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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

[ Vol. 14 , Issue. 7 ]

Author(s):

Lena Trifonov, Michal Afri, Krzysztof Palczewski, Edward E. Korshin* and Arie Gruzman*   Pages 688 - 694 ( 7 )

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)-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.

Keywords:

CMF-019, peptidomimetics, apelin, apelin receptor, expedient synthesis, benzimidazole scaffold.

Affiliation:

Department of Chemistry, Bar-Ilan University, Ramat-Gan, 5290002, Department of Chemistry, Bar-Ilan University, Ramat-Gan, 5290002, Department of Pharmacology, School of Medicine, Case Western Reserve University, Cleveland, OH, 44106-4965, Department of Chemistry, Bar-Ilan University, Ramat-Gan, 5290002, Department of Chemistry, Bar-Ilan University, Ramat-Gan, 5290002

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