title: In vivo evaluation of 1-benzyl-4-aminoindole-based thyroid hormone receptor β agonists: importance of liver selectivity in drug discovery.
abstract: We recently reported that the novel thyroid hormone receptor β (TRβ) selective agonists SKL-12846 and SKL-13784 reduce blood cholesterol levels without affecting thyroid-stimulating hormone (TSH) in cholesterol-fed rats. Our aim in this study was to elucidate what sets apart these SKL-compounds as TRβ agonists with no effect on TSH. To this end, we determined SKL-compounds pharmacokinetics and tissue distribution in normal rats and compared them to those of GC-1, a liver-selective TRβ agonist with concomitant effect on TSH. The present study explains why SKL-12846 and SKL-13784 have beneficial effects on lowering lipids without affecting heart rate and TSH production at the therapeutic dose in cholesterol-fed rats. In addition, we found that SKL-13784 shows no sign of escape phenomenon in fructose-fed rats. These results demonstrate the advantages of extremely high liver specificity to TRβ agonists. However, SKL-13784 has been found significantly to reduce endogenous T4 levels at doses lower than its lipid-lowering dose, which may raise concerns over this compound's ability to alter thyroid hormone metabolism in the liver. While the mechanism by which SKL-13784 reduces endogenous T4 levels is still unclear, our results would help design better liver-selective TRβ modulators.
authors.affiliation: Drug Discovery Laboratories, Sanwa Kagaku Kenkyusho, Co., Ltd.
authors.forename: Naoki
authors.initials: N
authors.lastname: Takahashi
authors.forename: Yukiyasu
authors.initials: Y
authors.lastname: Asano
authors.forename: Koji
authors.initials: K
authors.lastname: Maeda
authors.forename: Nobuhide
authors.initials: N
authors.lastname: Watanabe
mesh_terms: D000085:Acetates / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D000284:Administration, Oral; D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery / Q000379:methods*; D006339:Heart Rate / Q000187:drug effects; D015228:Hypertriglyceridemia / Q000097:blood / Q000188:drug therapy; D007211:Indoles / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D007275:Injections, Intravenous; D008055:Lipids / Q000097:blood; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008314:Malonates / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D015394:Molecular Structure; D010636:Phenols / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D037042:Thyroid Hormone Receptors beta / Q000819:agonists*; D013974:Thyroxine / Q000097:blood; D014018:Tissue Distribution; D014284:Triiodothyronine / Q000097:blood
chemical_list: D000085:Acetates; D001786:Blood Glucose; C413355:GC 1 compound; D007211:Indoles; D008055:Lipids; D008314:Malonates; D010636:Phenols; C000595301:SKL-12846; C000595302:SKL-13784; D037042:Thyroid Hormone Receptors beta; D014284:Triiodothyronine; D013974:Thyroxine