title: Thyroid receptor ligands. Part 2: Thyromimetics with improved selectivity for the thyroid hormone receptor beta.
abstract: A set of thyromimetics having improved selectivity for TR-beta1 were prepared by replacing the 3'-isopropyl group of 2 and 3 with substituents having increased steric bulk. From this limited SAR study, the most potent and selective compounds identified were derived from 2 and contained a 3'-phenyl moiety bearing small hydrophobic groups meta to the biphenyl link. X-ray crystal data of 15c complexed with TR-beta1 LBD shows methionine 442 to be displaced by the bulky R3' phenyl ethyl amide side chain. Movement of this amino acid side chain provides an expanded pocket for the bulky side chain while the ligand-receptor complex retains full agonist activity.
authors.affiliation: Pharmaceutical Research Institute, Bristol-Myers Squibb, Princeton, NJ 08543, USA. jon.hangeland@bms.com
authors.forename: Jon J
authors.initials: JJ
authors.lastname: Hangeland
authors.forename: Arthur M
authors.initials: AM
authors.lastname: Doweyko
authors.forename: Tamara
authors.initials: T
authors.lastname: Dejneka
authors.forename: Todd J
authors.initials: TJ
authors.lastname: Friends
authors.forename: Pratik
authors.initials: P
authors.lastname: Devasthale
authors.forename: Karin
authors.initials: K
authors.lastname: Mellström
authors.forename: Johnny
authors.initials: J
authors.lastname: Sandberg
authors.forename: Marlena
authors.initials: M
authors.lastname: Grynfarb
authors.forename: John S
authors.initials: JS
authors.lastname: Sack
authors.forename: Howard
authors.initials: H
authors.lastname: Einspahr
authors.forename: Mathias
authors.initials: M
authors.lastname: Färnegårdh
authors.forename: Bolette
authors.initials: B
authors.lastname: Husman
authors.forename: Jan
authors.initials: J
authors.lastname: Ljunggren
authors.forename: Konrad
authors.initials: K
authors.lastname: Koehler
authors.forename: Cheryl
authors.initials: C
authors.lastname: Sheppard
authors.forename: Johan
authors.initials: J
authors.lastname: Malm
authors.forename: Denis E
authors.initials: DE
authors.lastname: Ryono
mesh_terms: D019840:2-Propanol / Q000737:chemistry; D000596:Amino Acids / Q000737:chemistry; D001665:Binding Sites; D002460:Cell Line; D018360:Crystallography, X-Ray; D015195:Drug Design; D020128:Inhibitory Concentration 50; D008024:Ligands; D013329:Structure-Activity Relationship; D037042:Thyroid Hormone Receptors beta / Q000187:drug effects / Q000378:metabolism*; D013963:Thyroid Hormones / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D014284:Triiodothyronine / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology
chemical_list: D000596:Amino Acids; D008024:Ligands; D037042:Thyroid Hormone Receptors beta; D013963:Thyroid Hormones; D014284:Triiodothyronine; D019840:2-Propanol