Discovery of substituted benzamides as follicle stimulating hormone receptor allosteric modulators

• 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: OXFORD Elsevier Ltd 01.05.2014; Elsevier
• Subjects: Agonist; Allosteric Regulation - drug effects; Animals; Antagonist; Benzamides - chemistry; Benzamides - pharmacology; Cells, Cultured; Chemistry; Chemistry, Medicinal; Chemistry, Organic; 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; Life Sciences & Biomedicine; Ovary; PAM; Pharmacology & Pharmacy; Physical Sciences; Rats; Reproductive; Science & Technology; Ovary; Agonist; Reproductive; Infertility; GPCR; Antagonist; Gonadotropin; Glycoprotein hormone; PAM; FSH RECEPTOR; ACTIVATION; COMPLEX; AGONISTS; LUTEINIZING-HORMONE; REGION; ROLES; gonist; PAM A
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2014.03.018

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.