title: Thyroid receptor ligands. Part 8: Thyromimetics derived from N-acylated-alpha-amino acid derivatives displaying modulated pharmacological selectivity compared with KB-141.
abstract: Based on the scaffold of the pharmacologically selective thyromimetic 2b, structurally a close analog to KB-141 (2a), a number of novel N-acylated-alpha-amino acid derivatives were synthesized and tested in a TR radioligand binding assay as well as in a reporter cell assay. On the basis of TRbeta(1)-isoform selectivity and affinity, as well as affinity to the reporter cell assay, 3d was selected for further studies in the cholesterol-fed rat model. In this model 3d revealed an improved therapeutic window between cholesterol and TSH lowering but decreased margins versus tachycardia compared with 2a.
authors.affiliation: Karo Bio AB, Novum, Huddinge S-141 57, Sweden.
authors.forename: Neeraj
authors.initials: N
authors.lastname: Garg
authors.forename: Yi-Lin
authors.initials: YL
authors.lastname: Li
authors.forename: Ana Maria
authors.initials: AM
authors.lastname: Garcia Collazo
authors.forename: Chris
authors.initials: C
authors.lastname: Litten
authors.forename: Denis E
authors.initials: DE
authors.lastname: Ryono
authors.forename: Minsheng
authors.initials: M
authors.lastname: Zhang
authors.forename: Yolanda
authors.initials: Y
authors.lastname: Caringal
authors.forename: Robert P
authors.initials: RP
authors.lastname: Brigance
authors.forename: Wei
authors.initials: W
authors.lastname: Meng
authors.forename: William N
authors.initials: WN
authors.lastname: Washburn
authors.forename: Peter
authors.initials: P
authors.lastname: Agback
authors.forename: Karin
authors.initials: K
authors.lastname: Mellström
authors.forename: Stefan
authors.initials: S
authors.lastname: Rehnmark
authors.forename: Mahmoud
authors.initials: M
authors.lastname: Rahimi-Ghadim
authors.forename: Thomas
authors.initials: T
authors.lastname: Norin
authors.forename: Marlena
authors.initials: M
authors.lastname: Grynfarb
authors.forename: Johnny
authors.initials: J
authors.lastname: Sandberg
authors.forename: Gary
authors.initials: G
authors.lastname: Grover
authors.forename: Johan
authors.initials: J
authors.lastname: Malm
mesh_terms: D000596:Amino Acids / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D016466:CHO Cells; D002791:Cholesterol, Dietary / Q000008:administration & dosage; D006224:Cricetinae; D003412:Cricetulus; D008024:Ligands; D018716:Molecular Mimicry; D010647:Phenyl Ethers / Q000494:pharmacology*; D010648:Phenylacetates / Q000494:pharmacology*; D011869:Radioligand Assay; D051381:Rats; D011988:Receptors, Thyroid Hormone / Q000187:drug effects* / Q000378:metabolism
chemical_list: D000596:Amino Acids; D002791:Cholesterol, Dietary; C478108:KB 141; D008024:Ligands; D010647:Phenyl Ethers; D010648:Phenylacetates; D011988:Receptors, Thyroid Hormone