Benzopyrans as selective estrogen receptor beta agonists (SERBAs). Part 4: functionalization of the benzopyran A-ring.
Benzopyrans are selective estrogen receptor (ER) beta agonists (SERBAs), which bind the ER receptor subtypes alpha and beta in opposite orientations. We have used structure based drug design to show that this unique phenomena can be exploited via substitution at the 8-position of the benzopyran A-ring to disrupt binding to ERalpha, thus improving ERbeta subtype selectivity. X-ray cocrystal structures with ERalpha and ERbeta are supportive of this approach to improve selectivity in this structural class.
Norman
Bryan H
BH
Discovery Chemistry Research, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA. norman@lilly.com
Richardson
Timothy I
TI
Dodge
Jeffrey A
JA
Pfeifer
Lance A
LA
Durst
Gregory L
GL
Wang
Yong
Y
Durbin
Jim D
JD
Krishnan
Venkatesh
V
Dinn
Sean R
SR
Liu
Shengquan
S
Reilly
John E
JE
Ryter
Kendal T
KT
D001578:Benzopyrans / Q000737:chemistry / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D047629:Estrogen Receptor beta / Q000819:agonists*; D008024:Ligands; D008958:Models, Molecular
D001578:Benzopyrans; D047629:Estrogen Receptor beta; D008024:Ligands