title: The thyroid hormone mimetic compound KB2115 lowers plasma LDL cholesterol and stimulates bile acid synthesis without cardiac effects in humans.
abstract: Atherosclerotic cardiovascular disease is a major problem despite the availability of drugs that influence major risk factors. New treatments are needed, and there is growing interest in therapies that may have multiple actions. Thyroid hormone modulates several cardiovascular risk factors and delays atherosclerosis progression in humans. However, use of thyroid hormone is limited by side effects, especially in the heart. To overcome this limitation, pharmacologically selective thyromimetics that mimic metabolic effects of thyroid hormone and bypass side effects are under development. In animal models, such thyromimetics have been shown to stimulate cholesterol elimination through LDL and HDL pathways and decrease body weight without eliciting side effects. We report here studies on a selective thyromimetic [KB2115; (3-[[3,5-dibromo-4-[4-hydroxy-3-(1-methylethyl)-phenoxy]-phenyl]-amino]-3-oxopropanoic acid)] in humans. In moderately overweight and hypercholesterolemic subjects KB2115 was found to be safe and well tolerated and elicited up to a 40% lowering of total and LDL cholesterol after 14 days of treatment. Bile acid synthesis was stimulated without evidence of increased cholesterol production, indicating that KB2115 induced net cholesterol excretion. KB2115 did not provoke detectable effects on the heart, suggesting that the pharmacological selectivity observed in animal models translates to humans. Thus, selective thyromimetics deserve further study as agents to treat dyslipidemia and other risk factors for atherosclerosis.
authors.affiliation: Karo Bio AB, Novum Research Park, S-141 57 Huddinge, Sweden.
authors.forename: Anders
authors.initials: A
authors.lastname: Berkenstam
authors.forename: Jens
authors.initials: J
authors.lastname: Kristensen
authors.forename: Karin
authors.initials: K
authors.lastname: Mellström
authors.forename: Bo
authors.initials: B
authors.lastname: Carlsson
authors.forename: Johan
authors.initials: J
authors.lastname: Malm
authors.forename: Stefan
authors.initials: S
authors.lastname: Rehnmark
authors.forename: Neeraj
authors.initials: N
authors.lastname: Garg
authors.forename: Carl Magnus
authors.initials: CM
authors.lastname: Andersson
authors.forename: Mats
authors.initials: M
authors.lastname: Rudling
authors.forename: Folke
authors.initials: F
authors.lastname: Sjöberg
authors.forename: Bo
authors.initials: B
authors.lastname: Angelin
authors.forename: John D
authors.initials: JD
authors.lastname: Baxter
mesh_terms: D000293:Adolescent; D000328:Adult; D000813:Anilides / Q000737:chemistry / Q000494:pharmacology*; D001647:Bile Acids and Salts / Q000378:metabolism*; D008078:Cholesterol, LDL / Q000378:metabolism*; D004311:Double-Blind Method; D005260:Female; D006321:Heart / Q000187:drug effects*; D006801:Humans; D050356:Lipid Metabolism; D008297:Male; D008875:Middle Aged; D010919:Placebos; D012307:Risk Factors; D045162:Thiazolidinediones / Q000494:pharmacology; D013961:Thyroid Gland / Q000187:drug effects*; D013963:Thyroid Hormones / Q000378:metabolism*
chemical_list: C526273:3-((3,5-dibromo-4-(4-hydroxy-3-(1-methylethyl)phenoxy)phenyl)amino)-3-oxopropanoic acid; D000813:Anilides; D001647:Bile Acids and Salts; D008078:Cholesterol, LDL; D010919:Placebos; D045162:Thiazolidinediones; D013963:Thyroid Hormones