Thyroid receptor ligands. Part 4: 4'-amido bioisosteric ligands selective for the thyroid hormone receptor beta.
Based on the examination of the X-ray crystallographic structures of the LBD of TRalpha and TRbeta in complex with KB-141 (2), a number of novel 4'-hydroxy bioisosteric thyromimetics were prepared. Optimal affinity and beta-selectivity (33 times), was found with a medium-sized alkyl-substituted amido group; iso-butyl (12c). It can be concluded that bioisosteric replacements of the 4'-hydroxy position represent a new promising class of TRbeta-selective synthetic thyromimetics.
Li
Yi-Lin
YL
Karo Bio AB, Novum, Huddinge S-141 57, Sweden.
Litten
Chris
C
Koehler
Konrad F
KF
Mellström
Karin
K
Garg
Neeraj
N
Garcia Collazo
Ana Maria
AM
Färnegård
Mathias
M
Grynfarb
Marlena
M
Husman
Bolette
B
Sandberg
Johnny
J
Malm
Johan
J
D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D015195:Drug Design; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D010647:Phenyl Ethers / Q000737:chemistry; D010648:Phenylacetates / Q000737:chemistry; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship; D037021:Thyroid Hormone Receptors alpha / Q000187:drug effects; D037042:Thyroid Hormone Receptors beta / Q000187:drug effects*; D013963:Thyroid Hormones / Q000737:chemistry; D014284:Triiodothyronine / Q000737:chemistry
D000577:Amides; C478108:KB 141; D008024:Ligands; D010647:Phenyl Ethers; D010648:Phenylacetates; D037021:Thyroid Hormone Receptors alpha; D037042:Thyroid Hormone Receptors beta; D013963:Thyroid Hormones; D014284:Triiodothyronine