.alpha.-Hydroxy Phosphinyl-Based Inhibitors of Human Renin

Abstract

The design and application of alpha-hydroxy phosphonates, a new class of transition state analogs, toward the discovery of novel and potent inhibitors of the aspartyl protease renin is described. Tripeptidic alpha-hydroxy diethyl phosphonate 3, the first example in this series, was found to be a good inhibitor of human renin (IC50 = 29 nM), and preliminary studies led to the choice of alpha-hydroxy dimethyl phosphonate 15 (IC50 = 16 nM) as a base-line compound for further structure-activity relationship study. Corresponding phosphinate (28-30) and phosphine oxide (23 and 24) analogs of 15 were prepared to assess the steric and electronic requirements around the phosphorus center. Evaluation of these analogs suggested that the presence of at least one alkoxy group on phosphorus was a critical requirement for good activity. Inhibitors with leucine at P2 possessed better in vitro activity than the corresponding P2 histidine analogs (15, IC50 = 16 nM vs 37, IC50 = 220 nM; 33, IC50 = 8.5 nM vs 40, IC50 = 41 nM). Compound 34 (IC50 = 31 nM), the P3 aminocaproic analog of 15, showed complete and long-lasting inhibition of plasma renin activity while eliciting a 10-15 mmHg drop in mean arterial pressure when administered intravenously at 1 mumol/kg in conscious, sodium-depleted, cynomolgus monkeys. In summary, the alpha-hydroxy phosphonates represent a promising and structurally novel class of transition state analog inhibitors of human renin.

Calix[4]arene α-hydroxymethylphosphonic acids as potential inhibitors of protein tyrosine phosphatases

“…They can be used as antihypertensive [34] and antiviral agents [35], antibiotics [36] and pesticides [37]. Series of the compounds featuring aryl or heteroaryl 1-hydroxyphosphonate derivatives were investigated as inhibitors of CD45 [38].…”

Recent Advances in Biomimetic Synthesis Involving Cyclodextrins

“…In view of significant biological importance associated with -hydroxy phophonates, this synthon has attracted enhanced research interest. These are extensively used in pharmaceutical applications such as enzyme inhibitors of renin, HIV protease and EPSP synthase (Patel et al, 1995). They also exhibited potential biological activities, such as antibacterial, antiviral, anti-inflammatory, laxative, growth hormonal, and anticancer activities (Stowasser et al, 1992).…”

Asymmetric Synthesis of α-Substituted-β-Amino Phosphonates and Phosphinates and β-Amino Sulfur Analogs

“…For absolute stereochemical assignment, diastereoisomers 16 and 17 were converted to the corresponding oxazolidinones. Based on proton nuclear magnetic resonance ( 1 H NMR) and 13 C NMR data and NOE experiments in oxazolidinones, diastereoisomer 16 was designated as having the (S)-anti stereochemistry.…”

“…In the same way, hydrophosphinylation of N-protected a-aminoaldehyde 15 was achieved using phosphine oxides and alkyl alkylphosphinates. 13 When the bromomagnesium phosphine oxide generated in situ by treatment of diethyl phosphite with 3 eq. of ethylmagnesium bromide was trapped directly with aldehyde 15, b-amino-a-hydroxy phosphine oxide 21 was obtained in high yield (87%) as a 1 : 1 3).…”

“…Patel et al 12,13 have reported the synthesis of b-amino-a-hydroxy phosphonopeptides as inhibitors of human renin (Scheme 13.17). The synthesis of dipeptides 81, 82 and tripeptides 83-85 is based on a coupling of protected amino acids with b-amino-a-hydroxy phosphonate 80.…”