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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
12
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pubmed:dateCreated |
2009-6-18
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pubmed:databankReference |
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pubmed:abstractText |
Starting from known piperidine renin inhibitors, a new series of 3,9-diazabicyclo[3.3.1]nonene derivatives was rationally designed and prepared. Optimization of the positions 3, 6, and 7 of the diazabicyclonene template led to potent renin inhibitors. The substituents attached at the positions 6 and 7 were essential for the binding affinity of these compounds for renin. The introduction of a substituent attached at the position 3 did not modify the binding affinity but allowed the modulation of the ADME properties. Our efforts led to the discovery of compound (+)-26g that inhibits renin with an IC(50) of 0.20 nM in buffer and 19 nM in plasma. The pharmacokinetics properties of this and other similar compounds are discussed. Compound (+)-26g is well absorbed in rats and efficacious at 10 mg/kg in vivo.
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
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pubmed:status |
MEDLINE
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pubmed:month |
Jun
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pubmed:issn |
1520-4804
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pubmed:author |
pubmed-author:BezençonOlivierO,
pubmed-author:BinkertChristophC,
pubmed-author:BossChristophC,
pubmed-author:BurDanielD,
pubmed-author:CorminboeufOlivierO,
pubmed-author:DelahayeStéphaneS,
pubmed-author:FischliWalterW,
pubmed-author:GrisostomiCorinnaC,
pubmed-author:HessPatrickP,
pubmed-author:PradeLarsL,
pubmed-author:RemenLubosL,
pubmed-author:Richard-BildsteinSylviaS,
pubmed-author:SifferlenThierryT,
pubmed-author:SteinerBeatB,
pubmed-author:StricknerPanjaP,
pubmed-author:TreiberAlexanderA,
pubmed-author:WellerThomasT
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pubmed:issnType |
Electronic
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pubmed:day |
25
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pubmed:volume |
52
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
3689-702
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pubmed:meshHeading |
pubmed-meshheading:19358611-Azabicyclo Compounds,
pubmed-meshheading:19358611-Binding Sites,
pubmed-meshheading:19358611-Crystallography, X-Ray,
pubmed-meshheading:19358611-Dose-Response Relationship, Drug,
pubmed-meshheading:19358611-Drug Design,
pubmed-meshheading:19358611-Enzyme Inhibitors,
pubmed-meshheading:19358611-Models, Molecular,
pubmed-meshheading:19358611-Molecular Conformation,
pubmed-meshheading:19358611-Renin,
pubmed-meshheading:19358611-Structure-Activity Relationship
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pubmed:year |
2009
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pubmed:articleTitle |
Design and preparation of potent, nonpeptidic, bioavailable renin inhibitors.
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pubmed:affiliation |
Drug Discovery and Preclinical Research, Actelion Pharmaceuticals Ltd., Gewerbestrasse 16, CH-4123 Allschwil, Switzerland. olivier.bezencon@actelion.com
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pubmed:publicationType |
Journal Article
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