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 language | English |
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Pages (from-to) | 688-694 |
Number of pages | 7 |
Journal | Medicinal Chemistry |
Volume | 14 |
Issue number | 7 |
DOIs | |
State | Published - 2018 |
Bibliographical note
Funding Information: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).
Publisher Copyright:
© 2018 Bentham Science Publishers.
Keywords
- Apelin
- Apelin receptor
- Benzimidazole scaffold
- CMF-019
- Expedient synthesis
- Peptidomimetics