Design and synthesis of novel RXR-selective modulators with improved pharmacological profile.
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).
Department of Medicinal Chemistry, Ligand Pharmaceuticals Incorporated, 10275 Science Center Drive, San Diego, CA 92121, USA. pmichellys@gnf.org
Pierre-Yves
PY
Michellys
Marcus F
MF
Boehm
Jyun-Hung
JH
Chen
Timothy A
TA
Grese
Donald S
DS
Karanewsky
Mark D
MD
Leibowitz
Sha
S
Liu
Dale A
DA
Mais
Christopher M
CM
Mapes
Anne
A
Reifel-Miller
Katheen M
KM
Ogilvie
Deepa
D
Rungta
Anthony W
AW
Thompson
John S
JS
Tyhonas
Nathan
N
Yumibe
Robert J
RJ
Ardecky
D000818:Animals; D001667:Binding, Competitive; D002460:Cell Line; D003374:Coumarins / Q000138:chemical synthesis* / Q000494:pharmacology*; D015195:Drug Design; D007700:Kinetics; D008297:Male; D051379:Mice; D018168:Receptors, Retinoic Acid / Q000187:drug effects / Q000502:physiology*; D000072482:Retinoic Acid Receptor alpha; D047488:Retinoid X Receptors; D014157:Transcription Factors / Q000187:drug effects / Q000502:physiology*; D014212:Tretinoin / Q000493:pharmacokinetics; D000097768:Retinoic Acid Receptor gamma
D003374:Coumarins; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D047488:Retinoid X Receptors; D014157:Transcription Factors; D014212:Tretinoin; D000097768:Retinoic Acid Receptor gamma; C000607072:Rara protein, mouse; C082925:retinoic acid receptor beta