Design and synthesis of a novel series of [1-(4-hydroxy-benzyl)-1H-indol-5-yloxy]-acetic acid compounds as potent, selective, thyroid hormone receptor β agonists

Timothy P Burkholder; Brian E Cunningham; Joshua R Clayton; Peter A Lander; Matthew L Brown; Robert A Doti; Gregory L Durst; Chahrzad Montrose-Rafizadeh; Constance King; Harold E Osborne; Robert M Amos; Richard W Zink; Lawrence E Stramm; Thomas P Burris; Guemalli Cardona; Debra L Konkol; Charles Reidy; Michael E Christe; Michael J Genin

doi:10.1016/j.bmcl.2015.02.062

Design and synthesis of a novel series of [1-(4-hydroxy-benzyl)-1H-indol-5-yloxy]-acetic acid compounds as potent, selective, thyroid hormone receptor β agonists

Bioorg Med Chem Lett. 2015 Apr 1;25(7):1377-80. doi: 10.1016/j.bmcl.2015.02.062. Epub 2015 Mar 3.

Authors

Timothy P Burkholder¹, Brian E Cunningham¹, Joshua R Clayton¹, Peter A Lander¹, Matthew L Brown¹, Robert A Doti¹, Gregory L Durst¹, Chahrzad Montrose-Rafizadeh², Constance King², Harold E Osborne², Robert M Amos², Richard W Zink², Lawrence E Stramm², Thomas P Burris³, Guemalli Cardona³, Debra L Konkol⁴, Charles Reidy⁴, Michael E Christe⁴, Michael J Genin⁵

Affiliations

¹ Discovery Chemistry Research and Technology, Lilly Research Laboratories, A Division of Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA.
² Lead Optimization Biology, Lilly Research Laboratories, A Division of Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA.
³ Bone and Inflammation Therapeutic Area, Lilly Research Laboratories, A Division of Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA.
⁴ Diabetes Therapeutic Area, Lilly Research Laboratories, A Division of Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA.
⁵ Discovery Chemistry Research and Technology, Lilly Research Laboratories, A Division of Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA. Electronic address: geninmi@lilly.com.

PMID: 25752984
DOI: 10.1016/j.bmcl.2015.02.062

Abstract

The design, synthesis, and structure activity relationships for a novel series of indoles as potent, selective, thyroid hormone receptor β (TRβ) agonists is described. Compounds with >50× binding selectivity for TRβ over TRα were generated and evaluation of compound 1c from this series in a model of dyslipidemia demonstrated positive effects on plasma lipid endpoints in vivo.

Keywords: Agonist; Indole; TR-β; Thyroid hormone.

MeSH terms

Acetates / chemical synthesis
Acetates / chemistry
Acetates / pharmacology*
Dose-Response Relationship, Drug
Drug Design*
Humans
Indoles / chemical synthesis
Indoles / chemistry
Indoles / pharmacology*
Models, Molecular
Molecular Structure
Structure-Activity Relationship
Thyroid Hormone Receptors beta / agonists*

Substances

(1-(4-hydroxy-3-isopropyl-benzyl)-3-methyl-1H-indol-5-yloxy)acetic acid
Acetates
Indoles
Thyroid Hormone Receptors beta