agn-194204 and Hypertriglyceridemia

agn-194204 has been researched along with Hypertriglyceridemia* in 1 studies

Other Studies

1 other study(ies) available for agn-194204 and Hypertriglyceridemia

ArticleYear
Retinoid X receptor agonist elevation of serum triglycerides in rats by potentiation of retinoic acid receptor agonist induction or by action as single agents.
    Biochemical pharmacology, 2001, Dec-01, Volume: 62, Issue:11

    Hypertriglyceridemia is a major side-effect of retinoid therapy in humans. We previously reported that agonists for the retinoic acid receptors (RARs), but not the retinoid X receptors (RXRs), elevate serum triglycerides in male Fischer rats, and that, surprisingly, the RAR/RXR pan-agonists 9-cis-retinoic acid and AGN 191659 [(E)-5-[2-(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthyl)propen-1-yl]-2-thiophenecarboxylic acid] induce 2- to 3-fold higher levels of serum triglycerides than the RAR-selective agonists alone. We have now demonstrated that hypertriglyceridemia induced by an RAR agonist, AGN 190121 [4-[4-(2',6',6'-trimethylcyclohex-1-enyl)-but-1-yne-3-enyl]benzoic acid], is substantially potentiated by the RXR-selective agonists AGN 191701 [(E) 2-[2-(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthyl)propen-1-yl]-4-thiophene-carboxylic acid] and AGN 192849 [(3,5,5,8,8,-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl) (5 carboxypyrid-2-yl)sulfide] in a dose-dependent manner. RXR-specific retinoids, as previously reported, had no independent effect on serum triglycerides when tested at 24 hr after final dosing, but did elicit a reversible hypertriglyceridemia at 2.5 and 5 hr. This induction of serum triglycerides could not be blocked by the potent RAR-specific antagonist AGN 193109 [4-[(5,6-dihydro-5,5-dimethyl-8-(4-methylphenyl)-2-naphthalenyl)-ethynyl] benzoic acid]. The RXR ligand-induced hypertriglyceridemia was independent of the effect of feeding or fasting. The relative potencies of RXR-specific retinoids for acute triglyceride elevation (AGN 194204 [3,7-dimethyl-6S,7S-methano-7-[1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphth-7-yl] 2(E),4(E) heptadienoic acid] > AGN 192849 approximately AGN 191701) approximately correlated with potencies in the activation of the RXR receptors. The RAR/RXR pan-agonist effect included >50% inhibition of total heparin-releasable lipase activity in serum, consistent with inhibition of lipase-mediated triglyceride disposal. These data also indicate that RAR and RXR ligands can act synergistically to induce hypertriglyceridemia through distinct mechanisms of action.

    Topics: Animals; Benzoates; Carboxylic Acids; Dose-Response Relationship, Drug; Drug Synergism; Fasting; Fatty Acids, Unsaturated; Heparin; Hypertriglyceridemia; Hypoglycemic Agents; Male; Naphthalenes; Rats; Rats, Inbred F344; Receptors, Retinoic Acid; Retinoid X Receptors; Tetrahydronaphthalenes; Thiophenes; Transcription Factors; Triglycerides

2001