Discovery of a novel series of 6-azauracil-based thyroid hormone receptor ligands: potent, TR beta subtype-selective thyromimetics.
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.
Dow
Robert L
RL
Cardiovascular and Metabolic Diseases, Pfizer Global Research and Development, Groton, CT 06340, USA. robert_l_dow@groton.pfizer.com
Schneider
Steven R
SR
Paight
Ernest S
ES
Hank
Richard F
RF
Chiang
Phoebe
P
Cornelius
Peter
P
Lee
Eunsun
E
Newsome
William P
WP
Swick
Andrew G
AG
Spitzer
Josephine
J
Hargrove
Diane M
DM
Patterson
Terrell A
TA
Pandit
Jayvardhan
J
Chrunyk
Boris A
BA
LeMotte
Peter K
PK
Danley
Dennis E
DE
Rosner
Michele H
MH
Ammirati
Mark J
MJ
Simons
Samuel P
SP
Schulte
Gayle K
GK
Tate
Bonnie F
BF
DaSilva-Jardine
Paul
P
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
D007202:Indicators and Reagents; D008024:Ligands; D011988:Receptors, Thyroid Hormone; D013963:Thyroid Hormones; D014498:Uracil; C100248:azauracil