Document Detail

Novel 2,7-dialkyl-substituted 5(S)-amino-4(S)-hydroxy-8-phenyl-octanecarboxamide transition state peptidomimetics are potent and orally active inhibitors of human renin.
MedLine Citation:
PMID:  17824679     Owner:  NLM     Status:  MEDLINE    
The action of renin is the rate-limiting step of the renin-angiotensin system (RAS), a key regulator of blood pressure. Effective renin inhibitors directly block the RAS entirely at source and, thus, may provide a vital weapon for hypertension therapy. Our efforts toward identifying novel small-molecule peptidomimetic renin inhibitors have resulted in the design of transition-state isosteres such as 1 bearing an all-carbon 8-phenyl-octanecarboxamide framework. Optimization of the extended P3 portion of 1 and extensive P2' modifications provided analogues with improved in vitro potencies in the presence of plasma. X-ray resolution of rh-renin/38a in the course of SAR work surprisingly unveiled the exploitation of a previously unexplored pocket (S3sp) important for strong binding affinities. Several inhibitors demonstrated oral efficacy in sodium-depleted marmosets. The most potent, 38a, induced dose-dependently a pronounced reduction in mean arterial blood pressure, paralleled by complete blockade of active plasma renin, up to 8 h post-dose. Oral bioavailability of 38a was 16% in marmosets.
Richard Göschke; Stefan Stutz; Vittorio Rasetti; Nissim-Claude Cohen; Joseph Rahuel; Pascal Rigollier; Hans-Peter Baum; Peter Forgiarini; Christian R Schnell; Trixie Wagner; Markus G Gruetter; Walter Fuhrer; Walter Schilling; Frédéric Cumin; Jeanette M Wood; Jürgen Maibaum
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Publication Detail:
Type:  Journal Article     Date:  2007-09-08
Journal Detail:
Title:  Journal of medicinal chemistry     Volume:  50     ISSN:  0022-2623     ISO Abbreviation:  J. Med. Chem.     Publication Date:  2007 Oct 
Date Detail:
Created Date:  2007-09-27     Completed Date:  2007-11-21     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9716531     Medline TA:  J Med Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  4818-31     Citation Subset:  IM    
Novartis Institutes for BioMedical Research, NOVARTIS Pharma AG, CH-4002 Basel, Switzerland.
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MeSH Terms
Administration, Oral
Amides / chemical synthesis*,  chemistry,  pharmacology
Anisoles / chemical synthesis*,  chemistry,  pharmacology
Antihypertensive Agents / chemical synthesis*,  chemistry,  pharmacology
Biological Availability
Blood Pressure / drug effects
Crystallography, X-Ray
Heart Rate / drug effects
Models, Molecular
Molecular Mimicry
Molecular Structure
Octanoic Acids / chemical synthesis*,  chemistry,  pharmacology
Peptides / chemistry*
Protein Binding
Renin / antagonists & inhibitors*,  blood
Structure-Activity Relationship
Reg. No./Substance:
0/5-amino-4-hydroxy-7-(4-methoxy-3-(3-methoxypropyl)benzyl)-2,8-dimethylnonanoic acid butylamide; 0/Amides; 0/Anisoles; 0/Antihypertensive Agents; 0/Octanoic Acids; 0/Peptides; EC

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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