Thyroid receptor ligands. Part 8: Thyromimetics derived from N-acylated-alpha-amino acid derivatives displaying modulated pharmacological selectivity compared with KB-141.
Based on the scaffold of the pharmacologically selective thyromimetic 2b, structurally a close analog to KB-141 (2a), a number of novel N-acylated-alpha-amino acid derivatives were synthesized and tested in a TR radioligand binding assay as well as in a reporter cell assay. On the basis of TRbeta(1)-isoform selectivity and affinity, as well as affinity to the reporter cell assay, 3d was selected for further studies in the cholesterol-fed rat model. In this model 3d revealed an improved therapeutic window between cholesterol and TSH lowering but decreased margins versus tachycardia compared with 2a.
Garg
Neeraj
N
Karo Bio AB, Novum, Huddinge S-141 57, Sweden.
Li
Yi-Lin
YL
Garcia Collazo
Ana Maria
AM
Litten
Chris
C
Ryono
Denis E
DE
Zhang
Minsheng
M
Caringal
Yolanda
Y
Brigance
Robert P
RP
Meng
Wei
W
Washburn
William N
WN
Agback
Peter
P
Mellström
Karin
K
Rehnmark
Stefan
S
Rahimi-Ghadim
Mahmoud
M
Norin
Thomas
T
Grynfarb
Marlena
M
Sandberg
Johnny
J
Grover
Gary
G
Malm
Johan
J
D000596:Amino Acids / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D016466:CHO Cells; D002791:Cholesterol, Dietary / Q000008:administration & dosage; D006224:Cricetinae; D003412:Cricetulus; D008024:Ligands; D018716:Molecular Mimicry; D010647:Phenyl Ethers / Q000494:pharmacology*; D010648:Phenylacetates / Q000494:pharmacology*; D011869:Radioligand Assay; D051381:Rats; D011988:Receptors, Thyroid Hormone / Q000187:drug effects* / Q000378:metabolism
D000596:Amino Acids; D002791:Cholesterol, Dietary; C478108:KB 141; D008024:Ligands; D010647:Phenyl Ethers; D010648:Phenylacetates; D011988:Receptors, Thyroid Hormone