title: Discovery of a novel series of 6-azauracil-based thyroid hormone receptor ligands: potent, TR beta subtype-selective thyromimetics.
abstract: In this communication, we wish to describe the discovery of a novel series of 6-azauracil-based thyromimetics that possess up to 100-fold selectivities for binding and functional activation of the beta(1)-isoform of the thyroid receptor family. Structure-activity relationship studies on the 3,5- and 3'-positions provided compounds with enhanced TR beta affinity and selectivity. Key binding interactions between the 6-azauracil moiety and the receptor have been determined through of X-ray crystallographic analysis.
authors.affiliation: Cardiovascular and Metabolic Diseases, Pfizer Global Research and Development, Groton, CT 06340, USA. robert_l_dow@groton.pfizer.com
authors.forename: Robert L
authors.initials: RL
authors.lastname: Dow
authors.forename: Steven R
authors.initials: SR
authors.lastname: Schneider
authors.forename: Ernest S
authors.initials: ES
authors.lastname: Paight
authors.forename: Richard F
authors.initials: RF
authors.lastname: Hank
authors.forename: Phoebe
authors.initials: P
authors.lastname: Chiang
authors.forename: Peter
authors.initials: P
authors.lastname: Cornelius
authors.forename: Eunsun
authors.initials: E
authors.lastname: Lee
authors.forename: William P
authors.initials: WP
authors.lastname: Newsome
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Swick
authors.forename: Josephine
authors.initials: J
authors.lastname: Spitzer
authors.forename: Diane M
authors.initials: DM
authors.lastname: Hargrove
authors.forename: Terrell A
authors.initials: TA
authors.lastname: Patterson
authors.forename: Jayvardhan
authors.initials: J
authors.lastname: Pandit
authors.forename: Boris A
authors.initials: BA
authors.lastname: Chrunyk
authors.forename: Peter K
authors.initials: PK
authors.lastname: LeMotte
authors.forename: Dennis E
authors.initials: DE
authors.lastname: Danley
authors.forename: Michele H
authors.initials: MH
authors.lastname: Rosner
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Ammirati
authors.forename: Samuel P
authors.initials: SP
authors.lastname: Simons
authors.forename: Gayle K
authors.initials: GK
authors.lastname: Schulte
authors.forename: Bonnie F
authors.initials: BF
authors.lastname: Tate
authors.forename: Paul
authors.initials: P
authors.lastname: DaSilva-Jardine
mesh_terms: D018360:Crystallography, X-Ray; D015195:Drug Design; D006801:Humans; D007202:Indicators and Reagents; D008024:Ligands; D008958:Models, Molecular; D018716:Molecular Mimicry; D011485:Protein Binding; D011487:Protein Conformation; D011988:Receptors, Thyroid Hormone / Q000187:drug effects*; D013329:Structure-Activity Relationship; D013963:Thyroid Hormones / Q000494:pharmacology*; D014498:Uracil / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D007202:Indicators and Reagents; D008024:Ligands; D011988:Receptors, Thyroid Hormone; D013963:Thyroid Hormones; D014498:Uracil; C100248:azauracil