title: Discovery of novel indane derivatives as liver-selective thyroid hormone receptor β (TRβ) agonists for the treatment of dyslipidemia.
abstract: Thyromimetics that specifically target TRβ have been shown to reduce plasma cholesterol levels and avoid atherosclerosis through the promotion of reverse cholesterol transport in an animal model. We designed novel thyromimetics with high receptor (TRβ) and organ (liver) selectivity based on the structure of eprotirome (3) and molecular modeling. We found that indane derivatives are potent and dual-selective thyromimetics expected to avoid hypothyroidism in some tissues as well as heart toxicity. KTA-439 (29), a representative indane derivative, showed the same high human TRβ selectivity in a binding assay as 3 and higher liver selectivity than 3 in a cholesterol-fed rat model.
authors.affiliation: Central Research Laboratory, Kissei Pharmaceutical Co., Ltd, 4365-1, Kashiwabara, Hotaka, Azumino-City, Nagano 399-8304, Japan. hiroaki_shiohara@pharm.kissei.co.jp
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Shiohara
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Nakamura
authors.forename: Norihiko
authors.initials: N
authors.lastname: Kikuchi
authors.forename: Tomonaga
authors.initials: T
authors.lastname: Ozawa
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Nagano
authors.forename: Akane
authors.initials: A
authors.lastname: Matsuzawa
authors.forename: Hideki
authors.initials: H
authors.lastname: Ohnota
authors.forename: Takahide
authors.initials: T
authors.lastname: Miyamoto
authors.forename: Kazuo
authors.initials: K
authors.lastname: Ichikawa
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Hashizume
mesh_terms: D000818:Animals; D001120:Arginine / Q000737:chemistry; D002784:Cholesterol / Q000008:administration & dosage / Q000378:metabolism; D004195:Disease Models, Animal; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D050171:Dyslipidemias / Q000188:drug therapy / Q000378:metabolism*; D006801:Humans; D007189:Indans / Q000737:chemistry*; D008024:Ligands; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008314:Malonates / Q000138:chemical synthesis / Q000737:chemistry; D008958:Models, Molecular; D018716:Molecular Mimicry; D015394:Molecular Structure; D051381:Rats; D017208:Rats, Wistar; D054852:Small Molecule Libraries; D013329:Structure-Activity Relationship; D037042:Thyroid Hormone Receptors beta / Q000819:agonists* / Q000378:metabolism
chemical_list: D007189:Indans; D008024:Ligands; D008314:Malonates; D054852:Small Molecule Libraries; D037042:Thyroid Hormone Receptors beta; C013098:malonamic acid; D001120:Arginine; D002784:Cholesterol