title: Discovery of substituted benzamides as follicle stimulating hormone receptor allosteric modulators.
abstract: 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.
authors.affiliation: EMD Serono Research Institute, 45A Middlesex Turnpike, Billerica, MA 01821, United States; TocopheRx, Inc., Suite 1077, 15 New England Executive Park, Burlington, MA 01803, United States. Electronic address: henry.yu@emdserono.com.
authors.forename: Henry N
authors.initials: HN
authors.lastname: Yu
authors.affiliation: Scynexis, Inc., 3501 C Tricenter Boulevard, Durham, NC 27713, United States.
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Richardson
authors.affiliation: TocopheRx, Inc., Suite 1077, 15 New England Executive Park, Burlington, MA 01803, United States.
authors.forename: Selva
authors.initials: S
authors.lastname: Nataraja
authors.affiliation: EMD Serono Research Institute, 45A Middlesex Turnpike, Billerica, MA 01821, United States.
authors.forename: David J
authors.initials: DJ
authors.lastname: Fischer
authors.affiliation: EMD Serono Research Institute, 45A Middlesex Turnpike, Billerica, MA 01821, United States.
authors.forename: Venkataraman
authors.initials: V
authors.lastname: Sriraman
authors.affiliation: EMD Serono Research Institute, 45A Middlesex Turnpike, Billerica, MA 01821, United States.
authors.forename: Xuliang
authors.initials: X
authors.lastname: Jiang
authors.affiliation: Scynexis, Inc., 3501 C Tricenter Boulevard, Durham, NC 27713, United States.
authors.forename: Pandi
authors.initials: P
authors.lastname: Bharathi
authors.affiliation: Scynexis, Inc., 3501 C Tricenter Boulevard, Durham, NC 27713, United States.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Foglesong
authors.affiliation: Scynexis, Inc., 3501 C Tricenter Boulevard, Durham, NC 27713, United States.
authors.forename: Thomas F N
authors.initials: TF
authors.lastname: Haxell
authors.affiliation: Scynexis, Inc., 3501 C Tricenter Boulevard, Durham, NC 27713, United States.
authors.forename: Brian H
authors.initials: BH
authors.lastname: Heasley
authors.affiliation: Scynexis, Inc., 3501 C Tricenter Boulevard, Durham, NC 27713, United States.
authors.forename: Mathew
authors.initials: M
authors.lastname: Jenks
authors.affiliation: EMD Serono Research Institute, 45A Middlesex Turnpike, Billerica, MA 01821, United States.
authors.forename: Jane
authors.initials: J
authors.lastname: Li
authors.affiliation: EMD Serono Research Institute, 45A Middlesex Turnpike, Billerica, MA 01821, United States.
authors.forename: Melanie S
authors.initials: MS
authors.lastname: Dugas
authors.affiliation: EMD Serono Research Institute, 45A Middlesex Turnpike, Billerica, MA 01821, United States.
authors.forename: Regina
authors.initials: R
authors.lastname: Collis
authors.affiliation: EMD Serono Research Institute, 45A Middlesex Turnpike, Billerica, MA 01821, United States.
authors.forename: Hui
authors.initials: H
authors.lastname: Tian
authors.affiliation: TocopheRx, Inc., Suite 1077, 15 New England Executive Park, Burlington, MA 01803, United States.
authors.forename: Stephen
authors.initials: S
authors.lastname: Palmer
authors.affiliation: EMD Serono Research Institute, 45A Middlesex Turnpike, Billerica, MA 01821, United States.
authors.forename: Andreas
authors.initials: A
authors.lastname: Goutopoulos
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects*; D000818:Animals; D001549:Benzamides / Q000737:chemistry* / Q000494:pharmacology*; D016466:CHO Cells; D002478:Cells, Cultured; D003412:Cricetulus; D005260:Female; D005640:Follicle Stimulating Hormone / Q000819:agonists / Q000378:metabolism*; D006107:Granulosa Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D051381:Rats
chemical_list: D001549:Benzamides; D005640:Follicle Stimulating Hormone
keywords: Agonist; Antagonist; GPCR; Glycoprotein hormone; Gonadotropin; Infertility; Ovary; PAM; Reproductive