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rdf:type |
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lifeskim:mentions |
umls-concept:C0011860,
umls-concept:C0087111,
umls-concept:C0205177,
umls-concept:C0205250,
umls-concept:C0205531,
umls-concept:C0226896,
umls-concept:C0442027,
umls-concept:C1527415,
umls-concept:C1611934,
umls-concept:C1615610,
umls-concept:C1709630,
umls-concept:C1827106,
umls-concept:C1880355,
umls-concept:C1979963,
umls-concept:C2003903,
umls-concept:C2917389
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pubmed:issue |
15
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pubmed:dateCreated |
2005-7-21
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pubmed:abstractText |
Efforts to further elucidate structure-activity relationships (SAR) within our previously disclosed series of beta-quaternary amino acid linked l-cis-4,5-methanoprolinenitrile dipeptidyl peptidase IV (DPP-IV) inhibitors led to the investigation of vinyl substitution at the beta-position of alpha-cycloalkyl-substituted glycines. Despite poor systemic exposure, vinyl-substituted compounds showed extended duration of action in acute rat ex vivo plasma DPP-IV inhibition models. Oxygenated putative metabolites were prepared and were shown to exhibit the potency and extended duration of action of their precursors in efficacy models measuring glucose clearance in Zucker(fa/fa) rats. Extension of this approach to adamantylglycine-derived inhibitors led to the discovery of highly potent inhibitors, including hydroxyadamantyl compound BMS-477118 (saxagliptin), a highly efficacious, stable, and long-acting DPP-IV inhibitor, which is currently undergoing clinical trials for treatment of type 2 diabetes.
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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 |
Jul
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pubmed:issn |
0022-2623
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pubmed:author |
pubmed-author:Abboa-OffeiBenoniB,
pubmed-author:AugeriDavid JDJ,
pubmed-author:BetebennerDavid ADA,
pubmed-author:BillerScott ASA,
pubmed-author:CapMichaelM,
pubmed-author:ChangShu YSY,
pubmed-author:EganDonald MDM,
pubmed-author:HamannLawrence GLG,
pubmed-author:HanSong-PingSP,
pubmed-author:HuangQiQ,
pubmed-author:KhannaAshishA,
pubmed-author:KirbyMark SMS,
pubmed-author:MagninDavid RDR,
pubmed-author:MarcinkevicieneJovitaJ,
pubmed-author:ParkerRex ARA,
pubmed-author:RobertsonJames GJG,
pubmed-author:RoblJeffrey AJA,
pubmed-author:SimpkinsLigaya MLM,
pubmed-author:TaoLiL,
pubmed-author:TaunkPrakashP,
pubmed-author:TozzoEffieE,
pubmed-author:WangAiyingA,
pubmed-author:WelzelGustav EGE,
pubmed-author:XuZ CZC
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pubmed:issnType |
Print
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pubmed:day |
28
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pubmed:volume |
48
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
5025-37
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pubmed:dateRevised |
2011-11-17
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pubmed:meshHeading |
pubmed-meshheading:16033281-Adamantane,
pubmed-meshheading:16033281-Animals,
pubmed-meshheading:16033281-Biological Availability,
pubmed-meshheading:16033281-Blood Glucose,
pubmed-meshheading:16033281-Diabetes Mellitus, Type 2,
pubmed-meshheading:16033281-Dipeptides,
pubmed-meshheading:16033281-Dipeptidyl Peptidase 4,
pubmed-meshheading:16033281-Glucose Tolerance Test,
pubmed-meshheading:16033281-Glycine,
pubmed-meshheading:16033281-Humans,
pubmed-meshheading:16033281-Hypoglycemic Agents,
pubmed-meshheading:16033281-Insulin,
pubmed-meshheading:16033281-Male,
pubmed-meshheading:16033281-Mice,
pubmed-meshheading:16033281-Mice, Obese,
pubmed-meshheading:16033281-Microsomes, Liver,
pubmed-meshheading:16033281-Nitriles,
pubmed-meshheading:16033281-Proline,
pubmed-meshheading:16033281-Protease Inhibitors,
pubmed-meshheading:16033281-Rats,
pubmed-meshheading:16033281-Rats, Zucker,
pubmed-meshheading:16033281-Stereoisomerism,
pubmed-meshheading:16033281-Structure-Activity Relationship
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pubmed:year |
2005
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pubmed:articleTitle |
Discovery and preclinical profile of Saxagliptin (BMS-477118): a highly potent, long-acting, orally active dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes.
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pubmed:affiliation |
Department of Discovery Chemistry, Bristol-Myers Squibb, Pharmaceutical Research Institute, P.O. Box 5400, Princeton, New Jersey 08543-5400, USA. lawrence.hamann@bms.com
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pubmed:publicationType |
Journal Article,
In Vitro
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