Water Pollution and Fish Physiology, 2018
Renin is released by the kidney and catalyzes the conversion of angiotensinogen to angiotensin in the plasma. This latter protein is a powerful vasoconstrictor which causes an increase in blood pressure (Olson, 1992). Smart (1978) noted a marked increase in blood pressure in trout exposed to ammonia, although he used a very high concentration. A rise in blood pressure would increase the filtration rate by the kidney and thus an increase in urination.
Palladium-Catalyzed Coupling of Aryl Halides and Aryl Triflates to Itaconate Diesters: A Convenient Preparation of E-Benzylidenesuccinate Diesters
Published in Mike G. Scaros, Michael L. Prunier, Catalysis of Organic Reactions, 2017
Michelle A. Schmidt, John J. Talley, Mike G. Scaros, Peter K. Yonan
Certain chiral 2-benzylsuccinic acid derivatives, (2), function as suitable building blocks for peptidomimetic molecules. Incorporation of this structural motif into potential enzyme inhibitors is appealing due to the improved proteolytic stability with retention of stereochemical integrity they impart. This strategy has led to the development of potent inhibitors of renin, an aspartyl proteinase important in the blood pressure regulating cascade in man.1 In addition to aspartyl proteinase inhibition, successful inhibitors of certain metalloproteases based on chiral benzylsuccinates have been reported.2.3 Selected biologically active lignan derivatives possess structures that are obtainable from chiral benzylsuccinates4. Additionally, Curtius rearrangement of an appropriate chiral benzylsuccinic acid provides a route to chiral α-or β-benzylsubstituted β-amino acids. Incorporation of these β-amino acids into peptides constitutes a novel approach to peptide backbone modification. The widespread utility of these derivatives has, therefore, prompted us to explore the synthetic methodology for the preparation of aryhdenesuccinates, (1), key precursors to this important class of compounds.
Ease of restroom access influences fluid consumption habits and health in classroom teachers
Published in International Journal of Occupational Safety and Ergonomics, 2023
Lee J. Winchester, Alison L. Hooper, Cailin J. Kerch
Although the prominence of hypertension could also be related to job-associated stressors, it was found that access to restroom breaks negatively predicted both frequency of UTIs and hypertension. Teachers who reported being able to take a restroom break whenever needed had a 45% lower incidence rate of hypertension and a 70% lower risk of UTIs. This is likely due to dehydration and inadequate water consumption since low water intake was associated with greater frequency of both UTIs and hypertension. This makes sense since infrequent flushing of the urethra promotes UTIs [15], while hyperosmolality of the blood results in hormone release that elicits vascular constriction, raising blood pressure [13]. During periods of dehydration, angiotensin II, a product of the renin–angiotensin–aldosterone system, promotes renal sodium and water retention, thereby retaining blood fluid volume [19]. Angiotensin II production, along with low blood volume, stimulates the production of arginine vasopressin to enhance water volume retention in the blood [19]. However, both angiotensin II and arginine vasopressin are potent stimulators of arterial vascular constriction. Chronic stimulation of these factors can promote endothelial dysfunction and hypertension. Thus, it is plausible that the low fluid intake associated with the teaching profession could be exacerbating the incidence of hypertension observed among teachers. Although alterations to these health measures were not directly evaluated in this research study, it is clear that there are underlying issues with teacher classroom structure that are reducing teacher health and wellness.
Vitamin D supplementation alters the expression of genes associated with hypertension and did not induce DNA damage in rats
Published in Journal of Toxicology and Environmental Health, Part A, 2019
Carla Da Silva Machado, Alexandre Ferro Aissa, Diego Luis Ribeiro, Lusânia Maria Greggi Antunes
SHR fed the vitamin D3 control diet exhibited a distinct pattern of expression of genes associated with hypertension compared to WKY fed the vitamin D3 control diet. Upregulated gene expression related to vasoconstriction and lipid metabolism pathways, as well as downregulation gene expression related to vasodilation and hypoxia response pathways demonstrate that the innate condition of hypertension in SHR rats produced changes in the gene expression profile. The Agt (angiotensinogen) and Agt1a (angiotensin II receptor, type 1a) genes were upregulated in SHR, whereas Agt1b (angiotensin II receptor, type 1b) was downregulated. Angiotensin II receptor, type 1a exhibited a vasodilatation action, while angiotensin II receptor, type 1b a vasoconstriction. Angiotensinogen is a circulating protein that acts as a substrate of renin to produce angiotensin I and, subsequently, angiotensin II (Chappell 2015). Upregulation of Agt gene is a potential cause of elevated BP by elevating angiotensin II concentrations.
Baroreflex activation therapy systems: current status and future prospects
Published in Expert Review of Medical Devices, 2019
Gino Seravalle, Raffaella Dell’Oro, Guido Grassi
The impairment in cardiac function is associated with compensatory mechanisms to preserve the cardiovascular hemostasis. Two of the major involved are the sympathetic nervous system [19] and the renin–angiotensin–aldosterone system (RAAS) [20]. An alteration in cardiac function activates afferent stimuli from the baroreceptors to the central cardioregulatory areas, which in turn leads to an activation of the sympathetic nervous pathway [17]. An alteration in the renal perfusion may also activate the RAAS via renin release. Renin activates the system that determines the production of angiotensin II. Angiotensin II has several important effects by (a) exerting a central sympathoexcitation, (b) favoring sodium and water retention, (c) producing vasoconstrictive effects [21–23].