Small molecule piperazinyl-benzimidazole antagonists of the gonadotropin-releasing hormone (GnRH) receptor† †Electronic supplementary information (ESI) available: Detailed experimental procedures and analytical characterisation of all compounds. See DOI: 10.1039/c7md00320j

@article{Fjellaksel2017SmallMP,
  title={Small molecule piperazinyl-benzimidazole antagonists of the gonadotropin-releasing hormone (GnRH) receptor† †Electronic supplementary information (ESI) available: Detailed experimental procedures and analytical characterisation of all compounds. See DOI: 10.1039/c7md00320j},
  author={Richard Fjellaksel and Marc Boomgaren and Rune Sundset and Ira H. Haraldsen and J{\o}rn H. Hansen and Patrick Johannes Riss},
  journal={MedChemComm},
  year={2017},
  volume={8},
  pages={1965 - 1969}
}
In this communication, we report the synthesis and characterization of a library of small molecule antagonists of the human gonadotropin releasing hormone receptor based upon the 2-(4-tert-butylphenyl)-4-piperazinyl-benzimidazole scaffold via Cu-catalysed azide alkyne cycloaddition. 

Figures from this paper

Recent Development of Non-Peptide GnRH Antagonists
TLDR
All developed small molecule GnRH antagonists are summarized along with the most recent clinical data and therapeutic applications for hormone-dependent diseases targeting the GnRH receptor.
Discovery of a Lead Brain‐Penetrating Gonadotropin‐Releasing Hormone Receptor Antagonist with Saturable Binding in Brain
TLDR
Positron emission tomography imaging in rat under baseline conditions in comparison to pretreatment with a receptor‐saturating dose of GnRH antagonist revealed saturable uptake into the brain.
A Comprehensive Account on Recent Progress in Pharmacological Activities of Benzimidazole Derivatives
TLDR
This comprehensive review has summarized the bioactivity of the benzimidazole derivatives reported in recent literature (2012–2021) with their available structure-activity relationship.
An acylation‐Finkelstein approach to radioiodination of bioactives: The role of amide group anchimeric assistance
TLDR
A straightforward sequential acylation-Finkelstein approach to achieve iodination of amine containing bioactives and discloses a number of fundamental aspects of amide group anchimeric assistance in substitution reactions.
Evaluation by metabolic profiling and in vitro autoradiography of two promising GnRH-receptor ligands for brain SPECT imaging.
TLDR
A preclinical evaluation of the compound properties was performed to evaluate their potential as Single Photon Emission Computed Tomography (SPECT) radiotracers for imaging the GnRH-receptor and found that compounds 3 and 4 binds to rat Gn RH-R in different rat brain regions.
First in vivo evaluation of a potential SPECT brain radiotracer for the gonadotropin releasing hormone receptor
TLDR
The compound was found to possess nano molar affinity for the gonadotropin releasing hormone-receptor in a competition dependent inhibition study and liquid chromatography-mass spectrometry analysis in saline, human and rat serum resulted in 46%, 52% and 44% stability after incubation for 1 h respectively.

References

SHOWING 1-10 OF 19 REFERENCES
Discovery of 6-({4-[2-(4-tert-butylphenyl)-1H-benzimidazol-4-yl]piperazin-1-yl}methyl)quinoxaline (WAY-207024): an orally active antagonist of the gonadotropin releasing hormone receptor (GnRH-R).
A potent, highly insoluble, GnRH antagonist with a 2-phenyl-4-piperazinylbenzimidazole template and a quinoxaline-2,3-dione pharmacophore was modified to maintain GnRH antagonist activity and improve
Effect of Testosterone Suppression on the Pharmacokinetics of a Potent GnRH Receptor Antagonist
TLDR
The potent GnRH receptor antagonist AG-045572 is metabolized by hormone-dependent CYP3A in both rats and humans, and suppression of testosterone by pretreatment with AG-044572 “feminized” its own pharmacokinetics.
Drug Insight: clinical use of agonists and antagonists of luteinizing-hormone-releasing hormone
  • J. Engel, A. Schally
  • Medicine, Biology
    Nature Clinical Practice Endocrinology &Metabolism
  • 2007
TLDR
Analogs of LHRH are now a well-established means of treating sex-steroid-dependent, benign and malignant disorders, and have been successfully used to treat prostate cancer and benign prostatic hypertrophy.
Modulation of pharmacokinetics of radioiodinated sugar-conjugated somatostatin analogues by variation of peptide net charge and carbohydration chemistry.
TLDR
The evaluation of the potential of specific glycoside structures in combination with reduced peptide net charge to reduce kidney accumulation without affecting tumor accumulation was evaluated.
Development of neuropeptide drugs that cross the blood-brain barrier
TLDR
Several of the strategies that have been used to improve both bioavailability and BBB transport are discussed, with an emphasis on antibody based vector delivery, useful for large peptides/small proteins, and glycosylation, Useful for small peptides.
Pharmacotherapy of paraphilias with long-acting agonists of luteinizing hormone-releasing hormone: a systematic review.
TLDR
Although there is a need for further research, LHRH agonists offer a treatment option for patients with severe paraphilia, and a differentiated pharmacologic treatment regarding side effects, symptomatology, and severity is proposed.
...
...