Thyroid receptor ligands. Part 2: Thyromimetics with improved selectivity for the thyroid hormone receptor beta.
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.
Hangeland
Jon J
JJ
Pharmaceutical Research Institute, Bristol-Myers Squibb, Princeton, NJ 08543, USA. jon.hangeland@bms.com
Doweyko
Arthur M
AM
Dejneka
Tamara
T
Friends
Todd J
TJ
Devasthale
Pratik
P
Mellström
Karin
K
Sandberg
Johnny
J
Grynfarb
Marlena
M
Sack
John S
JS
Einspahr
Howard
H
Färnegårdh
Mathias
M
Husman
Bolette
B
Ljunggren
Jan
J
Koehler
Konrad
K
Sheppard
Cheryl
C
Malm
Johan
J
Ryono
Denis E
DE
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
D000596:Amino Acids; D008024:Ligands; D037042:Thyroid Hormone Receptors beta; D013963:Thyroid Hormones; D014284:Triiodothyronine; D019840:2-Propanol