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1.
Bioorg Med Chem Lett ; 13(22): 4071-5, 2003 Nov 17.
Article in English | MEDLINE | ID: mdl-14592510

ABSTRACT

New RXR-selective modulators possessing a 6-fluoro trienoic acid moiety (6Z olefin) or a fluorinated/heterocyclic-substituted benzene core ring, were synthesized in an expedient and selective way. A subset of these compounds was evaluated for their metabolic properties (exposure in IRC male mice) and show a dramatic increase of exposure compared to our reference compound, 3 (LG101506).


Subject(s)
Coumarins/chemical synthesis , Coumarins/pharmacology , Receptors, Retinoic Acid/physiology , Transcription Factors/physiology , Animals , Binding, Competitive , Cell Line , Drug Design , Kinetics , Male , Mice , Receptors, Retinoic Acid/drug effects , Retinoic Acid Receptor alpha , Retinoid X Receptors , Transcription Factors/drug effects , Tretinoin/pharmacokinetics , Retinoic Acid Receptor gamma
2.
J Med Chem ; 46(19): 4087-103, 2003 Sep 11.
Article in English | MEDLINE | ID: mdl-12954061

ABSTRACT

Retinoid X receptor:peroxisome proliferative-activated receptor (RXR:PPAR) heterodimers play a critical role in the regulation of glucose (RXR/PPARgamma) and lipid metabolism (RXR/PPARalpha). Previously, we described a concise structure-activity relationship study of selective RXR modulators possessing a (2E,4E,6Z)-3-methyl-7-(3,5-dialkyl-6-alkoxyphenyl)-octa-2,4,6-trienoic acid scaffold. These studies were focused on the 2-position alkoxy side chain. We describe here the design and synthesis of a novel series of RXR selective modulators possessing the same aromatic core structure with the addition of a ring locked 6-7-Z-olefin on the trienoic acid moiety. The synthesis and structure-activity relationship studies of these 6,7-locked cyclopentenyl, phenyl, thienyl, furan, and pyridine-trienoic acid derivatives is presented herein.


Subject(s)
Benzene Derivatives/chemistry , Benzene Derivatives/pharmacology , Caprylates/chemistry , Caprylates/pharmacology , Thiazolidinediones , Alkenes/chemistry , Alkenes/pharmacology , Animals , Benzene Derivatives/chemical synthesis , Caprylates/chemical synthesis , Cell Line , Chlorocebus aethiops , Dose-Response Relationship, Drug , Drug Design , Drug Synergism , Hypoglycemic Agents/chemistry , Hypoglycemic Agents/pharmacology , Male , Mice , Radioligand Assay , Rats , Rats, Sprague-Dawley , Receptors, Retinoic Acid/agonists , Receptors, Retinoic Acid/antagonists & inhibitors , Receptors, Retinoic Acid/genetics , Receptors, Retinoic Acid/metabolism , Retinoid X Receptors , Rosiglitazone , Structure-Activity Relationship , Thiazoles/pharmacology , Thyroxine/blood , Transcription Factors/agonists , Transcription Factors/antagonists & inhibitors , Transcription Factors/genetics , Transcription Factors/metabolism , Transfection , Triglycerides/blood
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