2-(3,5-Dimethylphenyl)tryptamine derivatives that bind to the GnRH receptor.

@article{Lin2001235DimethylphenyltryptamineDT,
  title={2-(3,5-Dimethylphenyl)tryptamine derivatives that bind to the GnRH receptor.},
  author={P Lin and Dominick Marino and J L Lo and Yi Yang and Kang Cheng and R. G. Smith and Michael H. Fisher and Matthew J. Wyvratt and Mark T. Goulet},
  journal={Bioorganic \& medicinal chemistry letters},
  year={2001},
  volume={11 8},
  pages={
          1073-6
        }
}
A series of 2-(3,5-dimethylphenyl)tryptamine derivatives was prepared and evaluated on a rat gonadotropin releasing hormone receptor assay. Some para-substituents on the 4-phenylbutyl side chain attached to the tryptamine nitrogen led to compounds with potent GnRH receptor binding. The study has helped define structural requirements for GnRH receptor binding for the 2-aryltryptamine GnRH antagonists. 
Heterocyclic derivatives of 2-(3,5-dimethylphenyl)tryptamine as GnRH receptor antagonists.
TLDR
A series of heterocyclic 2-(3,5-dimethylphenyl)tryptamine derivatives was prepared and evaluated on a rat gonadotropin releasing hormone receptor assay, with the most potent compound having an IC50 of 16 nM. Expand
Substituted indole-5-carboxamides and -acetamides as potent nonpeptide GnRH receptor antagonists.
TLDR
A functional assay for GnRH antagonism was even more sensitive to structural modification and revealed a strong preference for branched tertiary amides. Expand
Synthesis of chiral β-methyl tryptamine-derived GnRH antagonists
Abstract The stereospecific formation of 2-aryl-β-methyl tryptamine derivatives 15 and 16 from chiral 4-chloro-1-(3,5-dimethylphenyl)-3-methylbutanones is described. These intermediates were furtherExpand
2-Arylindoles as gonadotropin releasing hormone (GnRH) antagonists: optimization of the tryptamine side chain.
TLDR
A series of 2-arylindoles containing novel heteroaromatic substituents on the tryptamine tether was prepared and evaluated for their ability to act as gonadotropin releasing hormone (GnRH) antagonists, resulting in the discovery of compound 27kk which had excellent in vitro potency and oral efficacy in rodents. Expand
A convergent synthesis of (S)-β-methyl-2-aryltryptamine based gonadotropin releasing hormone antagonists
Abstract A practical synthesis of (S)-β-methyl-2-aryltryptamine based gonadotropin releasing hormone antagonists which features a palladium-catalyzed Larock indole synthesis and a palladium-catalyzedExpand
Potent nonpeptide GnRH receptor antagonists derived from substituted indole-5-carboxamides and -acetamides bearing a pyridine side-chain terminus.
TLDR
A pyridine side-chain terminus has been incorporated into the indole-5-carboxamide and indole -5-acetamide series of GnRH antagonists, and certain branched or cyclic tertiary amides were identified as preferred in each series. Expand
Orally bioavailable, indole-based nonpeptide GnRH receptor antagonists with high potency and functional activity.
TLDR
Improvements achieved by variation of the bicyclic amino moiety of the tertiary amide and by adjustment of the tether length to a pyridine or pyridone terminus culminated in analogue 24, which had oral activity in a rat model and acceptable oral bioavailability and half-life in dogs and monkeys. 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
Initial structure-activity relationship studies of a novel series of pyrrolo[1,2-a]pyrimid-7-ones as GnRH receptor antagonists.
Initial SAR studies on 1-aminomethyl-2-aryl-3-cyano-pyrrolo[1,2-a]pyrimid-7-one-6-carboxylates as human GnRH receptor antagonists were discussed. 2-(2-Methylaminoethyl)pyridine was discovered to be aExpand
Synthesis and structure-activity relationships of thieno[2,3-b]pyrroles as antagonists of the GnRH receptor.
TLDR
A new class of small-molecule GnRH antagonists, the thieno[2,3-b]pyrroles, was designed and substitution at the C4 position was investigated; it was observed that introducing piperazines and piperidines improved the physical properties of the compounds while retaining good in vitro potency. Expand
...
1
2
3
...

