Non-peptide Renin Inhibitors Containing 2-(((3-Phenylpropyl)phosphoryl)oxy)alkanoic Acid Moieties as P2-P3 Replacements

Abstract

A series of novel renin inhibitors containing 2-(((3-phenylpropyl)phosphoryl)oxy)alkanoic acid moieties as P2-P3 surrogates are presented. The P2-P3 mimetics were obtained from (omega-phenylalkyl)-phosphinic acids 1a-c and 2-hydroxyalkanoic acid benzyl esters 2a-f by N,N'-dicyclohexylcarbodiimide-mediated coupling and subsequent oxidation with sodium metaperjodate. Ester cleavage of these derivatives and coupling with P1-P1' transition-state mimetics I-VII provided highly selective compounds with inhibitory potencies in the lower nanomolar range. Small renin inhibitors, such as analogues 8c and 8h with molecular weights of 539 and 537, respectively, could be prepared. These compounds exhibited IC50 values of about 20 nM against human plasma renin. Compound 7i was examined in vivo for its hypotensive effect. In salt-depleted cynomolgus monkeys, 7i inhibited plasma renin activity almost completely and lowered blood pressure after oral administration of a dose of 30 mg/kg.

Synthesis of (R)-Lactic Acid and (2R,5R)-2-tert-Butyl-5-methyl-1,3-dioxolan-4-one

“…However, as recently noted by Ley and co-workers in the course of adapting the process to flow chemistry, 5 lactic acid is exceptionally water soluble, so general methods described for a range of hydroxy acids may not be suitable for this particular case. The reports of conventional (i.e., non-flow) lactic acid synthesis from alanine may be divided into those for which formation of (R)-lactic acid, 6,7 or (S)-lactic acid 8,9 has been carried out but the detailed procedure reported is either general or for another amino acid, and those for which (R)-lactic acid 10,11 or (S)-lactic acid 10,12 has been prepared but no detailed procedure is given at all. After considerable experimentation, we have been able to combine certain features of these procedures to develop a convenient and reliable method that has been used to produce over 100 grams of the product.…”

“…After this, the solution was reduced in volume by evaporation under reduced pressure with the minimum of heating to minimise formation of dimer and polymer. The residual aqueous phase was then extracted exhaustively with ethyl acetate, following the method reported for norleucine, 7 and also based upon the use of isopropyl acetate in the large-scale formation of phenyllactic acid. 13 This approach was successful in separating the product from the inorganic salts, which remained in the aqueous phase, and drying and evaporation of the combined extracts gave the product.…”

UN PROCEDIMIENTO “SUAVE” PARA LA SÍNTESIS DE DIVERSOS ALIL Y BENCIL Α-Hidroxiésteres EMPLEANDO O-Alil(bencil)-N,n’-Diciclohexilisourea

“…R f (SiO 2 ) = 0,56 (n-hexane : diethyl ether, 1 : 1, v : v). 2-Hydroxyhexanoic acid benzyl ester (9b) 12 Colourless oil (1,38 g, 6,2 mmol, 87%) from 0,94 g (7,1 mmol) of 2-hydroxyhexanoic acid and 2,24 g (7,1 mmol) of O-benzyl isourea 5 dissolved in 50 mL of dry THF, stirring and refluxing for 19 h under argon atmosphere. The product was purified by…”

Design, synthesis, and metal binding of novel Pseudo‐ oligopeptides containing two phosphinic acid groups

“…Phosphinic acid compounds have shown advantages in both chemical and enzymatic stabilities over other phosphorus analogs, such as phosphonates [P(O,OH)O] and phosphonamides [P(O,OH)NH]. The incorporation of the phosphinic moiety has provided an efficient approach for discovering and developing novel inhibitors targeting such diverse enzymes including thermolysin,1, 2 matrix metalloproteinases,3–11 N ‐acetylated‐α‐linked acidic dipeptidase (NAALADase),12–15 angiotensin converting enzyme,16, 17 HIV‐1 protease,18 renin,19, 20 thrombin,21 farnesyltransferase,22 glutamine synthetase,23 folylpoly‐gamma‐glutamate synthetase,24, 25 etc. In our efforts to discover and develop novel peptidomimetics that selectively chelate metals, we became interested in pseudopeptides containing two phosphinic acid moieties 26.…”