A new class of benzimidazole-5-sulfonamides has been identified as nonpeptide luteinizing hormone-releasing hormone (LHRH) antagonists. Initial structure-activity relationships are presented resulting in compounds 19 and 28 with submicromolar dual functional activity on human and rat receptors.
[Show abstract][Hide abstract] ABSTRACT: 1-(1H-Benzimidazol-5-yl)-3-tert-butylurea derivatives have been identified as a novel class of non-peptide luteinizing hormone-releasing hormone (LHRH) antagonists. Herein, we disclose the synthesis and structure-activity relationships (SAR) of this class resulting in the identification of compound 12c, with dual functional activity on human and rat receptors (rat LHRH: IC50=120 nM; human LHRH: IC50=18 nM). These SAR studies suggest that 1-(1H-benzimidazol-5-yl)-3-tert-butylurea is a new pharmacophore for small molecule LHRH antagonists.
[Show abstract][Hide abstract] ABSTRACT: Herein we report the development of novel, potent and non-peptide luteinizing hormone releasing hormone (LHRH) antagonists. The optimization towards derivatives free from mechanism-based CYP3A4 inhibition is described. The identification of a main metabolite guided us towards structural modifications of the benzyl moiety, which resulted in significant improvements of the CYP3A4 profile, while maintaining potent LHRH antagonist activity.
[Show abstract][Hide abstract] ABSTRACT: Gonadotropin releasing hormone (GnRH), also known as luteinising hormone releasing hormone (LHRH), is a decapeptide released from the hypothalamus that binds to the G-protein-coupled GnRH receptor located on the pituitary gland. This receptor plays an important role in human reproduction, reproductive and proliferative diseases such as endometriosis, uterine fibroids, precocious puberty, prostate/breast/ovarian cancers and prostatic hyperplasia, conditions that can be potentially treated by GnRH receptor agonists or antagonists. Peptidic GnRH receptor agonists and antagonists have long been used for the treatment of several disorders, but the problems associated with peptides have encouraged the research and development of orally bioavailable peptidomimetic small-molecule GnRH receptor antagonists. This review summarises the patent literature during 2001 – 2005 on small-molecule GnRH receptor antagonists.
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