PATENT HIGHLIGHT pubs.acs.org/acsmedchemlett
Targeting the Follicle Stimulating Hormone Receptor (FSHR) To Treat Fertility Disorders Ahmed F. Abdel-Magid* Therachem Research Medilab (India) Pvt. Ltd., Jaipur, India Patent Application Title:
Benzamides
Patent Application Number: US 2016/0022670 A1 Priority Application: US 61/526,342
Publication date: Priority date:
US 61/508,861
Jan 28, 2016 Aug 23, 2011 Jul 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 disorders
Summary:
The invention in this patent application relates to 4-(1-piperazinyl)benzamides represented generally by formula (I). The compounds
Biological Target:
Follicle stimulating hormone receptor (FSHR)
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 30 ,50 -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.
Received: February 25, 2016 Published: March 04, 2016 r 2016 American Chemical Society
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ACS Medicinal Chemistry Letters
PATENT HIGHLIGHT
Important Compound Classes:
Key Structures:
The inventors listed 609 examples of formula (I) including the structures below:
Biological Assay:
Assay A: EC50 of cyclic AMP production in CHO FSHR cells + EC20 FSH
Biological Data:
Assay B: Rat Granulosa EC50 FSH 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:
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), 5262. (2.) Lalioti, M. D. Curr. Opin. Obstet. Gynecol. 2011, 23 (3), 158167. (3.) Tao, Y.-X.; Segaloff, D.L. Prog. Mol. Biol. Transl. Sci. 2009, 89, 11531.
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dx.doi.org/10.1021/acsmedchemlett.6b00082 |ACS Med. Chem. Lett. 2016, 7, 345–347
ACS Medicinal Chemistry Letters
PATENT HIGHLIGHT
’ AUTHOR INFORMATION Corresponding Author
*Address: 1383 Jasper Drive, Ambler, Pennsylvania 19002, United States. Tel: 215-913-7202. E-mail:
[email protected]. Notes
The authors declare no competing financial interest.
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