title: Investigation of a thiazolidinone derivative as an allosteric modulator of follicle stimulating hormone receptor: evidence for its ability to support follicular development and ovulation.
abstract: FSH signalling through its cognate receptor is critical for follicular development and ovulation. An earlier study had documented thiazolidinone derivatives to activate FSH receptor expressed in CHO cells and rat granulosa cells; however development of this compound for clinical use was halted for unobvious reasons. The objective of the current study is to extend the previous investigations in detail on the ability of thiazolidinone derivative (henceforth referred to as Compound 5) to activate FSH signalling and learn the barriers that preclude development of this derivative for clinical purposes. Our results demonstrate that the Compound 5 in a dose-dependent manner stimulated cAMP production, activated AKT and ERK signalling pathways and induced estradiol production in cultured rat granulosa cells. Compound 5 also caused dose-dependent increase in estradiol production from human granulosa cells. In increasingly more complex in vitro systems, Compound 5 was able to induce the expansion of mouse cumulus-oocyte-complex and support in vitro development of mouse preantral follicle to preovulatory stage and release of oocyte from the follicle. In vivo, the compound stimulated preovulatory follicular development and ovulation in immature rats. Pharmacokinetic and safety investigations reveal poor oral availability and genotoxicity. Together, our results document Compound 5 to act as a FSHR allosteric modulator but have poor pharmacological properties for development of an oral FSH receptor modulator.
authors.affiliation: EMD Serono Research and Development Institute, Billerica, MA 01821, United States. Electronic address: venkat.sriraman@emdserono.com.
authors.forename: Venkataraman
authors.initials: V
authors.lastname: Sriraman
authors.affiliation: EMD Serono Research and Development Institute, Billerica, MA 01821, United States.
authors.forename: Deborah
authors.initials: D
authors.lastname: Denis
authors.affiliation: EMD Serono Research and Development Institute, Billerica, MA 01821, United States.
authors.forename: Daniel
authors.initials: D
authors.lastname: de Matos
authors.affiliation: EMD Serono Research and Development Institute, Billerica, MA 01821, United States; TocopheRx, Suite 1077, 15 New England Executive Park, Burlington, MA 01803, United States.
authors.forename: Henry
authors.initials: H
authors.lastname: Yu
authors.affiliation: TocopheRx, Suite 1077, 15 New England Executive Park, Burlington, MA 01803, United States.
authors.forename: Stephen
authors.initials: S
authors.lastname: Palmer
authors.affiliation: TocopheRx, Suite 1077, 15 New England Executive Park, Burlington, MA 01803, United States.
authors.forename: Selva
authors.initials: S
authors.lastname: Nataraja
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects / Q000502:physiology; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004958:Estradiol / Q000378:metabolism; D005260:Female; D006107:Granulosa Cells / Q000187:drug effects* / Q000378:metabolism*; D006801:Humans; D051379:Mice; D006080:Ovarian Follicle / Q000187:drug effects / Q000254:growth & development* / Q000378:metabolism; D010060:Ovulation / Q000187:drug effects* / Q000378:metabolism*; D051381:Rats; D011962:Receptors, FSH / Q000502:physiology*; D053778:Thiazolidines / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D011962:Receptors, FSH; D053778:Thiazolidines; D004958:Estradiol
keywords: FSH receptor; FSH signalling; FSHR agonist; Follicular development; Glycoprotein hormone receptors; Ovulation