Thyroid receptor ligands. Part 5: novel bicyclic agonist ligands selective for the thyroid hormone receptor beta.
Based on the examination of the crystal structure of rat TRbeta complexed with 3,5,3'-triiodo-l-thyronine (2) a novel TRbeta-selective indole derivative 6b was prepared and tested in vitro. This compound was found to be 14 times selective for TRbeta over TRalpha in binding and its beta-selectivity could be rationalized through the comparison of the X-ray crystallographic structures of 6b complexed with TRalpha and TRbeta.
Garcia Collazo
Ana-Maria
AM
Karo Bio AB, Novum, Huddinge SE-141 57, Sweden.
Koehler
Konrad F
KF
Garg
Neeraj
N
Färnegårdh
Mathias
M
Husman
Bolette
B
Ye
Liu
L
Ljunggren
Jan
J
Mellström
Karin
K
Sandberg
Johnny
J
Grynfarb
Marlena
M
Ahola
Harri
H
Malm
Johan
J
D000818:Animals; D018360:Crystallography, X-Ray; D003500:Cyclization; D006801:Humans; D007211:Indoles / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D008024:Ligands; D015394:Molecular Structure; D051381:Rats; D013379:Substrate Specificity; D037042:Thyroid Hormone Receptors beta / Q000819:agonists* / Q000737:chemistry / Q000378:metabolism*; D013974:Thyroxine / Q000138:chemical synthesis / Q000737:chemistry
D007211:Indoles; D008024:Ligands; D037042:Thyroid Hormone Receptors beta; D013974:Thyroxine