A potent, nonpeptidyl 1H-quinolone antagonist for the gonadotropin-releasing hormone receptor.

@article{DeVita2001APN,
  title={A potent, nonpeptidyl 1H-quinolone antagonist for the gonadotropin-releasing hormone receptor.},
  author={Robert J. DeVita and Thomas F. Walsh and J. R. Young and J. Jiang and Feroze Ujjainwalla and Richard B. Toupence and Mamta Parikh and S X Huang and Jason A. Fair and Mark T. Goulet and Matthew J. Wyvratt and J L Lo and Ning Ren and Joel B. Yudkovitz and Yi Yang and Kang Cheng and Jisong Cui and George R Mount and Susan P. Rohrer and James M. Schaeffer and L Rhodes and Jennifer E. Drisko and Erin McGowan and Duncan Euan Macintyre and Stella H. Vincent and Josephine R. Carlin and Jennifer Cameron and R. G. Smith},
  journal={Journal of medicinal chemistry},
  year={2001},
  volume={44 6},
  pages={
          917-22
        }
}
Extensive development of the structure-activity relationships of a screening lead determined three important pharmacophores for gonadotropin-releasing hormone (GnRH) receptor antagonist activity. Incorporation of the 3,4,5-trimethylphenyl group at the 3-position, 2-(2(S)-azetidinyl)ethoxy group at the 4-position, and N-4-pyrimidinylcarboxamide at the 6-position of the quinolone core resulted in the identification of 4-(2-(azetidin-2(S)-yl)ethoxy)-7-chloro-2-oxo-3-(3,4,5-trimethylphenyl)-1,2… Expand
Synthesis and structure-activity relationships of uracil derived human GnRH receptor antagonists: (R)-3-[2-(2-amino)phenethyl]-1-(2,6-difluorobenzyl)-6-methyluracils containing a substituted thiophene or thiazole at C-5.
TLDR
The synthesis of a series of (R)-3-[2-(2-amino)phenethyl]-1-(2,6-difluorobenzyl)-6-methyluracils containing a substituted thiophene or thiazole at C-5 is described, leading to the discovery that a 2-thienyl or (2-phenyl)thiazol-4-yl group is required for optimal receptor binding. Expand
Synthesis and structure-activity relationships of thieno[2,3-d]pyrimidine-2,4-dione derivatives as potent GnRH receptor antagonists.
The synthesis and SAR studies of thieno[2,3-d]pyrimidine-2,4-diones as human GnRH receptor antagonists to treat reproductive diseases are discussed. It was found that the 2-(2-pyridyl)ethyl group onExpand
Benzimidazoles as non-peptide luteinizing hormone-releasing hormone (LHRH) antagonists. Part 3: Discovery of 1-(1H-benzimidazol-5-yl)-3-tert-butylurea derivatives.
TLDR
These SAR studies suggest that 1-(1H-benzimidazol-5-yl)-3-tert-butylurea is a new pharmacophore for small molecule LHRH antagonists. Expand
Biological Characterization of a Novel, Orally Active Small Molecule Gonadotropin-Releasing Hormone (GnRH) Antagonist Using Castrated and Intact Rats
TLDR
Data suggest that CMPD1 is a potent, selective, orally active GnRH receptor antagonist that may have potential application as a therapeutic agent for treating hormone-dependent cancers and diseases. Expand
Discovery of 1-{4-[1-(2,6-difluorobenzyl)-5-[(dimethylamino)methyl]-3-(6-methoxypyridazin-3-yl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl]phenyl}-3-methoxyurea (TAK-385) as a potent, orally active, non-peptide antagonist of the human gonadotropin-releasing hormone receptor.
TLDR
Compound 16b showed potent in vitro GnRH antagonistic activity in the presence of fetal bovine serum (FBS) without CYP inhibition and is currently under clinical development with the code name of TAK-385. Expand
Synthesis and structure-activity relationships of (R)-1-alkyl-3-[2-(2-amino)phenethyl]-5-(2-fluorophenyl)-6-methyluracils as human GnRH receptor antagonists.
TLDR
The synthesis of a series of (R)-1-alkyl-3-[2-amino)phenethyl]-5-(2-fluorophenyl)-6-methyluracils is discussed, which led to the discovery that an electron-deficient 2,6-disubstituted benzyl group is required for optimal receptor binding. Expand
Kinetics of nonpeptide antagonist binding to the human gonadotropin-releasing hormone receptor: Implications for structure-activity relationships and insurmountable antagonism.
TLDR
Evaluating the receptor binding kinetics of nonpeptide antagonists revealed SAR, not evident in standard competition assays, that defined at least in part the mode of functional antagonism by the ligands, of importance for the future definition of non peptide ligand SAR and for the identification of potentially useful slowly dissociating antagonists for the GnRH receptor. Expand
Synthesis and initial structure-activity relationships of a novel series of imidazolo[1,2-a]pyrimid-5-ones as potent GnRH receptor antagonists.
TLDR
SAR studies of 2-arylimidazolo[1,2-a]pyrimid-5-ones 10a-m resulted in the discovery of a series of potent nonpeptide human GnRH receptor antagonists, which were derived from initial lead 3a. Expand
Pharmacological characterization of a novel nonpeptide antagonist of the human gonadotropin-releasing hormone receptor, NBI-42902.
TLDR
Overall, these data provide a benchmark of pharmacological characteristics required for a nonpeptide GnRH antagonist to effectively suppress gonadotropins in humans and suggest that NBI-42902 may have clinical utility as an oral agent for suppression of the hypothalamic-pituitary-gonadal axis. Expand
Syntheses and structure-activity relationship studies of piperidine-substituted quinolones as nonpeptide gonadotropin releasing hormone antagonists.
TLDR
This study showed that GnRH binding potency was tolerated by a small group at the 6-position of the piperidine, and blocking the 6 position by a trifluoromethyl group reduced clearance rate and increased oral bioavailability. Expand
...
1
2
3
4
5
...