Synthesis and biological evaluation of piperazinyl heterocyclic antagonists of the gonadotropin releasing hormone (GnRH) receptor
| Autor: | Charles William Mann, Lloyd M. Garrick, Matthew D. Vera, Linda Shanno, Jeffrey C. Pelletier, John F. Rogers, Diane B. Hauze, Jay E. Wrobel, Daniel M. Green, Irene Feingold, Murty Chengalvala, John F. Mehlmann, Joseph T. Lundquist, Joshua E. Cottom |
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| Rok vydání: | 2010 |
| Předmět: |
Male
medicine.medical_specialty Benzimidazole medicine.drug_class Clinical Biochemistry Biological Availability Pharmaceutical Science Gonadotropin-releasing hormone Pharmacology Biochemistry Piperazines Gonadotropin-releasing hormone antagonist Rats Sprague-Dawley chemistry.chemical_compound Heterocyclic Compounds Internal medicine Drug Discovery medicine Animals Humans Receptor Molecular Biology Cells Cultured G protein-coupled receptor Chemistry Organic Chemistry Biological activity In vitro Rats Endocrinology Molecular Medicine Antagonism Receptors LHRH Half-Life |
| Zdroj: | Bioorganic & Medicinal Chemistry Letters. 20:2512-2515 |
| ISSN: | 0960-894X |
| Popis: | Antagonism of the gonadotropin releasing hormone (GnRH) receptor has resulted in positive clinical results in reproductive tissue disorders such as endometriosis and prostate cancer. Following the recent discovery of orally active GnRH antagonists based on a 4-piperazinylbenzimidazole template, we sought to investigate the properties of heterocyclic isosteres of the benzimidazole template. We report here the synthesis and biological activity of eight novel scaffolds, including imidazopyridines, benzothiazoles and benzoxazoles. The 2-(4-tert-butylphenyl)-8-(piperazin-1-yl)imidazo[1,2-a]pyridine ring system was shown to have nanomolar binding potency at the human and rat GnRH receptors as well as functional antagonism in vitro. Additional structure–activity relationships within this series are reported along with a pharmacokinetic comparison to the benzimidazole-based lead molecule. |
| Databáze: | OpenAIRE |
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