Thyroid receptor ligands. Part 4: 4'-amido bioisosteric ligands selective for the thyroid hormone receptor beta

Yi-Lin Li; Chris Litten; Konrad F Koehler; Karin Mellström; Neeraj Garg; Ana Maria Garcia Collazo; Mathias Färnegård; Marlena Grynfarb; Bolette Husman; Johnny Sandberg; Johan Malm

doi:10.1016/j.bmcl.2005.11.002

Thyroid receptor ligands. Part 4: 4'-amido bioisosteric ligands selective for the thyroid hormone receptor beta

Bioorg Med Chem Lett. 2006 Feb 15;16(4):884-6. doi: 10.1016/j.bmcl.2005.11.002. Epub 2005 Nov 21.

Authors

Yi-Lin Li¹, Chris Litten, Konrad F Koehler, Karin Mellström, Neeraj Garg, Ana Maria Garcia Collazo, Mathias Färnegård, Marlena Grynfarb, Bolette Husman, Johnny Sandberg, Johan Malm

Affiliation

¹ Karo Bio AB, Novum, Huddinge S-141 57, Sweden.

PMID: 16303304
DOI: 10.1016/j.bmcl.2005.11.002

Abstract

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.

Publication types

Comparative Study

MeSH terms

Amides / chemical synthesis
Amides / chemistry
Amides / pharmacology*
Crystallography, X-Ray
Drug Design
Humans
Ligands
Models, Molecular
Molecular Conformation
Molecular Structure
Phenyl Ethers / chemistry
Phenylacetates / chemistry
Protein Conformation
Protein Structure, Tertiary
Structure-Activity Relationship
Thyroid Hormone Receptors alpha / drug effects
Thyroid Hormone Receptors beta / drug effects*
Thyroid Hormones / chemistry
Triiodothyronine / chemistry

Substances

Amides
KB 141
Ligands
Phenyl Ethers
Phenylacetates
Thyroid Hormone Receptors alpha
Thyroid Hormone Receptors beta
Thyroid Hormones
Triiodothyronine