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Design, synthesis and pharmacological evaluation of tricyclic derivatives as selective RXFP4 agonists

Lin, Lin; Lin, Guangyao; Zhou, Qingtong; Bathgate, Ross AD; Gong, Grace Qun; Yang, Dehua; Liu, Qing; (2021) Design, synthesis and pharmacological evaluation of tricyclic derivatives as selective RXFP4 agonists. Bioorganic Chemistry , 110 , Article 104782. 10.1016/j.bioorg.2021.104782. Green open access

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Abstract

Relaxin family peptide receptors (RXFPs) are the potential therapeutic targets for neurological, cardiovascular, and metabolic indications. Among them, RXFP3 and RXFP4 (formerly known as GPR100 or GPCR142) are homologous class A G protein-coupled receptors with short N-terminal domain. Ligands of RXFP3 or RXFP4 are only limited to endogenous peptides and their analogues, and no natural product or synthetic agonists have been reported to date except for a scaffold of indole-containing derivatives as dual agonists of RXFP3 and RXFP4. In this study, a new scaffold of tricyclic derivatives represented by compound 7a was disclosed as a selective RXFP4 agonist after a high-throughput screening campaign against a diverse library of 52,000 synthetic and natural compounds. Two rounds of structural modification around this scaffold were performed focusing on three parts: 2-chlorophenyl group, 4-hydroxylphenyl group and its skeleton including cyclohexane-1,3-dione and 1,2,4-triazole group. Compound 14b with a new skeleton of 7,9-dihydro-4H-thiopyrano[3,4-d][1,2,4]triazolo[1,5-a]pyrimidin-8(5H)-one was thus obtained. The enantiomers of 7a and 14b were also resolved with their 9-(S)-conformer favoring RXFP4 agonism. Compared with 7a, compound 9-(S)-14b exhibited 2.3-fold higher efficacy and better selectivity for RXFP4 (selective ratio of RXFP4 vs. RXFP3 for 9-(S)-14b and 7a were 26.9 and 13.9, respectively).

Type: Article
Title: Design, synthesis and pharmacological evaluation of tricyclic derivatives as selective RXFP4 agonists
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/j.bioorg.2021.104782
Publisher version: https://doi.org/10.1016/j.bioorg.2021.104782
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher's terms and conditions.
Keywords: Synthesis, Structure-activity relationship, Relaxin family peptide receptor 4, Selective agonist, Molecular docking
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Oncology
URI: https://discovery.ucl.ac.uk/id/eprint/10176105
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