1zeo
From Proteopedia
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|ACTIVITY= | |ACTIVITY= | ||
|GENE= PPARG, NR1C3 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens]) | |GENE= PPARG, NR1C3 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens]) | ||
| + | |DOMAIN= | ||
| + | |RELATEDENTRY= | ||
| + | |RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1zeo FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1zeo OCA], [http://www.ebi.ac.uk/pdbsum/1zeo PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=1zeo RCSB]</span> | ||
}} | }} | ||
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==Overview== | ==Overview== | ||
The synthesis and structure-activity relationships of novel series of alpha-aryloxyphenylacetic acids as PPARalpha/gamma dual agonists are reported. The initial search for surrogates of the ester group in the screen lead led first to the optimization of a subseries with a ketone moiety. Further efforts to modify the ketone subseries led to the design and synthesis of two new subseries containing fused heterocyclic ring systems. All these analogues were characterized by their "super" PPARalpha agonist activity and weak or partial agonist activity on PPARgamma in PPAR-GAL4 transactivation assays despite their similar binding affinities for both receptors. The cocrystal structures of compounds 7 and rosiglitazone with PPARgamma-LBD were compared, and significant differences were found in their interactions with the receptor. Select analogues in each subseries were further evaluated for in vivo efficacy. They all showed excellent anti-hyperglycemic efficacy in a db/db mouse model and hypolipidemic activity in hamster and dog models without provoking the typical PPARgamma-associated side effects in the rat tolerability assay. | The synthesis and structure-activity relationships of novel series of alpha-aryloxyphenylacetic acids as PPARalpha/gamma dual agonists are reported. The initial search for surrogates of the ester group in the screen lead led first to the optimization of a subseries with a ketone moiety. Further efforts to modify the ketone subseries led to the design and synthesis of two new subseries containing fused heterocyclic ring systems. All these analogues were characterized by their "super" PPARalpha agonist activity and weak or partial agonist activity on PPARgamma in PPAR-GAL4 transactivation assays despite their similar binding affinities for both receptors. The cocrystal structures of compounds 7 and rosiglitazone with PPARgamma-LBD were compared, and significant differences were found in their interactions with the receptor. Select analogues in each subseries were further evaluated for in vivo efficacy. They all showed excellent anti-hyperglycemic efficacy in a db/db mouse model and hypolipidemic activity in hamster and dog models without provoking the typical PPARgamma-associated side effects in the rat tolerability assay. | ||
| - | |||
| - | ==Disease== | ||
| - | Known diseases associated with this structure: Abdominal body fat distribution, modifier of OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=601487 601487]], Diabetes mellitus, insulin-resistant, with acanthosis nigricans and hypertension OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=601487 601487]], Glioblastoma, susceptibility to OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=601487 601487]], Insulin resistance, severe, digenic OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=601487 601487]], Lipodystrophy, familial partial OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=601487 601487]], Obesity, resistance to OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=601487 601487]], Obesity, severe OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=601487 601487]] | ||
==About this Structure== | ==About this Structure== | ||
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[[Category: Shi, G Q.]] | [[Category: Shi, G Q.]] | ||
[[Category: Zhou, G.]] | [[Category: Zhou, G.]] | ||
| - | [[Category: C01]] | ||
[[Category: alpha helix sandwich]] | [[Category: alpha helix sandwich]] | ||
[[Category: lbd]] | [[Category: lbd]] | ||
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[[Category: ppar-rxr heterodimer]] | [[Category: ppar-rxr heterodimer]] | ||
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Mar 31 01:34:53 2008'' |
Revision as of 22:34, 30 March 2008
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| , resolution 2.50Å | |||||||
|---|---|---|---|---|---|---|---|
| Ligands: | |||||||
| Gene: | PPARG, NR1C3 (Homo sapiens) | ||||||
| Resources: | FirstGlance, OCA, PDBsum, RCSB | ||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||
Crystal Structure of Human PPAR-gamma Ligand Binding Domain Complexed with an Alpha-Aryloxyphenylacetic Acid Agonist
Overview
The synthesis and structure-activity relationships of novel series of alpha-aryloxyphenylacetic acids as PPARalpha/gamma dual agonists are reported. The initial search for surrogates of the ester group in the screen lead led first to the optimization of a subseries with a ketone moiety. Further efforts to modify the ketone subseries led to the design and synthesis of two new subseries containing fused heterocyclic ring systems. All these analogues were characterized by their "super" PPARalpha agonist activity and weak or partial agonist activity on PPARgamma in PPAR-GAL4 transactivation assays despite their similar binding affinities for both receptors. The cocrystal structures of compounds 7 and rosiglitazone with PPARgamma-LBD were compared, and significant differences were found in their interactions with the receptor. Select analogues in each subseries were further evaluated for in vivo efficacy. They all showed excellent anti-hyperglycemic efficacy in a db/db mouse model and hypolipidemic activity in hamster and dog models without provoking the typical PPARgamma-associated side effects in the rat tolerability assay.
About this Structure
1ZEO is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.
Reference
Design and synthesis of alpha-aryloxyphenylacetic acid derivatives: a novel class of PPARalpha/gamma dual agonists with potent antihyperglycemic and lipid modulating activity., Shi GQ, Dropinski JF, McKeever BM, Xu S, Becker JW, Berger JP, MacNaul KL, Elbrecht A, Zhou G, Doebber TW, Wang P, Chao YS, Forrest M, Heck JV, Moller DE, Jones AB, J Med Chem. 2005 Jun 30;48(13):4457-68. PMID:15974597
Page seeded by OCA on Mon Mar 31 01:34:53 2008
