Gonadotropin Releasing Hormone (GnRH) Analogs

Inventors: Jean Rivier, John Porter, Steven Koerber, Carl Hoeger
Potential Uses: Drug Development, Oncology, Fertility
Potent GnRH antagonists with significantly increased duration of action, useful for applications including fertility regulation, endometriosis, hormone-dependent tumors, and precocious puberty.

GnRH is a hypothalamic decapeptide that stimulates the secretion of the pituitary gonadotropins, luteinizing hormone (LH) and follicle-stimulating hormone (FSH). These hormones modulate the levels of testosterone and estrogen in the body. The amino acid sequence of GnRH was discovered in 1971, and spawned the development of GnRH agonists and antagonists with many scientific and pharmaceutical perspectives. Certain advantages of antagonists are that they require a shorter administration period and pituitary suppression is immediately reversible after withdrawal of the antagonist.

A breakthrough made at the Salk Institute was the discovery that acylated 4-aminophenylalanines in the L- and D-configurations at positions 5 and 6 respectively and an isopropyl-lysine at position 8 along with other established modifications at positions 1, 2, 3 and 10 yielded potent GnRH analogs with significantly increased duration of action.

These antagonists are useful as fertility regulators (in vitro fertilization) and for the treatment of pathological conditions such as precocious puberty, hirsutism, acne, hormone dependent neoplasia, uterine myoma, amenorrhea, dysmenorrhea, endometriosis, PMS, ovarian and mammary cystic diseases, such as PCO, and hormone-dependent tumors, including malignant and benign prostatic, mammary, ovarian and testicular tumors.