Pharmacology of novel imidazole alcohol inhibitors of primate renin

DeForrest, Jack M.; Waldron, Thomas L.; Oehl, R. S.; Scalese, Robert J.; Free, Charles A.; Weller, Harold N.; Ryono, Denis E.

doi:10.1097/00004872-198904002-00004

Cited by 6 publications

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“…Preparation of (ISM l-(Cyclohexylmethyl)-2-(diethylphosphinyl)-2-hydroxyethyI]carbamic Acid, 1,1-Dimethylethyl Ester (21). A solution of diethyl phosphite (Aldrich;2.29 g,16.6 mmol) in THF (8.3 mL) was added dropwise over a period of 10 min to a flask containing a 3 M ethereal solution of ethylmagnesium bromide (16.6 mL, 3 M solution, 49.8 mmol) and 8.3 mL of THF at 0 °C.…”

Section: Nmr (Cdc13)mentioning

confidence: 99%

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

Dv¹,

Rielly-Gauvin²,

De³

et al. 1995

J. Med. Chem.

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182

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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.

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Section: Nmr (Cdc13)mentioning

confidence: 99%