Search tips
Search criteria 


Logo of acsmedlettACS PublicationsThis JournalSearchSubmit a manuscript
ACS Medicinal Chemistry Letters
ACS Med Chem Lett. 2016 April 14; 7(4): 345–347.
Published online 2016 March 4. doi:  10.1021/acsmedchemlett.6b00082
PMCID: PMC4834643

Targeting the Follicle Stimulating Hormone Receptor (FSHR) To Treat Fertility Disorders

Patent Application Title:Benzamides
Patent Application Number:US 2016/0022670 A1Publication date:Jan 28, 2016
Priority Application:US 61/526,342Priority date:Aug 23, 2011
US 61/508,861Jul 18, 2011
Inventors:Yu, H.; Goutopoulos, A.; Richardson, T. E.; Li, J.; Heasley, B. H.; Bharathi, P.
Assignee Company:Merck Patent GmbH, Darmstadt (DE)
Disease Area:Fertility disordersBiological Target:Follicle stimulating hormone receptor (FSHR)
Summary:The invention in this patent application relates to 4-(1-piperazinyl)benzamides represented generally by formula (I). The compounds of formulas (I) possess activities as positive allosteric modulators of the follicle stimulating hormone receptor (FSHR) and may potentially provide useful treatment of fertility disorders.
Gonadotropins constitute a family of glycoprotein polypeptide hormones. Members of this family include the follicle-stimulating hormone (FSH), the luteinizing hormone (LH), the thyroid-stimulating hormone (TSH), and the chorionic gonadotropin (CG). FSH, LH, and TSH are secreted by the anterior pituitary gland, while CG is secreted by the placenta. Gonadotropins perform important functions related to metabolism, temperature regulation, normal growth regulation, and the reproductive process. They also act on specific gonadal cell types to initiate ovarian and testicular differentiation and steroidogenesis. These hormones are heterodimeric glycoproteins, which contain two peptide subunits, a common α-subunit and distinct β-subunits, that confer receptor binding specificity.
The follicle-stimulating hormone (FSH) is produced at the anterior pituitary under the influence of gonadotropin-releasing hormone and estrogens. It is also produced from the placenta during pregnancy. It is the major hormone that regulates secretion of estrogens and is essential for the stimulation of follicle development and maturation in females. It is also responsible for the integrity of the seminiferous tubules and acts on Sertoli cells to support gametogenesis in males. The receptor that interacts with FSH is the FSH receptor (FSHR), which is a member of the rhodopsin-like G-protein coupled receptor family. This family of receptors is characterized by three extracellular domains: a hydrophilic amino-terminal domain; a hydrophobic transmembrane domain, and a carboxy-terminal intracellular or cytoplasmic domain that contains potential phosphorylation sites (serine, threonine, and tyrosine residues). FSHR is expressed on testicular Sertoli cells and ovarian granulosa cells. The activation of FSHR stimulates the activity of adenylyl cyclase, which increases the level of the intracellular second messenger adenosine 3′,5′-monophosphate (cAMP). Consequently, this increases the rate of steroid synthesis and secretion.
Annually, there are about 2.4 million reported cases of couples experiencing infertility in the USA. FSH is used as an effective treatment of infertility. The treatment includes parenteral administration of FSH by specialists to induce ovulation or controlled ovarial hyperstimulation. Ovulation induction aims at achieving a single follicle to ovulate, while controlled ovarial hyperstimulation is directed at harvesting multiple oocytes for use in various in vitro assisted reproductive technologies, e.g., in vitro fertilization (IVF). It is worth noting that FSH is also used clinically to treat male hypogonadism and male infertility, e.g., some types of spermatogenesis failure.
FSH is obtained either by extraction of urine or through recombinant DNA technology. These methods can only result in limited availability of FSH and high cost of its production. In addition, the FSH treatment suffers from the lack of oral dosing and the need of extensive monitoring by specialist physicians, which adds considerably to the cost of treatment. Therefore, it will be beneficial to identify nonpeptidic small molecules as substitutes for FSH that may potentially be developed as orally administered treatments for fertility disorders. The inventors referenced several low molecular weight FSH mimetics with agonistic properties, which are known in the art. However, there is still a need for identifying other low molecular weight FSH hormone mimetics such as the compounds disclosed in this patent application that act as FSHR agonists to selectively activate FSHR and may potentially provide an effective treatment for fertility disorders.
Important Compound Classes:
An external file that holds a picture, illustration, etc.
Object name is ml-2016-00082w_0001.jpg
Key Structures:The inventors listed 609 examples of formula (I) including the structures below:
An external file that holds a picture, illustration, etc.
Object name is ml-2016-00082w_0002.jpg
Biological Assay:Assay A: EC50 of cyclic AMP production in CHO FSHR cells + EC20 FSH
Assay B: Rat Granulosa EC50 FSH
Biological Data:The inventors tested the compounds of the inventions using the two above assays. The results obtained from the representative examples are listed in the following table:
An external file that holds a picture, illustration, etc.
Object name is ml-2016-00082w_0004.jpg
Recent Review Articles:1. Valenti D.; La Vignera S.; Condorelli R. A.; Rago R.; Barone N.; Vicari E.; Calogero A. E.Nat. Rev. Urol. 2013, 10 (1), 52–62.
2. Lalioti M. D.. Curr. Opin. Obstet. Gynecol. 2011, 23 (3), 158–167. [PubMed]
3. Tao Y.-X.; Segaloff D.L.Prog. Mol. Biol. Transl. Sci. 2009, 89, 115–31. [PubMed]


The authors declare no competing financial interest.

Articles from ACS Medicinal Chemistry Letters are provided here courtesy of American Chemical Society