Title: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
VOLUME: 14 ISSUE: 7
Author(s):Lena Trifonov, Michal Afri, Krzysztof Palczewski, Edward E. Korshin* and Arie Gruzman*
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
Keywords:CMF-019, peptidomimetics, apelin, apelin receptor, expedient synthesis, benzimidazole scaffold.
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.