title: Novel (2E,4E,6Z)-7-(2-alkoxy-3,5-dialkylbenzene)-3-methylocta-2,4,6-trienoic acid retinoid X receptor modulators are active in models of type 2 diabetes.
abstract: Previous data have shown that RXR-selective agonists (e.g., 3 and 4) are insulin sensitizers in rodent models of non-insulin-dependent diabetes mellitus (NIDDM). Unfortunately, they also produce dramatic increases in triglycerides and profound suppression of the thyroid hormone axis. Here we describe the design and synthesis of new RXR modulators that retain the insulin-sensitizing activity of RXR agonists but produce substantially reduced side effects. These molecules bind selectively and with high affinity to RXR and, unlike RXR agonists, do not activate RXR homodimers. To further evaluate the antidiabetic activity of these RXR modulators, we have designed a concise and systematic structure-activity relationship around the 2E,4E,6Z-7-aryl-3-methylocta-2,4,6-trienoic acid scaffold. Selected compounds have been evaluated using insulin-resistant rodents (db/db mice) to characterize effects on glucose homeostasis. Our studies demonstrate the effectiveness of RXR modulators in lowering plasma glucose in the db/db mouse model.
authors.affiliation: Department of Medicinal Chemistry, Ligand Pharmaceuticals, Incorporated, 10275 Science Center Drive, San Diego, California 92121, USA. pmichellys@ligand.com
authors.forename: P Y
authors.initials: PY
authors.lastname: Michellys
authors.forename: R J
authors.initials: RJ
authors.lastname: Ardecky
authors.forename: J H
authors.initials: JH
authors.lastname: Chen
authors.forename: D L
authors.initials: DL
authors.lastname: Crombie
authors.forename: G J
authors.initials: GJ
authors.lastname: Etgen
authors.forename: M M
authors.initials: MM
authors.lastname: Faul
authors.forename: A L
authors.initials: AL
authors.lastname: Faulkner
authors.forename: T A
authors.initials: TA
authors.lastname: Grese
authors.forename: R A
authors.initials: RA
authors.lastname: Heyman
authors.forename: D S
authors.initials: DS
authors.lastname: Karanewsky
authors.forename: K
authors.initials: K
authors.lastname: Klausing
authors.forename: M D
authors.initials: MD
authors.lastname: Leibowitz
authors.forename: S
authors.initials: S
authors.lastname: Liu
authors.forename: D A
authors.initials: DA
authors.lastname: Mais
authors.forename: C M
authors.initials: CM
authors.lastname: Mapes
authors.forename: K B
authors.initials: KB
authors.lastname: Marschke
authors.forename: A
authors.initials: A
authors.lastname: Reifel-Miller
authors.forename: K M
authors.initials: KM
authors.lastname: Ogilvie
authors.forename: D
authors.initials: D
authors.lastname: Rungta
authors.forename: A W
authors.initials: AW
authors.lastname: Thompson
authors.forename: J S
authors.initials: JS
authors.lastname: Tyhonas
authors.forename: M F
authors.initials: MF
authors.lastname: Boehm
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D002210:Caprylates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D003924:Diabetes Mellitus, Type 2 / Q000097:blood*; D007004:Hypoglycemic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007333:Insulin Resistance; D008297:Male; D051379:Mice; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D018168:Receptors, Retinoic Acid / Q000187:drug effects* / Q000378:metabolism; D047488:Retinoid X Receptors; D013329:Structure-Activity Relationship; D014157:Transcription Factors / Q000187:drug effects* / Q000378:metabolism
chemical_list: D001786:Blood Glucose; D002210:Caprylates; D007004:Hypoglycemic Agents; D018168:Receptors, Retinoic Acid; D047488:Retinoid X Receptors; D014157:Transcription Factors