An expedient synthesis of CMF-019: (s)-5-methyl-3-{1-(pentan-3-yl)-2-(thiophen-2-ylmethyl)-1h-benzo[d]imidazole-5-carboxamido}hexanoic acid, a potent apelin receptor (APJ) agonist

Lena Trifonov, Michal Afri, Krzysztof Palczewski, Edward E. Korshin, Arie Gruzman

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

Abstract

Background: Apelin receptor (APJ) is a G protein-coupled receptor (GPCR) activated by the endogenous peptide apelin. The apelin–APJ system has emerged as an important regulator of cardiovascular homeostasis. Recently, a potent benzimidazole-derived apelin peptidomimetic, CMF-019, was patented but without a comprehensive description of its synthesis and a complete spectroscopic characterization of the intermediates. Objective: Here, a detailed preparation of CMF-019 through a modified and improved synthetic pathway is described. Method: In particular, the benzimidazole ring in 7 was tailored by the condensation of methyl 3-amino-4-(pentan-3-ylamino)benzoate (4) with (thiophene-2-yl)acetimidate salt 6. Saponification of 7 and the subsequent condensation of the free acid 8 with the corresponding enantiopure β-amino acid methyl ester generated methyl (S)-5-methyl-3-{1-(pentan-3-yl)-2-(thiophen-2-ylmethyl)-1H-benzo[d]imidazole-5-carboxamido}hexanoate (9). Hydrolysis of the latter with KOH in THF/water, followed by HPLC-purification, afforded the desired product, CMF-019 (potassium salt) 10. Results & Conclusion: The approach reported herein enables preparation of 10 at a total yield of 12% over seven linear steps. Additionally, it does not require applying expensive designated microwave reactors and high-pressure hydrogenators. Thus, the elaborate synthesis provides a latent availability of potent agonist 10 for further exploring the physiologically essential apelin-APJ system.

Original languageEnglish
Pages (from-to)688-694
Number of pages7
JournalMedicinal Chemistry
Volume14
Issue number7
DOIs
StatePublished - 2018

Bibliographical note

Publisher Copyright:
© 2018 Bentham Science Publishers.

Funding

We thank Gila Levy for her assistance with the polarimetric measurements and Steve Manch for English editing. This study was supported by a Bar-Ilan University new faculty grant (AG), by the Israel Ministry of Immigration and Integration through Kamea fellowship (EEK), and by EY024864 and EY027283 grants (KP).

FundersFunder number
Israel Ministry of Immigration and IntegrationEY027283, EY024864
National Eye InstituteR24EY027283
Bar-Ilan University

    Keywords

    • Apelin
    • Apelin receptor
    • Benzimidazole scaffold
    • CMF-019
    • Expedient synthesis
    • Peptidomimetics

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