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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
25
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pubmed:dateCreated |
1999-1-7
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pubmed:abstractText |
We have identified a novel series of antidiabetic N-(2-benzoylphenyl)-L-tyrosine derivatives which are potent, selective PPARgamma agonists. Through the use of in vitro PPARgamma binding and functional assays (2S)-3-(4-(benzyloxy)phenyl)-2-((1-methyl-3-oxo-3-phenylpropenyl)+ ++amin o)propionic acid (2) was identified as a structurally novel PPARgamma agonist. Structure-activity relationships identified the 2-aminobenzophenone moiety as a suitable isostere for the chemically labile enaminone moiety in compound 2, affording 2-((2-benzoylphenyl)amino)-3-(4-(benzyloxy)phenyl)propionic acid (9). Replacement of the benzyl group in 9 with substituents known to confer in vivo potency in the thiazolidinedione (TZD) class of antidiabetic agents provided a dramatic increase in the in vitro functional potency and affinity at PPARgamma, affording a series of potent and selective PPARgamma agonists exemplified by (2S)-((2-benzoylphenyl)amino)-3-¿4-[2-(methylpyridin-2-ylamino+ ++)ethoxy ]phenyl¿propionic acid (18), 3-¿4-[2-(benzoxazol-2-ylmethylamino)ethoxy]phenyl¿-(2S)-((2- benzoylph enyl)amino)propanoic acid (19), and (2S)-((2-benzoylphenyl)amino)-3-¿4-[2-(5-methyl-2-phenyloxazol-4-y l)e thoxy]phenyl¿propanoic acid (20). Compounds 18 and 20 show potent antihyperglycemic and antihyperlipidemic activity when given orally in two rodent models of type 2 diabetes. In addition, these analogues are readily prepared in chiral nonracemic fashion from L-tyrosine and do not show a propensity to undergo racemization in vitro. The increased potency of these PPARgamma agonists relative to troglitazone may translate into superior clinical efficacy for the 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 |
http://linkedlifedata.com/resource/pubmed/chemical/Aminopyridines,
http://linkedlifedata.com/resource/pubmed/chemical/Blood Glucose,
http://linkedlifedata.com/resource/pubmed/chemical/DNA-Binding Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Hypoglycemic Agents,
http://linkedlifedata.com/resource/pubmed/chemical/Hypolipidemic Agents,
http://linkedlifedata.com/resource/pubmed/chemical/Ligands,
http://linkedlifedata.com/resource/pubmed/chemical/Lipids,
http://linkedlifedata.com/resource/pubmed/chemical/Oxazoles,
http://linkedlifedata.com/resource/pubmed/chemical/Propionic Acids,
http://linkedlifedata.com/resource/pubmed/chemical/Receptors, Cytoplasmic and Nuclear,
http://linkedlifedata.com/resource/pubmed/chemical/Recombinant Fusion Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Transcription Factors,
http://linkedlifedata.com/resource/pubmed/chemical/Tyrosine
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pubmed:status |
MEDLINE
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pubmed:month |
Dec
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pubmed:issn |
0022-2623
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pubmed:author |
pubmed-author:BlanchardS GSG,
pubmed-author:BrackeenM FMF,
pubmed-author:BrownK KKK,
pubmed-author:CobbJ EJE,
pubmed-author:CollinsJ LJL,
pubmed-author:HarringtonW WWWJr,
pubmed-author:HashimM AMA,
pubmed-author:HenkeB RBR,
pubmed-author:Hull-RydeE AEA,
pubmed-author:KaldorII,
pubmed-author:KliewerS ASA,
pubmed-author:LeesnitzerL MLM,
pubmed-author:LehmannJ MJM,
pubmed-author:LenhardJ MJM,
pubmed-author:LimaM EME,
pubmed-author:MillerJ FJF,
pubmed-author:MookR ARAJr,
pubmed-author:NobleS ASA,
pubmed-author:OliverWWJr,
pubmed-author:Orband-MillerL ALA,
pubmed-author:ParksD JDJ,
pubmed-author:PlunketK DKD,
pubmed-author:SzewczykJ RJR,
pubmed-author:WillsonT MTM
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pubmed:issnType |
Print
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pubmed:day |
3
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pubmed:volume |
41
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
5020-36
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pubmed:dateRevised |
2010-11-18
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pubmed:meshHeading |
pubmed-meshheading:9836620-Administration, Oral,
pubmed-meshheading:9836620-Aminopyridines,
pubmed-meshheading:9836620-Animals,
pubmed-meshheading:9836620-Blood Glucose,
pubmed-meshheading:9836620-Cell Line,
pubmed-meshheading:9836620-DNA-Binding Proteins,
pubmed-meshheading:9836620-Diabetes Mellitus, Experimental,
pubmed-meshheading:9836620-Humans,
pubmed-meshheading:9836620-Hypoglycemic Agents,
pubmed-meshheading:9836620-Hypolipidemic Agents,
pubmed-meshheading:9836620-Ligands,
pubmed-meshheading:9836620-Lipids,
pubmed-meshheading:9836620-Male,
pubmed-meshheading:9836620-Mice,
pubmed-meshheading:9836620-Oxazoles,
pubmed-meshheading:9836620-Propionic Acids,
pubmed-meshheading:9836620-Radioligand Assay,
pubmed-meshheading:9836620-Rats,
pubmed-meshheading:9836620-Receptors, Cytoplasmic and Nuclear,
pubmed-meshheading:9836620-Recombinant Fusion Proteins,
pubmed-meshheading:9836620-Stereoisomerism,
pubmed-meshheading:9836620-Structure-Activity Relationship,
pubmed-meshheading:9836620-Transcription Factors,
pubmed-meshheading:9836620-Transfection,
pubmed-meshheading:9836620-Tyrosine
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pubmed:year |
1998
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pubmed:articleTitle |
N-(2-Benzoylphenyl)-L-tyrosine PPARgamma agonists. 1. Discovery of a novel series of potent antihyperglycemic and antihyperlipidemic agents.
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pubmed:affiliation |
Glaxo Wellcome Research and Development, Five Moore Drive, Research Triangle Park, North Carolina 27709, USA. brh14990@glaxowellcome.com
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pubmed:publicationType |
Journal Article
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