Source:http://linkedlifedata.com/resource/pubmed/id/19891440
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| Predicate | Object |
|---|---|
| rdf:type | |
| lifeskim:mentions | |
| pubmed:issue |
24
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| pubmed:dateCreated |
2009-12-17
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| pubmed:abstractText |
We have focused on optimization of the inadequate pharmacokinetic profile of trans-4-substituted cyclohexanecarboxylic acid 5, which is commonly observed in many small molecule very late antigen-4 (VLA-4) antagonists. We modified the lipophilic moiety in 5 and found that reducing the polar surface area of this moiety results in improvement of the PK profile. Consequently, our efforts have led to the discovery of trans-4-[1-[[2,5-dichloro-4-(1-methyl-3-indolylcarboxamido)phenyl]acetyl]-(4S)-methoxy-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylic acid (14e) with potent activity (IC(50) = 5.4 nM) and significantly improved bioavailability in rats, dogs, and monkeys (100%, 91%, 68%), which demonstrated excellent oral efficacy in murine and guinea pig models of asthma. Based on its overall profile, compound 14e was progressed into clinical trails. In a single ascending-dose phase I clinical study, compound 14e exhibited favorable oral exposure as expected and had no serious adverse events.
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| pubmed:language |
eng
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| pubmed:journal | |
| pubmed:citationSubset |
IM
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| pubmed:chemical | |
| pubmed:status |
MEDLINE
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| pubmed:month |
Dec
|
| pubmed:issn |
1520-4804
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| pubmed:author |
pubmed-author:ChibaJunJ,
pubmed-author:IigouYutakaY,
pubmed-author:IimuraShinS,
pubmed-author:KumagiMidoriM,
pubmed-author:MachinagaNobuoN,
pubmed-author:MatsumotoKeikoK,
pubmed-author:MuroFumihitoF,
pubmed-author:NakayamaAtsushiA,
pubmed-author:SatohAtsushiA,
pubmed-author:SetoguchiMasakiM,
pubmed-author:SugimotoYuuichiY,
pubmed-author:TairaTomoeT,
pubmed-author:TakashiTohruT,
pubmed-author:TakayamaGensukeG,
pubmed-author:YokoyamaMikaM,
pubmed-author:YonedaYoshiyukiY
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| pubmed:issnType |
Electronic
|
| pubmed:day |
24
|
| pubmed:volume |
52
|
| pubmed:owner |
NLM
|
| pubmed:authorsComplete |
Y
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| pubmed:pagination |
7974-92
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| pubmed:meshHeading |
pubmed-meshheading:19891440-Administration, Oral,
pubmed-meshheading:19891440-Animals,
pubmed-meshheading:19891440-Biological Availability,
pubmed-meshheading:19891440-CHO Cells,
pubmed-meshheading:19891440-Cricetinae,
pubmed-meshheading:19891440-Cricetulus,
pubmed-meshheading:19891440-Cyclohexanecarboxylic Acids,
pubmed-meshheading:19891440-Dogs,
pubmed-meshheading:19891440-Guinea Pigs,
pubmed-meshheading:19891440-Haplorhini,
pubmed-meshheading:19891440-Humans,
pubmed-meshheading:19891440-Indoles,
pubmed-meshheading:19891440-Integrin alpha4beta1,
pubmed-meshheading:19891440-Mice,
pubmed-meshheading:19891440-Pyrrolidines,
pubmed-meshheading:19891440-Rats,
pubmed-meshheading:19891440-Rats, Sprague-Dawley,
pubmed-meshheading:19891440-Structure-Activity Relationship
|
| pubmed:year |
2009
|
| pubmed:articleTitle |
Discovery of trans-4-[1-[[2,5-Dichloro-4-(1-methyl-3-indolylcarboxamido)phenyl]acetyl]-(4S)-methoxy-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylic acid: an orally active, selective very late antigen-4 antagonist.
|
| pubmed:affiliation |
R&D Division, Daiichi Sankyo Co., Ltd., Tokyo 134-8630, Japan. muro.fumihito.iy@daiichisankyo.co.jp
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| pubmed:publicationType |
Journal Article
|