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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
7
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pubmed:dateCreated |
2007-3-13
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pubmed:abstractText |
A novel series of pyrrolidine-constrained phenethylamines were developed as dipeptidyl peptidase IV (DPP4) inhibitors for the treatment of type 2 diabetes. The cyclohexene ring of lead-like screening hit 5 was replaced with a pyrrolidine to enable parallel chemistry, and protein co-crystal structural data guided the optimization of N-substituents. Employing this strategy, a >400x improvement in potency over the initial hit was realized in rapid fashion. Optimized compounds are potent and selective inhibitors with excellent pharmacokinetic profiles. Compound 30 was efficacious in vivo, lowering blood glucose in ZDF rats that were allowed to feed freely on a mixed meal.
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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 |
Apr
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pubmed:issn |
0960-894X
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pubmed:author |
pubmed-author:BackesBradley JBJ,
pubmed-author:BallaronStephen JSJ,
pubmed-author:BenoDavid W ADW,
pubmed-author:Black-SchaeferCandaceC,
pubmed-author:HamiltonGregory LGL,
pubmed-author:Kempf-GroteAnita JAJ,
pubmed-author:KopeckaHanaH,
pubmed-author:LaiChunqiuC,
pubmed-author:LongeneckerKentonK,
pubmed-author:LubbenThomas HTH,
pubmed-author:MadarDavid JDJ,
pubmed-author:MikaAmanda KAK,
pubmed-author:PeiZhonghuaZ,
pubmed-author:ShamHing LHL,
pubmed-author:StashkoMichael AMA,
pubmed-author:StewartKentK,
pubmed-author:TianZhenpingZ,
pubmed-author:TrevillyanJames MJM,
pubmed-author:ZinkerBradley ABA,
pubmed-author:von GeldernThomas WTW
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pubmed:issnType |
Print
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pubmed:day |
1
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pubmed:volume |
17
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
2005-12
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pubmed:dateRevised |
2010-11-18
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pubmed:meshHeading |
pubmed-meshheading:17276063-Animals,
pubmed-meshheading:17276063-Blood Glucose,
pubmed-meshheading:17276063-Chemistry, Pharmaceutical,
pubmed-meshheading:17276063-Cyclohexenes,
pubmed-meshheading:17276063-Diabetes Mellitus, Type 2,
pubmed-meshheading:17276063-Dipeptidyl-Peptidase IV Inhibitors,
pubmed-meshheading:17276063-Drug Design,
pubmed-meshheading:17276063-Enzyme Inhibitors,
pubmed-meshheading:17276063-Female,
pubmed-meshheading:17276063-Hypoglycemic Agents,
pubmed-meshheading:17276063-Models, Chemical,
pubmed-meshheading:17276063-Molecular Conformation,
pubmed-meshheading:17276063-Phenethylamines,
pubmed-meshheading:17276063-Pyrrolidines,
pubmed-meshheading:17276063-Rats
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pubmed:year |
2007
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pubmed:articleTitle |
Pyrrolidine-constrained phenethylamines: The design of potent, selective, and pharmacologically efficacious dipeptidyl peptidase IV (DPP4) inhibitors from a lead-like screening hit.
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pubmed:affiliation |
Metabolic Disease Research, Abbott Laboratories, Abbott Park Road, Abbott Park, IL 60064-6099, USA. bradley.backes@abbott.com
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pubmed:publicationType |
Journal Article
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