Angiotensin synthesis

The Paal-Knorr furan synthesis can also be used to prepare 2,5-arylalkylfurans, as illustrated in the following example. Salimbeni produced furan 29 from dione 28 and subsequently used the furan as an intermediate for the production of angiotensin II receptor antagonists. ... 

Give an mRNA sequence that will code for the synthesis of angiotensin II. 

Endothelial cells are the major source of ET-1-synthesis. ET-1 is also produced by astrocytes, neurons, hepatocytes, bronchial epithelial cells, renal epithelial and mesangial cells. Physiological stimuli of ET-1-synthesis in endothelial cells are angiotensin II, catecholamines, thrombin, growth factors, insulin, hypoxia and shear stress. Inhibitors of ET-1 synthesis are atrial natriuretic peptide, prostaglandin E2 and prostacyclin. ET-2 is mainly synthesized in kidney, intestine, myocardium and placenta and ET-3 is predominantely produced by neurons, astrocytes and renal epithelial cells. 

The kidney contains the major site of renin synthesis, the juxtaglomerular cells in the wall of the afferent arteriole. From these cells, renin is secreted not only into the circulation but also into the renal interstitium. Moreover, the enzyme is produced albeit in low amounts by proximal tubular cells. These cells also synthesize angiotensinogen and ACE. The RAS proteins interact in the renal interstitium and in the proximal tubular lumen to synthesize angiotensin II. In the proximal tubule, angiotensin II activates the sodium/hydrogen exchanger (NHE) that increases sodium reabsorption. Aldosterone elicits the same effect in the distal tubule by activating epithelial sodium channels (ENaC) and the sodium-potassium-ATPase. Thereby, it also induces water reabsotption and potassium secretion. 

In the interstitium, angiotensin II induces proliferation of mesangial cells and fibroblasts and the synthesis of collagen and other matrix molecules by these cells via the ATI receptor. Moreover, by the concomitant stimulation of chemoattractant cytokines, inflammation is induced. These processes are mediated by endothelin, transforming growth factor(3, and reactive oxygen species, and finally lead to interstitial fibrosis and glomerulosclerosis observed in hypertension and diabetes. 

In 2004, Alterman et al. apphed their cyanation protocol to the synthesis of N-(t-butyl)-3-(4-cyanobenzyl)-5-isobutylthiophene-2-sulfonamide [61]. Deprotection of the sulfonamide followed by carbamate formation via reaction with butyl chloroformate finally gave the target compoimd for biological evaluation as a selective angiotensin 11 AT2 receptor agonist (Scheme 65). The cyano derivative, however, showed only a low affinity for the AT2 receptor (Ki value >10 p,M). 

The zona glomerulosa is responsible for the production of the mineralocorticoids aldosterone, deoxycorticosterone, and 18-hydroxy-deoxycorticosterone. Aldosterone promotes renal sodium retention and excretion of potassium. Its synthesis and release are regulated by renin in response to decreased vascular volume and renal perfusion. Adrenal aldosterone production is regulated by the renin-angiotensin-aldosterone system. 

Murugesan N, Gu Z, Fadnis L, et al. Dual angiotensin II and endothelin A receptor antagonists synthesis of 2 -substituted N-3-isoxazolyl biphenylsulfonamides with improved potency and pharmacokinetics. J Med Chem 2005 48 171-179. 

The synthesis of the octapeptide isoleucine-5-angiotensin Z-Asp(NH2)-Arg(N02)-Val-Tyr-Ile-His-Pro-Phe-OCH3 using CDI as condensing agent was achieved by preparing the four required dipeptides (1—2), (3-4), (5-6), (7-8), two tetrapeptides (1-4) and (5-8), and finally the octapeptide itself. 123... 

The final stages of the synthesis of (—)-A-58365B, a Streptomyces metabolite that inhibits the angiotensin-converting enzyme, involve several reactions at substituents attached to ring carbon atoms of a quinolizidine system. Thus, ozonolysis of the exocyclic methylene side chain of compound 107, followed by base-induced elimination and carboxyl deprotection, gave 108 (Scheme 12) <1999JOC1447>. 

The same group of authors has recently reported a combination of various palladium- and copper-catalyzed Suzuki, cyanation, and Ullmann condensation reactions for the synthesis of thiophene-based selective angiotensin II AT2 receptor antagonists (Scheme 6.24) [55],... 

A deficiency in the local synthesis of vasodilating substances in the vascular endothelium, such as prostacyclin, bradykinin, and nitric oxide, or an increase in production of vasoconstricting substances such as angiotensin II and endothelin I ... 

I to angiotensin II, a potent vasoconstrictor and stimulator of aldosterone secretion. ACE inhibitors also block the degradation of bradykinin and stimulate the synthesis of other vasodilating substances including prostaglandin E2 and prostacyclin. The fact that ACE inhibitors lower BP in patients with normal plasma renin activity suggests that bradykinin and perhaps tissue production of ACE are important in hypertension. 

Petrillo, E.W. and Spitzmiller, E.R., Synthesis of 2-phosphonopyrrolidine and its substitution for proline in an inhibitor of angiotensin-converting enzyme, Tetrahedron Lett., 4929, 1979. 

Govindarajan G, EbleDM, Lucchesi PA, Samarel AM 2000 Focal adhesion kinase is involved in angiotensin Il-mediated protein synthesis in cultured vascular smooth muscle cells. Circ Res... 

Compound (—)-A58365A 285, whose new synthesis was reported, is an angiotensin-converting enzyme (ACE) inhibitor, active at nanomolar concentrations <19990L83>. 

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