Source:http://linkedlifedata.com/resource/pubmed/id/21163664
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| Predicate | Object |
|---|---|
| rdf:type | |
| lifeskim:mentions | |
| pubmed:issue |
1
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| pubmed:dateCreated |
2011-1-3
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| pubmed:abstractText |
We have previously discovered nicotinic acid derivative 1 as a structurally novel dipeptidyl peptidase IV (DPP-4) inhibitor. In this study, we obtained the X-ray co-crystal structure between nicotinic acid derivative 1 and DPP-4. From these X-ray co-crystallography results, to achieve more potent inhibitory activity, we targeted Arg125 as a potential amino acid residue because it was located near the pyridine core, and some known DPP-4 inhibitors were reported to interact with this residue. We hypothesized that the guanidino group of Arg125 could interact with two hydrogen-bond acceptors in a bidentate manner. Therefore, we designed a series of 3-pyridylacetamide derivatives possessing an additional hydrogen-bond acceptor that could have the desired bidentate interaction with Arg125. We discovered the dihydrochloride of 1-{[5-(aminomethyl)-2-methyl-4-(4-methylphenyl)-6-(2-methylpropyl)pyridin-3-yl]acetyl}-l-prolinamide (13j) to be a potent and selective DPP-4 inhibitor that could interact with the guanidino group of Arg125 in a unique bidentate manner.
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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 |
Jan
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| pubmed:issn |
1464-3391
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| pubmed:author |
pubmed-author:AertgeertsKathleenK,
pubmed-author:AmanoMichikoM,
pubmed-author:AsakawaTomokoT,
pubmed-author:BannoYoshihiroY,
pubmed-author:FujimotoTatsuhikoT,
pubmed-author:FunamiMiyukiM,
pubmed-author:IkedoKojiK,
pubmed-author:KataokaOsamuO,
pubmed-author:KosakaTakuoT,
pubmed-author:MaezakiHironobuH,
pubmed-author:MiyamotoYasufumiY,
pubmed-author:MoritohYusukeY,
pubmed-author:OiSatoruS,
pubmed-author:SuzukiNobuhiroN,
pubmed-author:TakeuchiKojiK,
pubmed-author:TaniAkiyoshiA,
pubmed-author:TsubotaniShigetoshiS,
pubmed-author:YamamotoYoshioY,
pubmed-author:YamashitaTohruT,
pubmed-author:YanoJasonJ
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| pubmed:copyrightInfo |
Copyright © 2010 Elsevier Ltd. All rights reserved.
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| pubmed:issnType |
Electronic
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| pubmed:day |
1
|
| pubmed:volume |
19
|
| pubmed:owner |
NLM
|
| pubmed:authorsComplete |
Y
|
| pubmed:pagination |
172-85
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| pubmed:meshHeading |
pubmed-meshheading:21163664-Acetamides,
pubmed-meshheading:21163664-Arginine,
pubmed-meshheading:21163664-Crystallography, X-Ray,
pubmed-meshheading:21163664-Dipeptidyl-Peptidase IV Inhibitors,
pubmed-meshheading:21163664-Drug Design,
pubmed-meshheading:21163664-Models, Molecular,
pubmed-meshheading:21163664-Structure-Activity Relationship
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| pubmed:year |
2011
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| pubmed:articleTitle |
Design and synthesis of 3-pyridylacetamide derivatives as dipeptidyl peptidase IV (DPP-4) inhibitors targeting a bidentate interaction with Arg125.
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| pubmed:affiliation |
Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 17-85, Jusohonmachi 2-Chome, Yodogawa-ku, Osaka 532-8686, Japan. Miyamoto_Yasufumi@takeda.co.jp
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| pubmed:publicationType |
Journal Article
|