Gonadotropin Releasing Hormone (GnRH, also known as Luteinizing Hormone Releasing Hormone, LHRH) is a decapeptide hormone produced in the hypothalamus. Upon release it is transported to the pituitary, where it causes the secretion of Follicle Stimulating Hormone (FSH) and Luteinizing Hormone (LH). These two hormones then act at the ovaries (in females) or the testes (in males). They control folliculogenesis and ovulation in females and the release of steroid hormones in both males and females.
It is widely recognised that over-secretion of steroid hormones can be detrimental to the health. For example, certain neoplasms (such as breast and prostate cancer) and endometriosis are promoted by high steroid levels. Agents that modulate the hypothalamic-pituitary-gonadal axis are therefore of therapeutic interest. The first compounds used clinically were GnRH super-agonists. These are analogues of GnRH that retain all the biological actions of the native hormone, but which are administered in such a way as to cause chronic activation of the GnRH receptors. Within a period of a few days this chronic activation causes down-regulation of the receptor signaling, and FSH and LH levels fall. The disadvantage with these agents is that, in the first few days, they cause an over-production of FSH and LH which can result in a “flare” reaction. Because of this, attention then moved to the development of GnRH antagonists. Modification of the peptide sequence has led to the discovery of a number of peptide antagonists that are now in clinical trials. However, because these compounds are still peptides, they must be given parenterally (usually by subcutaneous or intramuscular injection). They are also relatively expensive to make and purify. Accordingly, there exists a need for therapeutically effective non-peptide GnRH antagonists, and particularly for compounds that can be administered orally and that are inexpensive.