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

被引:9
作者
Trifonov, Lena [1 ]
Afri, Michal [1 ]
Palczewski, Krzysztof [2 ]
Korshin, Edward E. [1 ]
Gruzman, Arie [1 ]
机构
[1] Bar Ilan Univ, Dept Chem, IL-5290002 Ramat Gan, Israel
[2] Case Western Reserve Univ, Sch Med, Dept Pharmacol, Cleveland, OH 44106 USA
关键词
CMF-019; peptidomimetics; apelin; apelin receptor; expedient synthesis; benzimidazole scaffold; SMALL MOLECULES; BENZIMIDAZOLE; PROTEIN; DERIVATIVES; INHIBITORS; NITRILES; ANALOGS; SYSTEM;
D O I
10.2174/1573406414666180412154952
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
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 beta-amino acid methyl ester generated methyl (S)-5-methyl-3-11-(pentan-3-yl)-2-(thiophen-2-ylmethyl)-1H-benzo[d]imidazole-5-carboxamidolhexanoate (9). Hydrolysis of the latter with KOH in THE/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.
引用
收藏
页码:688 / 694
页数:7
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