Small molecule antagonists of the gonadotropin-releasing hormone (GnRH) receptor: Structure–activity relationships of small heterocyclic groups appended to the 2-phenyl-4-piperazinyl-benzimidazole template
| Autor: | Lloyd M. Garrick, John F. Mehlmann, Diane B. Hauze, Joshua E. Cottom, Daniel M. Green, Jeffrey C. Pelletier, Murty Chengalvala, Irene Feingold, Joseph T. Lundquist, John F. Rogers, Charles William Mann, Linda Shanno, Jay E. Wrobel, Christine Huselton, Wenling Kao, Kees Kenneth L |
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| Rok vydání: | 2009 |
| Předmět: |
medicine.medical_specialty
Benzimidazole Time Factors Clinical Biochemistry Administration Oral Pharmaceutical Science Gonadotropin-releasing hormone Peptide hormone Biochemistry Piperazines Structure-Activity Relationship chemistry.chemical_compound Heterocyclic Compounds Oral administration Internal medicine Drug Discovery medicine Animals Receptor Molecular Biology Volume of distribution Chemistry Organic Chemistry Antagonist Luteinizing Hormone Rats Bioavailability Endocrinology Models Animal Molecular Medicine Benzimidazoles Receptors LHRH |
| Zdroj: | Bioorganic & Medicinal Chemistry Letters. 19:1986-1990 |
| ISSN: | 0960-894X |
| DOI: | 10.1016/j.bmcl.2009.02.043 |
| Popis: | A previous report described the serum LH suppression pharmacology of the 2-phenyl-4-piperazinyl-benzimidazole N-ethyluracil GnRH receptor antagonist 1 following oral administration in rats. A series of small heterocycles were appended to the 2-(4-tert-butylphenyl)-4-piperazinyl-benzimidazole template in place of the N-ethyluracil. Two imidazole analogues, 32 and 41, were shown to possess substantial in vitro potency at the target receptor (hGnRH IC50 = 7 and 18 nM, respectively) and aqueous solubility (55 and 100 μg/mL at pH 7.4, respectively). Both compounds had high oral bioavailability in rats and 32 was further examined in an orchidectomized rat model for serum LH suppression based on increased volume of distribution over 41. Serum LH levels trended lower in orchidectomized rats following oral administration of 32. |
| Databáze: | OpenAIRE |
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