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.
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.
Discovery Chemistry Research and Technology, Lilly Research Laboratories, A Division of Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA.
Timothy P
TP
Burkholder
Discovery Chemistry Research and Technology, Lilly Research Laboratories, A Division of Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA.
Brian E
BE
Cunningham
Discovery Chemistry Research and Technology, Lilly Research Laboratories, A Division of Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA.
Joshua R
JR
Clayton
Discovery Chemistry Research and Technology, Lilly Research Laboratories, A Division of Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA.
Peter A
PA
Lander
Discovery Chemistry Research and Technology, Lilly Research Laboratories, A Division of Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA.
Matthew L
ML
Brown
Discovery Chemistry Research and Technology, Lilly Research Laboratories, A Division of Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA.
Robert A
RA
Doti
Discovery Chemistry Research and Technology, Lilly Research Laboratories, A Division of Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA.
Gregory L
GL
Durst
Lead Optimization Biology, Lilly Research Laboratories, A Division of Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA.
Chahrzad
C
Montrose-Rafizadeh
Lead Optimization Biology, Lilly Research Laboratories, A Division of Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA.
Constance
C
King
Lead Optimization Biology, Lilly Research Laboratories, A Division of Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA.
Harold E
HE
Osborne
Lead Optimization Biology, Lilly Research Laboratories, A Division of Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA.
Robert M
RM
Amos
Lead Optimization Biology, Lilly Research Laboratories, A Division of Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA.
Richard W
RW
Zink
Lead Optimization Biology, Lilly Research Laboratories, A Division of Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA.
Lawrence E
LE
Stramm
Bone and Inflammation Therapeutic Area, Lilly Research Laboratories, A Division of Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA.
Thomas P
TP
Burris
Bone and Inflammation Therapeutic Area, Lilly Research Laboratories, A Division of Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA.
Guemalli
G
Cardona
Diabetes Therapeutic Area, Lilly Research Laboratories, A Division of Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA.
Debra L
DL
Konkol
Diabetes Therapeutic Area, Lilly Research Laboratories, A Division of Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA.
Charles
C
Reidy
Diabetes Therapeutic Area, Lilly Research Laboratories, A Division of Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA.
Michael E
ME
Christe
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.
Michael J
MJ
Genin
D000085:Acetates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D037042:Thyroid Hormone Receptors beta / Q000819:agonists*
C000603596:(1-(4-hydroxy-3-isopropyl-benzyl)-3-methyl-1H-indol-5-yloxy)acetic acid; D000085:Acetates; D007211:Indoles; D037042:Thyroid Hormone Receptors beta
Agonist; Indole; TR-β; Thyroid hormone