Small molecule piperazinyl-benzimidazole antagonists of the gonadotropin-releasing hormone (GnRH) receptor

Fjellaksel, Richard; Boomgaren, Marc; Sundset, Rune; Haraldsen, Ira; Hansen, Jørn H.; Riss, Patrick J.

doi:10.1039/c7md00320j

Cited by 7 publications

(14 citation statements)

References 19 publications

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“…The key bioactive intermediate 1 was synthesized according to previously published procedures in 37% overall yield from 2,6‐difluoronitrobenzene (Scheme ) . This template has been shown to effect binding to the GnRH receptor while maintaining acceptable blood‐brain barrier penetration properties . Moreover, our approach relies on the presence of an N―H moiety amenable to acylation chemistry which makes compound 1 an ideal test substrate.…”

Section: Resultsmentioning

confidence: 99%

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An acylation‐Finkelstein approach to radioiodination of bioactives: The role of amide group anchimeric assistance

Fjellaksel

Dugalic

Demissie

et al. 2018

J of Physical Organic Chem

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Herein, we report a straightforward sequential acylation-Finkelstein approach to achieve iodination of amine containing bioactives. The utility was demonstrated by successful radiolabelling with 123 I in high radiochemical yield. Moreover, microwave-assisted Finkelstein reaction can be employed to enhance conversion and reaction rates to obtain the desired iodides. The method is of interest for radioiodination of amine-containing bioactives. The mechanistic details of the iodination process were studied by kinetics and density functional theory calculations, which revealed the mechanistic complexity of the reaction involving amide group anchimeric assistance. We disclose a number of fundamental aspects of amide group anchimeric assistance in substitution reactions.

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Section: Resultsmentioning

confidence: 99%

“…Compound 1 was obtained as previously described , as a white powder (489 mg, 96% yield). Purity 97.2% 1 H‐NMR (400 MHz DMSO‐d6), δ in ppm = 9.67 (Br s, 1H), 8.49 (d, 8.0 Hz, 2H), 7.71(d, 8.0 Hz, 2H), 7.53(d, 8.0 Hz, 1H), 7.48 (t, 1H), 7.13 (d, 8.0 Hz, 1H), 3.45 to 3.37(m, 8H), 1.34 (s, 9H).…”

Section: Methodsmentioning

confidence: 99%

An acylation‐Finkelstein approach to radioiodination of bioactives: The role of amide group anchimeric assistance

Fjellaksel

Dugalic

Demissie

et al. 2018

J of Physical Organic Chem

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“…We have recently revealed the discovery of GnRH‐R antagonist candidates based on a benzimidazole‐piperazine molecular scaffold suitable for SPECT imaging, compounds 1 and 2 , Figure . Further diversification from the initial study led to the discovery of two highly promising 123 I‐labelled triazole‐benzimidazole GnRH‐R antagonists, compounds 3 and 4 , Figure…”

Section: Introductionmentioning

confidence: 99%

“…Previously disclosed compounds. Compounds 1 and 2 from the initial study . Compounds 3 and 4 were developed in the continuation of the initial study.…”

Section: Introductionmentioning

confidence: 99%

Evaluation by metabolic profiling and in vitro autoradiography of two promising GnRH‐receptor ligands for brain SPECT imaging

Fjellaksel

Moldes-Anaya

Vasskog

et al. 2020

Labelled Comp Radiopharmac

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The increased expression of gonadotropin releasing hormone receptor (GnRH-R) in brain has been strongly linked to Alzheimer disease. Therefore, the development of radiolabeled imaging agents for GnRH-R is relevant for early diagnosis of Alzheimer disease. We have recently disclosed the discovery of two promising compounds displaying nanomolar-range affinity for the GnRH-R. In the present study, 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. The compounds were assessed in vitro by performing serum stability analysis by human and rat serum, metabolic profiling by human liver microsomes, and exploratory rat brain autoradiography. The investigated compounds displayed satisfactory stability against human, rat serum, and liver microsomal metabolism, which favors their potential as SPECT-imaging agents. Additionally, we identified and quantified the formation rate of the metabolites by fragmentation of up to LIST OF ABBREVIATIONS: GNRH, gonadotropin releasing hormone; GNRH-R, gonadotropin releasing hormone receptor; HPG, hypothalamic pituitary gland; HPLC-MS/MS, high performance liquid chromatography mass spectrometry; IHC, immunohistochemistry; LC-MS, liquid chromatography mass spectrometry; LHRH, luteinizing hormone releasing hormone; NADP, nicotinamide adenine dinucleotide phosphate; NADPH, dihydronicotinamide adenine dinucleotide phosphate; SPECT, single photon emission computed tomography. 72J Label Compd Radiopharm. 2020;63:72-84. wileyonlinelibrary.com/journal/jlcr five mass spectrometric stages. The GnRH-R rat brain specificity of these compounds was tested in competition with a known ligand for the receptor and the in vitro autoradiography confirmed that compounds 3 and 4 binds to rat GnRH-R in different rat brain regions. K E Y W O R D Sautoradiography, gonadotropin, in vitro, metabolic profiling, SPECT

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“…In this study our main goal was to develop a PET imaging probe for GnRHÀ R in brain. [16][17][18] In more detail, we were interested in the development of a moderate-strength GnRHÀ R antagonist to target brain imaging of GnRHÀ R as means to detect and characterise brain cancer, both primary tumours and metastases, as well as to elucidate CNS mechanisms of behaviour, brain damage and cognition involving GnRHÀ R. [9][10][11] In our reasoning, a reversibly binding antagonist of GnRHÀ R would be particularly interesting because of its lack of receptor stimulatory side effects and superior passive tissue permeability to peptide agonists. [12] Several classes of small-molecular antagonist have been investigated for imaging GnRHÀ R, and tested for positron emission tomography (PET) imaging in the brain, however, without success.…”

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

et al. 2020

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We report the synthesis, radiosynthesis and biological characterisation of two gonadotropin‐releasing hormone receptor (GnRH−R) antagonists with nanomolar binding affinity. A small library of GnRH−R antagonists was synthesised in 20–67 % overall yield with the aim of identifying a high‐affinity antagonist capable of crossing the blood–brain barrier. Binding affinity to rat GnRH−R was determined by autoradiography in competitive‐binding studies against [125I]buserelin, and inhibition constants were calculated by using the Cheng–Prusoff equation. The radioligands were obtained in 46–79 % radiochemical yield and >95 % purity and with a molar activity of 19–38 MBq/nmol by direct nucleophilic radiofluorination. Positron emission tomography imaging in rat under baseline conditions in comparison to pretreatment with a receptor‐saturating dose of GnRH antagonist revealed saturable uptake (0.1 %ID/mL) into the brain.

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Small molecule piperazinyl-benzimidazole antagonists of the gonadotropin-releasing hormone (GnRH) receptor

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-tert-butylphenyl)-4-piperazinyl-benzimidazole scaffold via Cu-catalysed azide alkyne cycloaddition.

Cited by 7 publications

References 19 publications

An acylation‐Finkelstein approach to radioiodination of bioactives: The role of amide group anchimeric assistance

An acylation‐Finkelstein approach to radioiodination of bioactives: The role of amide group anchimeric assistance

Evaluation by metabolic profiling and in vitro autoradiography of two promising GnRH‐receptor ligands for brain SPECT imaging

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

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