title: Design, synthesis, and structure-activity relationship studies of novel 6,7-locked-[7-(2-alkoxy-3,5-dialkylbenzene)-3-methylocta]-2,4,6-trienoic acids.
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.
authors.affiliation: Department of Medicinal Chemistry, Ligand Pharmaceuticals, Inc., 10275 Science Center Drive, San Diego, California 92121, USA. pmichellys@gnf.org
authors.forename: Pierre-Yves
authors.initials: PY
authors.lastname: Michellys
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Ardecky
authors.forename: Jyun-Hung
authors.initials: JH
authors.lastname: Chen
authors.forename: Jennifer
authors.initials: J
authors.lastname: D'Arrigo
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Grese
authors.forename: Donald S
authors.initials: DS
authors.lastname: Karanewsky
authors.forename: Mark D
authors.initials: MD
authors.lastname: Leibowitz
authors.forename: Sha
authors.initials: S
authors.lastname: Liu
authors.forename: Dale A
authors.initials: DA
authors.lastname: Mais
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Mapes
authors.forename: Chahrzad
authors.initials: C
authors.lastname: Montrose-Rafizadeh
authors.forename: Katheen M
authors.initials: KM
authors.lastname: Ogilvie
authors.forename: Anne
authors.initials: A
authors.lastname: Reifel-Miller
authors.forename: Deepa
authors.initials: D
authors.lastname: Rungta
authors.forename: Anthony W
authors.initials: AW
authors.lastname: Thompson
authors.forename: John S
authors.initials: JS
authors.lastname: Tyhonas
authors.forename: Marcus F
authors.initials: MF
authors.lastname: Boehm
mesh_terms: D000475:Alkenes / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001555:Benzene Derivatives / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D002210:Caprylates / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D002460:Cell Line; D002522:Chlorocebus aethiops; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004357:Drug Synergism; D007004:Hypoglycemic Agents / Q000737:chemistry / Q000494:pharmacology; D008297:Male; D051379:Mice; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D018168:Receptors, Retinoic Acid / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D047488:Retinoid X Receptors; D000077154:Rosiglitazone; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000494:pharmacology; D045162:Thiazolidinediones; D013974:Thyroxine / Q000097:blood; D014157:Transcription Factors / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D014280:Triglycerides / Q000097:blood
chemical_list: D000475:Alkenes; D001555:Benzene Derivatives; D002210:Caprylates; D007004:Hypoglycemic Agents; D018168:Receptors, Retinoic Acid; D047488:Retinoid X Receptors; D013844:Thiazoles; D045162:Thiazolidinediones; D014157:Transcription Factors; D014280:Triglycerides; D000077154:Rosiglitazone; D013974:Thyroxine