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.
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.
Michellys
Pierre-Yves
PY
Department of Medicinal Chemistry, Ligand Pharmaceuticals, Inc., 10275 Science Center Drive, San Diego, California 92121, USA. pmichellys@gnf.org
Ardecky
Robert J
RJ
Chen
Jyun-Hung
JH
D'Arrigo
Jennifer
J
Grese
Timothy A
TA
Karanewsky
Donald S
DS
Leibowitz
Mark D
MD
Liu
Sha
S
Mais
Dale A
DA
Mapes
Christopher M
CM
Montrose-Rafizadeh
Chahrzad
C
Ogilvie
Katheen M
KM
Reifel-Miller
Anne
A
Rungta
Deepa
D
Thompson
Anthony W
AW
Tyhonas
John S
JS
Boehm
Marcus F
MF
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
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