References

SHOWING 1-10 OF 14 REFERENCES
Heterocyclic derivatives of 2-(3,5-dimethylphenyl)tryptamine as GnRH receptor antagonists.
TLDR
A series of heterocyclic 2-(3,5-dimethylphenyl)tryptamine derivatives was prepared and evaluated on a rat gonadotropin releasing hormone receptor assay, with the most potent compound having an IC50 of 16 nM. Expand
SAR studies of novel 5-substituted 2-arylindoles as nonpeptidyl GnRH receptor antagonists.
The discovery of the potency-enhancing effect of 5-substitutions on the novel 2-arylindoles as nonpeptidyl GnRH receptor antagonists led to the identification of several analogues with highExpand
Potent antagonists of gonadotropin releasing hormone receptors derived from quinolone-6-carboxamides.
TLDR
Synthetic access to diverse quinolone-6-carboxamides was achieved via the palladium-catalyzed amino-carbonylation reactions of iodide 4 with various amines, which were especially potent, functional antagonists of rat and human GnRH receptors. Expand
Quinolones as gonadotropin releasing hormone (GnRH) antagonists: simultaneous optimization of the C(3)-aryl and C(6)-substituents.
TLDR
A series of 3-arylquinolones was prepared and evaluated for their ability to act as gonadotropin releasing hormone (GnRH) antagonists and the 3,4,5-trimethylphenyl substituent (23h) was found to be optimal. Expand
Investigation of the 4-O-alkylamine substituent of non-peptide quinolone GnRH receptor antagonists.
TLDR
The key amine pharmacophore for binding to the rat GnRH receptor was most active in the S-configuration and Ring size was not important for potency with 4, 5, 6, and 7-membered ring amines exhibiting similar potency. Expand
Initial structure-activity relationship of a novel class of nonpeptidyl GnRH receptor antagonists: 2-arylindoles.
TLDR
A nonpeptidyl GnRH receptor antagonist, with a unique 2-arylindole core, was identified through the Merck in-house screening for binding affinity on the rat Gn RH receptor and exhibits a 60-fold improvement in binding activity over the initial lead. Expand
A potent, nonpeptidyl 1H-quinolone antagonist for the gonadotropin-releasing hormone receptor.
TLDR
Quinolone 1 is a potent nonpeptidyl antagonist for the human GnRH receptor that is efficacious for the suppression of luteinizing hormone and testosterone in primates. Expand
Identification and initial structure-activity relationships of a novel non-peptide quinolone GnRH receptor antagonist.
TLDR
Substantial improvements in potency were achieved by addition of an alkyl amine at the 4-position, a 3,5-dimethylphenyl group at the 3-position and 6-nitro-7-chloro-substitution of the 1 H-quinolone core. Expand
A Locus of the Gonadotropin-releasing Hormone Receptor That Differentiates Agonist and Antagonist Binding Sites (*)
  • Wei Zhou, V. Rodic, +6 authors S. Sealfon
  • Chemistry, Medicine
  • The Journal of Biological Chemistry
  • 1995
TLDR
The results indicate that a charge-strengthened hydrogen bond donor is required at this locus for high affinity agonist binding but not forHigh affinity antagonist binding. Expand
Identification of Phe313 of the gonadotropin-releasing hormone (GnRH) receptor as a site critical for the binding of nonpeptide GnRH antagonists.
TLDR
Results show that Phe313 of the GnRH receptor is critical for the binding of this structural class of GnRH antagonists and that the dog receptor can be "humanized" by substituting Leu for Phe. Expand
...
1
2
...