Structural modification of the P2' position of 2,7-dialkyl-substituted 5(S)-amino-4(S)-hydroxy-8-phenyl-octanecarboxamides: the discovery of aliskiren, a potent nonpeptide human renin inhibitor active after once daily dosing in marmosets
| Autor: | Walter Fuhrer, Jeanette Marjorie Wood, N. C. Cohen, Stefan Stutz, Walter Schilling, Jiirgen Maibaum, Christian Schnell, Richard Dr. Göschke, Yasuchika Yamaguchi, Pascal Rigollier, Joseph Rahuel, Hans-Peter Baum, Frederic Cumin, Markus Gruetter |
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| Rok vydání: | 2007 |
| Předmět: |
Models
Molecular medicine.drug_class Administration Oral Blood Pressure Pharmacology Crystallography X-Ray Renin inhibitor chemistry.chemical_compound Structure-Activity Relationship Fumarates In vivo Oral administration Heart Rate Drug Discovery Renin–angiotensin system Renin medicine Potency Animals Humans Antihypertensive Agents biology Molecular Structure Chemistry Callithrix Stereoisomerism Aliskiren Amides Kinetics Blood pressure Enzyme inhibitor biology.protein Molecular Medicine Caprylates Protein Binding |
| Zdroj: | Journal of medicinal chemistry. 50(20) |
| ISSN: | 0022-2623 |
| Popis: | Due to its function in the rate limiting initial step of the renin-angiotensin system, renin is a particularly promising target for drugs designed to control hypertension, a growing risk to health worldwide. Despite vast efforts over more than two decades, no orally efficacious renin inhibitor had reached the market. As a result of a structure-based topological design approach, we have identified a novel class of small-molecule inhibitors with good oral blood-pressure lowering effects in primates. Further lead optimization aimed for improvement of in vivo potency and duration of action, mainly by P2' modifications at the hydroxyethylene transition-state isostere. These efforts resulted in the discovery of aliskiren (46, CGP060536B, SPP100), a highly potent, selective inhibitor of renin, demonstrating excellent efficacy in sodium-depleted marmosets after oral administration, with sustained duration of action in reducing dose-dependently mean arterial blood pressure. Aliskiren has recently received regulatory approval by the U.S. Food and Drug Administration for the treatment of hypertension. |
| Databáze: | OpenAIRE |
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