Synthesis of retinoid X receptor-specific ligands that are potent inducers of adipogenesis in 3T3-L1 cells.
A novel series of oxime ligands has been synthesized that displays potent, specific activation of the retinoid X receptors (RXRs). The oximes of 3-substituted (tetramethyltetrahydronaphthyl)carbonylbenzoic acids are readily available by condensation with hydroxyl- or methoxylamine; alkylation of the hydroxyl oxime provides a variety of analogues. Oximes and variously substituted oxime derivatives demonstrate high binding affinity for the RXRs and specific RXR activation and, hence, are called rexinoids. These oxime rexinoids are activators of the RXR:PPARgamma heterodimer and are potent inducers of differentiation of 3T3-L1 preadipocytes to adipocytes. We have recently reported that ligands which activate the RXR:PPARgamma heterodimer in this manner are effective in the treatment of type II diabetes (non-insulin-dependent diabetes mellitus, NIDDM). Thus, these new oxime rexinoids are potential therapeutic agents for the treatment of metabolic disorders, such as obesity and diabetes.
Departments of Medicinal Chemistry, Retinoid Research, and New Leads Discovery, Ligand Pharmaceuticals, Incorporated, 10255 Science Center Drive, San Diego, California 92121, USA.
S S
SS
Canan Koch
L J
LJ
Dardashti
R M
RM
Cesario
G E
GE
Croston
M F
MF
Boehm
R A
RA
Heyman
A M
AM
Nadzan
D016475:3T3 Cells; D017667:Adipocytes / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D000818:Animals; D001565:Benzoates / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D001667:Binding, Competitive; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D018360:Crystallography, X-Ray; D004268:DNA-Binding Proteins / Q000378:metabolism*; D008024:Ligands; D051379:Mice; D010091:Oximes / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000096:biosynthesis; D018168:Receptors, Retinoic Acid / Q000819:agonists* / Q000096:biosynthesis / Q000378:metabolism; D011994:Recombinant Proteins / Q000819:agonists / Q000096:biosynthesis / Q000378:metabolism; D047488:Retinoid X Receptors; D014157:Transcription Factors / Q000819:agonists* / Q000096:biosynthesis / Q000378:metabolism; D014162:Transfection; D014280:Triglycerides / Q000378:metabolism
C117667:4-((3,5,5,8,8-pentamethyl--5,6,7,8-tetrahydro-2-naphthyl)carbonyl)benzoic acid O-methyloxime; C117666:4-((3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)carbonyl)benzoic acid oxime; D001565:Benzoates; D004268:DNA-Binding Proteins; D008024:Ligands; D010091:Oximes; D018160:Receptors, Cytoplasmic and Nuclear; D018168:Receptors, Retinoic Acid; D011994:Recombinant Proteins; D047488:Retinoid X Receptors; D014157:Transcription Factors; D014280:Triglycerides