title: Non-peptidic GnRH receptor antagonists.
abstract: Gonadotropin-releasing hormone (GnRH) or luteinizing hormone-releasing hormone (LHRH) is a decapeptide (pGlu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH2) hypothalamic hormone that acts upon 7-trans membrane spanning GnRH receptors in the pituitary. This action leads to the secretion of the gonadotropins, luteinizing hormone (LH) and follicle-stimulating hormone (FSH) that in turn act on the reproductive organs regulating gonadal steroid production, spermatogenesis and follicular development. Peptidic agonists of the GnRH receptor have been known for many years and are currently employed therapeutically in the treatment of prostate and breast tumours, uterine fibroids, precocious puberty, endometriosis, premenstrual syndrome, contraception and infertility. Peptidic antagonists to date have only been employed commercially in the treatment of infertility during assisted reproductive therapy; however, many peptidic antagonists are currently in late stage development for many of the aforementioned indications. Whilst peptidic agonists and antagonists of the GnRH receptor have been discovered and exploited clinically, they are limited to predominantly parenteral administration due to their poor oral bioavailability. Recently, several small molecule GnRH antagonist series have been discovered offering the prospect of orally active therapeutics based on GnRH receptor antagonism. This article will review the current medicinal chemistry literature and structure activity relationships known for non-peptidic GnRH receptor antagonists.
authors.affiliation: Ardana Bioscience, 58 Queen Street, Edinburgh, EH2 3NS, Scotland, UK. richard@ardana.co.uk
authors.forename: Richard E
authors.initials: RE
authors.lastname: Armer
authors.forename: Kathryn H
authors.initials: KH
authors.lastname: Smelt
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000627:therapeutic use; D002986:Clinical Trials as Topic; D005260:Female; D007987:Gonadotropin-Releasing Hormone / Q000502:physiology; D006727:Hormone Antagonists / Q000737:chemistry / Q000627:therapeutic use; D006801:Humans; D007246:Infertility / Q000188:drug therapy; D008297:Male; D011471:Prostatic Neoplasms / Q000188:drug therapy; D011966:Receptors, LHRH / Q000819:agonists / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D006727:Hormone Antagonists; D011966:Receptors, LHRH; D007987:Gonadotropin-Releasing Hormone