Medicinal Chemistry ( IF 1.9 ) Pub Date : 2018-10-31 , DOI: 10.2174/1573406414666180412154952 Lena Trifonov 1 , Michal Afri 1 , Krzysztof Palczewski 2 , Edward E. Korshin 1 , Arie Gruzman 1
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.
中文翻译:
CMF-019的简便合成方法:(S)-5-甲基-3- {1-(戊-3-基)-2-(噻吩-2-基甲基)-1H-苯并[d]咪唑-5-甲酰胺基}己酸,有效的Apelin受体(APJ)激动剂
背景:Apelin受体(APJ)是由内源性肽Apelin激活的G蛋白偶联受体(GPCR)。apelin-APJ系统已成为心血管稳态的重要调节剂。最近,一种强效的苯并咪唑衍生的阿珀林肽模拟物CMF-019获得了专利,但没有对其合成方法和中间体的完整光谱表征进行全面描述。
目的:在此,将描述通过改良和改进的合成途径的CMF-019的详细制备方法。
方法:特别地,7-中的苯并咪唑环是通过将3-氨基-4-(戊-3-基氨基)苯甲酸甲酯(4)与(噻吩-2-基)乙酰基亚氨酸盐6缩合而制得的。随后将游离酸8与相应的对映纯β-氨基酸甲酯缩合,生成甲基(S)-5-甲基-3- {1-(戊基-3-基)-2-(噻吩-2-基甲基) -1H苯并[d]咪唑-5-甲酰胺}己酸酯(9)。后者用KOH在THF /水中的水解,然后HPLC纯化,得到所需的产物CMF-019(钾盐)10。
结果与结论:本文报道的方法可在七个线性步骤中以10%的总产率制备10种化合物。另外,它不需要应用昂贵的指定微波反应器和高压氢化器。因此,精细的合成为进一步探索生理必需的apelin-APJ系统提供了有效的激动剂10的潜在可用性。