Renin inhibitors containing a pyridyl amino diol derived C-terminus
| Autor: | Wolfgang Linz, Kleemann Heinz-Werner, Holger Heitsch, Rainer Henning, Wolf Ulrich Nickel, Hansjoerg Urbach, Adalbert Wagner, Dieter Ruppert |
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| Rok vydání: | 1993 |
| Předmět: |
Male
Stereochemistry Pyridines Guinea Pigs Blood Pressure Pharmacology chemistry.chemical_compound Structure-Activity Relationship Dogs Species Specificity In vivo Drug Discovery Renin–angiotensin system Renin Animals Humans Amino Acids IC50 chemistry.chemical_classification Sheep biology Biological activity Stereoisomerism Macaca mulatta Amino acid Rats Enzyme chemistry Succinic acid Enzyme inhibitor biology.protein Molecular Medicine Female Oligopeptides |
| Zdroj: | Journal of medicinal chemistry. 36(19) |
| ISSN: | 0022-2623 |
| Popis: | Based on the concept of transition-state analogs, a series of nonpeptide renin inhibitors with the new (2S,3R,4S)-2-amino-1-cyclohexyl-3,4-dihydroxy-6-(2-pyridyl)hexane moiety at the C-terminal functionality were synthesized and evaluated for inhibition of renin both in vitro and in vivo. All compounds exhibited potencies in the nanomolar or even subnanomolar range when tested versus human renin in vitro. Selected inhibitors were evaluated in anesthetized, sodium-depleted rhesus monkeys and produced a marked reduction in mean arterial blood pressure (MAP) upon intraduodenal administration of a dose of 2 mg/kg. Compound 38 (S 2864) containing an amino piperidyl succinic acid derived N-terminal is the most promising member in this series. 38 inhibited human renin with an IC50 of 0.38 nM, did not affect other human aspartic proteinases, and decreased mean arterial blood pressure significantly by 27% with a duration of action of 90 min after administration of 2 mg/kg id in anesthetized, sodium-depleted rhesus monkeys. |
| Databáze: | OpenAIRE |
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