Small Molecule Piperazinyl-benzimidazole Antagonists of the Gonadotropin-releasing Hormone (GnRH) Receptor

Overview

Journal Medchemcomm

Publisher Royal Society of Chemistry

Specialty Chemistry

Date 2018 Aug 16

PMID 30108717

Citations 4

Authors

Richard Fjellaksel

Marc Boomgaren

Rune Sundset

Ira H Haraldsen

Jorn H Hansen

Patrick J Riss

Affiliations

Soon will be listed here.

Abstract

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--butylphenyl)-4-piperazinyl-benzimidazole scaffold Cu-catalysed azide alkyne cycloaddition. Our main purpose was to find a more soluble compound based on the WAY207024 lead with nanomolar potency to inhibit the GnRH receptor. A late stage diversification by the use of click chemistry was, furthermore developed to allow for expansion of the library in future optimisations. All compounds were tested in a functional assay to determine the individual potency of inhibiting stimulation of the receptor by the endogenous agonist GnRH. In conclusion, we found that compound showed improved solubility compared to WAY207024 and nanomolar affinity to GnRH receptor.

Citing Articles

A Comprehensive Account on Recent Progress in Pharmacological Activities of Benzimidazole Derivatives.

Brishty S, Hossain M, Khandaker M, Faruque M, Osman H, Rahman S Front Pharmacol. 2021; 12:762807.

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Discovery of a Lead Brain-Penetrating Gonadotropin-Releasing Hormone Receptor Antagonist with Saturable Binding in Brain.

Bekker R, Fjellaksel R, Hjornevik T, Nuruddin S, Rafique W, Hansen J ChemMedChem. 2020; 15(17):1624-1628.

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First in vivo evaluation of a potential SPECT brain radiotracer for the gonadotropin releasing hormone receptor.

Fjellaksel R, Oteiza A, Martin-Armas M, Riss P, Hjelstuen O, Kuttner S BMC Res Notes. 2018; 11(1):811.

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Recent Development of Non-Peptide GnRH Antagonists.

Tukun F, Olberg D, Riss P, Haraldsen I, Kaass A, Klaveness J Molecules. 2017; 22(12).

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