Discovery of substituted benzamides as follicle stimulating hormone receptor allosteric modulators

Discovery of substituted benzamides as follicle stimulating hormone receptor allosteric modulators

Follicle-stimulating hormone (FSH), acting on its receptor (FSHR), plays a pivotal role in the stimulation of follicular development and maturation. Multiple injections of protein formulations are used during clinical protocols for ovulation induction and for in vitro fertilization that are followed...

Full description

Saved in:
Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters Vol. 24; no. 9; pp. 2168 - 2172
Main Authors: Yu, Henry N., Richardson, Thomas E., Nataraja, Selva, Fischer, David J., Sriraman, Venkataraman, Jiang, Xuliang, Bharathi, Pandi, Foglesong, Robert J., Haxell, Thomas F.N., Heasley, Brian H., Jenks, Mathew, Li, Jane, Dugas, Melanie S., Collis, Regina, Tian, Hui, Palmer, Stephen, Goutopoulos, Andreas
Format: Journal Article
Language:English
Published: England Elsevier Ltd 01-05-2014
Subjects:
Agonist
Allosteric Regulation - drug effects
Animals
Antagonist
Benzamides - chemistry
Benzamides - pharmacology
Cells, Cultured
CHO Cells
Cricetulus
Female
Follicle Stimulating Hormone - agonists
Follicle Stimulating Hormone - metabolism
Glycoprotein hormone
Gonadotropin
GPCR
Granulosa Cells - drug effects
Granulosa Cells - metabolism
Humans
Infertility
Ovary
PAM
Rats
Reproductive
Ovary
Agonist
Reproductive
Infertility
GPCR
Antagonist
Gonadotropin
Glycoprotein hormone
PAM
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Follicle-stimulating hormone (FSH), acting on its receptor (FSHR), plays a pivotal role in the stimulation of follicular development and maturation. Multiple injections of protein formulations are used during clinical protocols for ovulation induction and for in vitro fertilization that are followed by a selection of assisted reproductive technologies. In order to increase patient convenience and compliance several research groups have searched for orally bioavailable FSH mimetics for innovative fertility medicines. We report here the discovery of a series of substituted benzamides as positive allosteric modulators (PAM) targeting FSHR. Optimization of this series has led to enhanced activity in primary rat granulosa cells, as well as remarkable selectivity against the closely related luteinizing hormone receptor (LHR) and thyroid stimulating hormone receptor (TSHR). Two modulators, 9j and 9k, showed promising in vitro and pharmacokinetic profiles.
Bibliography:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
ObjectType-Article-2
ObjectType-Feature-1
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2014.03.018