Recent Development of Non-Peptide GnRH Antagonists

  title={Recent Development of Non-Peptide GnRH Antagonists},
  author={Feng-Ling Tukun and Dag Erlend Olberg and Patrick Johannes Riss and Ira H. Haraldsen and Anita Kaass and Jo Klaveness},
  journal={Molecules : A Journal of Synthetic Chemistry and Natural Product Chemistry},
The decapeptide gonadotropin-releasing hormone, also referred to as luteinizing hormone-releasing hormone with the sequence (pGlu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH2) plays an important role in regulating the reproductive system. It stimulates differential release of the gonadotropins FSH and LH from pituitary tissue. To date, treatment of hormone-dependent diseases targeting the GnRH receptor, including peptide GnRH agonist and antagonists are now available on the market. The inherited… 

Eliminating Hormones With Orally Active Gonadotropin-releasing Hormone Antagonists.

This review will briefly describe the development of GnRH analogues, review the evolution of orally active small-molecule GnRH antagonists and provide an overview of the expanding role of small- molecule gnRH antagonists in clinical practice.

Gonadotropin Releasing Hormone and GnRH Receptor: Structure, Function and Drug Development.

This review aims at shedding light in the versatile function of GnRH and GnRH receptor and offers an apprehensive summary regarding the development and function of different agonists, antagonists and non-peptide GnRH analogues.

Structure of the human gonadotropin-releasing hormone receptor GnRH1R reveals an unusual ligand binding mode

Insight is provided into the ligand binding mode of GnRH1R and an atomic framework for rational drug design is offered and an interesting N-terminus that could co-occupy the enlarged orthosteric binding site together with elagolix is revealed.

Synthesis, molecular modeling and functional evaluation of a GnRH antagonist

The results imply that the synthesized peptides 1, 2, 3, and 5 are GnRH antagonists and selective for GnRH receptors on the surface of tumor cells.

Role of Gonadotropin-Releasing Hormone (GnRH) in Ovarian Cancer

The role of GnRH in ovarian cancer development, progression and therapy is given and the effects on ovarian tumors can be indirect or direct.

Discovery and Characterization of BAY 1214784, an Orally Available Spiroindoline Derivative Acting as a Potent and Selective Antagonist of the Human Gonadotropin-Releasing Hormone Receptor as Proven in a First-in-Human Study in Postmenopausal Women.

In a first-in-human study in postmenopausal women, once daily treatment with compound BAY 1214784 effectively lowered plasma luteinizing hormone levels by up to 49%, at the same time being associated with low pharmacokinetic variability and good tolerability.

Treatment of Breast Cancer With Gonadotropin-Releasing Hormone Analogs

The administration of GnRH analogs is able to reduce circulating concentrations of estrogen in premenopausal women through their action on the hypothalamus–pituitary–ovarian axis, consequently reducing the growth of breast tumors and disease recurrence.

Discovery of the thieno[2,3-d]pyrimidine-2,4-dione derivative 21a: A potent and orally bioavailable gonadotropin-releasing hormone receptor antagonist.

Compound 21a was well tolerated and efficacious in preclinical studies to suppress blood testosterone levels, which merits further investigation as a candidate novel GnRH-R antagonist for clinical studies.

Current approaches to overcome the side effects of GnRH analogs in the treatment of patients with uterine fibroids

The results regarding the efficacy of new-generation oral GnRH-antagonists, such as elagolix, relugolix and linzagolix are promising and offer potential prospect for the future therapy of UFs, however, these antagonists must be combined with hormonal add-back therapy to minimize the resultant hypoestrogenic side effects such as bone loss.

Relugolix is the first and currently only Orally-Administered GnRH Receptor Antagonist Approved for the treatment of Prostate Cancer: A Review

Relugolix is the first (and currently only) orally-administered GnRH receptor antagonist approved for the treatment of prostate cancer-similar therapies such as degarelix require subcutaneous administration-and therefore provides a less burdensome therapeutic option for patients who might otherwise require clinic visits for administration by healthcare professionals.



Recent advances in small molecule gonadotrophin-releasing hormone receptor antagonists

This review summarises the patent applications of small molecule human GnRH receptor antagonists from 1994 to August 2003 and concludes that a small molecule antagonist is more preferable than a peptide antagonist because it also provides the possibility of oral administration, therefore allowing dose flexibility and better patient acceptance.

The discovery of novel small molecule non-peptide gonadotropin releasing hormone (GnRH) receptor antagonists.

Non-peptide gonadotropin-releasing hormone receptor antagonists.

Several GnRH agonist peptides are now commercially available in long acting injectable depot formulations for gonadal suppression and have found widespread utility for a range of steroid hormone dependent diseases and assisted reproductive therapy.

Luteinizing hormone-releasing hormone antagonists

An overview of the most relevant LH-RH antagonists and their therapeutic applications is given and work in progress is focused on further development of both peptidic and orally active non-peptidic LH- RH antagonists.

Gonadotropin-releasing hormone and its analogues.

The Food and Drug Administration approvals of GnRH-agonist analogues for the treatment of prostate cancer, endometriosis, and precocious puberty, as well as the use of natural GnRH to induce ovulation, are examples of the clinical usefulness of these fundamental observations.

Discovery of a novel, orally active, small molecule gonadotropin-releasing hormone (GnRH) receptor antagonist.

The synthesis, in vitro characterization, pharmacokinetics, and pharmacodynamics of an orally bioavailable, potent, small molecule GnRH receptor antagonist N-4,6-dimethoxy-2-[(3-morpholin-4-ylpropyl)amino]pyrimidin-5-yl}-5 and 2-furamide are reported.

Gonadotrophin-Releasing Hormone Agonists

GnRH agonists are successfully employed in the management of precocious puberty, ovulation induction, prostatic cancer, premenopausal breast cancer, endometriosis, uterine leiomyoma, and for the preparation of female patients undergoing laparotomic, vaginal or endoscopic surgery.