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
| Autor: | Krzysztof Palczewski, Edward E. Korshin, Arie Gruzman, Michal Afri, Lena Trifonov |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Agonist Hexanoic acid Apelin Receptors Benzimidazole Molecular Structure medicine.drug_class Stereochemistry Peptidomimetic Article Apelin 03 medical and health sciences chemistry.chemical_compound 030104 developmental biology Enantiopure drug chemistry Drug Discovery medicine Imidazole Benzimidazoles Amino Acids Branched-Chain Apelin receptor |
| Zdroj: | Medicinal Chemistry. 14:688-694 |
| ISSN: | 1573-4064 |
| DOI: | 10.2174/1573406414666180412154952 |
| Popis: | 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)-1Hbenzo[ 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. |
| Databáze: | OpenAIRE |
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