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  • Flexible alignment of isopropylphenylaminobenzimidazole with


    Flexible alignment of 7-isopropylphenylaminobenzimidazole 16 with the lead ARCA Cy3 EGFP mRNA 1 was performed using MOE. It was found that the aryl group of compound 16, exemplified as a yellow circle in Figure 2, overlapped well with the corresponding alkyl chain of compound 1 as well as the other key functional groups including an HBA and a pendant aryl group exemplified as white circles. In addition, the aryl group of compound 16 might be able to accommodate three-dimensionally compared with the alkyl group of compound 1. That means that the aryl group would occupy unknown space and enhance potency. This superimposition study suggested that the newly designed compounds should exhibit potent inhibitory activity. The aryl amino series, having diverse size of substituents with electron-deficient or electron-donating characteristics, was targeted for SAR studies. In this study, another anilino group at the 2-position was fixed in 4-chloro or bromo-2-methoxy-6-methylanilines, because 7-dialkylamino-1H-benzimidazoles having these groups exhibited potent and comparable CRF1 receptor binding activity. We also investigated novel synthetic methods to prepare 2,7-diarylaminobenzimidazoles. In this report, the synthesis and the biological activities of a novel series of 7-arylamino-1H-benzimidazoles, as well as SAR study results are discussed.
    Results and discussion
    Conclusion In this study, a novel series of 7-arylamino-1H-benzimidazole was synthesized and evaluated as CRF1 receptor antagonists. The aromatic groups at the 7-N-position of the benzimidazole were introduced by palladium-catalyzed coupling reactions of 7-aminobenzimidazole 5 or 7-bromobenzimidazole 8 in the presence of bulky phosphine ligands, S-Phos or X-Phos. The synthetic route of the key intermediates, 2-chlorobenzimidazole 10, can be selected depending on the electron density of the benzimidazole core. These investigations successfully provided a novel synthetic method for preparing 2,7-diarylaminobenzimidazoles. The synthesized target compounds were evaluated in an in vitro CRF1 receptor-binding assay and the SAR study was examined. The results suggested that diverse substituents on the anilino group at the 7-position were tolerable for binding activity, and small alkyl groups at the 7-N-position were better than bulky groups. It was revealed that an aryl group at the 7-N-position of a benzimidazole core could replace an alkyl group and occupy the lipophilic pocket of the CRF1 receptor. The selected compound having potent human CRF1 receptor binding inhibition activity, 16g, also showed human CRF1 antagonistic activity in cAMP accumulation assay. Furthermore, this compound exhibited ex vivo CRF binding inhibitory activity in mice, suggesting that this compound can be well absorbed orally and easily penetrate the brain. It was found that the novel benzimidazole series with an aryl group as well as an alkyl group at the 7-N-position resulted in compounds exhibiting potent activity as CRF1 receptor antagonists.
    Acknowledgements The authors thank Dr. Takanobu Kuroita for helpful discussions during the preparation of the manuscript. The authors also thank Dr. Katsumi Kobayashi, Mr. Takuto Kojima and Mr. Yoshirou Tomimatsu for helpful discussions during the preparation of the research report. We also thank Mr. Kenichi Kuroshima and Mr. Yuji Shimizu for performing the in vitro CRF1 binding assays and human CRF-stimulated cAMP accumulation assays. The authors extend our gratitude to Dr. Steve Boyd, Dr. Christopher Siedem, Dr. Suk Young Cho, Mr. Scott Pratt, Dr. Tim Turner, and Dr. Kevin Condroski for their valuable discussions on structural modification.
    Introduction The dorsal periaqueductal gray matter (dPAG) is a midbrain site markedly involved in fear/anxiety-evoked responses as well as in nociception (see, for example, Bandler and Carrive, 1988, Deakin and Graeff, 1991, Fardin et al., 1984a, Fardin et al., 1984b, Litvin et al., 2007). Chemical or electrical stimulation of dPAG elicits defensive behavior such as freezing, flight and fight reaction, escalation of risk assessment behavior and arousal (e.g., Bandler and Carrive, 1988, Schenberg et al., 2005) and autonomic activation (e.g., tachycardia, hypertension, tachypnea — Bandler et al., 1991, Hayward et al., 2003, McDougall et al., 1985). These responses are generally accompanied by antinociception (e.g., Coimbra and Brandão, 1997, Fanselow, 1991).