|
rdf:type |
|
|
lifeskim:mentions |
|
|
pubmed:issue |
15
|
|
pubmed:dateCreated |
2011-7-19
|
|
pubmed:abstractText |
Dipeptidyl peptidase IV (DPP-4) inhibition is a validated therapeutic option for type 2 diabetes, exhibiting multiple antidiabetic effects with little or no risk of hypoglycemia. In our studies involving non-covalent DPP-4 inhibitors, a novel series of quinoline-based inhibitors were designed based on the co-crystal structure of isoquinolone 2 in complex with DPP-4 to target the side chain of Lys554. Synthesis and evaluation of designed compounds revealed 1-[3-(aminomethyl)-4-(4-methylphenyl)-2-(2-methylpropyl)quinolin-6-yl]piperazine-2,5-dione (1) as a potent, selective, and orally active DPP-4 inhibitor (IC??=1.3 nM) with long-lasting ex vivo activity in dogs and excellent antihyperglycemic effects in rats. A docking study of compound 1 revealed a hydrogen-bonding interaction with the side chain of Lys554, suggesting this residue as a potential target site useful for enhancing DPP-4 inhibition.
|
|
pubmed:language |
eng
|
|
pubmed:journal |
|
|
pubmed:citationSubset |
IM
|
|
pubmed:chemical |
|
|
pubmed:status |
MEDLINE
|
|
pubmed:month |
Aug
|
|
pubmed:issn |
1464-3391
|
|
pubmed:author |
pubmed-author:AertgeertsKathleenK,
pubmed-author:AsakawaTomokoT,
pubmed-author:BannoYoshihiroY,
pubmed-author:FunamiMiyukiM,
pubmed-author:IkedoKojiK,
pubmed-author:KataokaOsamuO,
pubmed-author:KosakaTakuoT,
pubmed-author:MaezakiHironobuH,
pubmed-author:MiyamotoYasufumiY,
pubmed-author:MoritouYuusukeY,
pubmed-author:OiSatoruS,
pubmed-author:SasakiMasakoM,
pubmed-author:SuzukiNobuhiroN,
pubmed-author:TakeuchiKojiK,
pubmed-author:TaniAkiyoshiA,
pubmed-author:TawadaMichikoM,
pubmed-author:TsubotaniShigetoshiS,
pubmed-author:YamamotoYoshioY,
pubmed-author:YanoJasonJ
|
|
pubmed:copyrightInfo |
Copyright © 2011 Elsevier Ltd. All rights reserved.
|
|
pubmed:issnType |
Electronic
|
|
pubmed:day |
1
|
|
pubmed:volume |
19
|
|
pubmed:owner |
NLM
|
|
pubmed:authorsComplete |
Y
|
|
pubmed:pagination |
4482-98
|
|
pubmed:meshHeading |
pubmed-meshheading:21741847-Animals,
pubmed-meshheading:21741847-Caco-2 Cells,
pubmed-meshheading:21741847-Cell Line,
pubmed-meshheading:21741847-Diabetes Mellitus, Type 2,
pubmed-meshheading:21741847-Dipeptidyl Peptidase 4,
pubmed-meshheading:21741847-Dipeptidyl-Peptidase IV Inhibitors,
pubmed-meshheading:21741847-Dogs,
pubmed-meshheading:21741847-Female,
pubmed-meshheading:21741847-Humans,
pubmed-meshheading:21741847-Hypoglycemic Agents,
pubmed-meshheading:21741847-Lysine,
pubmed-meshheading:21741847-Quinolines,
pubmed-meshheading:21741847-Rats,
pubmed-meshheading:21741847-Rats, Wistar
|
|
pubmed:year |
2011
|
|
pubmed:articleTitle |
Discovery of potent, selective, and orally bioavailable quinoline-based dipeptidyl peptidase IV inhibitors targeting Lys554.
|
|
pubmed:affiliation |
Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 17-85, Jusohomachi 2-chome, Yodogawa-ku, Osaka 532-8686, Japan.
|
|
pubmed:publicationType |
Journal Article,
Research Support, U.S. Gov't, Non-P.H.S.
|
