Chapter 9. Inhibitors of the Renin-Angiotensin System

N-(.alpha.-hydroxyalkanoyl) derivatives of Leu-Val-Phe-OCH3 as inhibitors of renin

“…The replacement of the N-terminal leucyl residue of 1 with -hydroxyalkanoyl residues led to more active inhibitors in every case except one. The sole exception was D-a-hydroxyisovaleryl-Leu-VaI-Phe-OCH3 (5). This derivative had only two-thirds the activity of 1.…”

“…Anal. (C26H41N30e) C, , N. D-a-Hydroxyisovaleryl-Leu-VaI-Phe-OCH3 (5): yield 66% after recrystallization from a mixture of EtOAc and petroleum ether; mp 170-173 °C; [a]25D +3.9°(c 1.0, CHC13). Anal.…”

“…Activated human amniotic prorenin served as the source of renin for these studies. The procedures for the purification and pepsin activation of human amniotic prorenin have been described previously.11 The K, of each compound was determined through the use of Dixon plots.12 Data for these plots were obtained by measuring the reaction velocities of renin at two concentrations of porcine angiotensinogen (0.1 and 0.2 µ ) in the presence of varying concentrations of each inhibitor ([1] = 0.25-1.25 mM; [2] = 0.1-0.35 mM; [3], [4], [6], and [7] = 0.3-0.9 mM; [5] and [8] = 0.5-1.5 mM).…”

Angiotensin II analogs. 12. Role of the aromatic ring of position 8 phenylalanine in pressor activity

“…[Sar\Leu8]AII was more potent and longer acting than [Ind8]AII as an angiotensin II inhibitor. These results suggest that incorporation of a conformationally constrained aromatic ring in position 8 of angiotensin analogues can be an effective approach to the development of potent inhibitors with low pressor activity.…”

Synthesis of (2S,4S)-2-Substituted-3- (3-Sulfanylpropanoyl)-6- Oxohexahydropyrimidine-4-Carboxylic Acids as Potential Antihypertensive Drugs

“…This enzyme is involved in the regulator system rennin-angiotensin-aldosterone, and the distortion of its operation results in the majority of hypertensive human diseases [1]- [3]. The first of the drugs from this series was captopril, (S)-N-(3-sulfanyl-2-methyl-1-oxopropyl)-L-proline [4]. The later research on development of antihypertensive substances, ACE inhibitors, was directed to the replacement of the natural amino acid L-proline in the captopril molecule by synthetic cyclic amino acids of the heterocyclic series, among them derivatives of 1,3-oxazolidine [5], 1,3-thiazolidine [6], pipecoline [7], quinazoline [8], indole [9], and azepine [10].…”