Discovery of MT-1207: A Novel, Potent Multitarget Inhibitor as a Promising Clinical Candidate for the Treatment of Hypertension

Wang, Peng; Zhu, Huajian; Tian, Jia-Sheng; Zhu, Wenjian; Xu, Shengtao; Yao, Hong; Liu, Jie; Zhu, Zheying; Miao, Chao-Yu; Xu, Jinyi

Abstract

Herein, a series of novel arylpiperazine (piperidine) derivatives were designed, synthesized, and evaluated for mechanisms of action through in vitro and in vivo studies. The most promising compound, II-13 (later named as MT-1207), is a potent α1 and 5-HT2A receptor antagonist with remarkable IC50 in the picomolar level. Importantly, in the in vivo assay, II-13 achieved an effective blood pressure (BP) reduction in the 2K2C rat model without damaging renal function. Compound II-13, with its significant advantages in terms of pharmacological effects, pharmacokinetic parameters, and a large safety window, was extensively investigated. Moreover, data also showed that compound II-13 had fewer side effects in a postural BP assay and could prevent the onset of postural hypotension. Together, these results suggested that compound II-13 is a highly potent antihypertensive drug candidate with multitarget mechanisms of action in preclinical models. Currently, MT-1207 is in phase II hypertensive clinical trials in China.

Citation

Wang, P., Zhu, H., Tian, J.-S., Zhu, W., Xu, S., Yao, H., Liu, J., Zhu, Z., Miao, C.-Y., & Xu, J. (2024). Discovery of MT-1207: A Novel, Potent Multitarget Inhibitor as a Promising Clinical Candidate for the Treatment of Hypertension. Journal of Medicinal Chemistry, 67(18), 16128-16144. https://doi.org/10.1021/acs.jmedchem.4c00626

• Journal Article Type: Article
• Acceptance Date: Jun 25, 2024
• Online Publication Date: Jul 5, 2024
• Publication Date: Sep 26, 2024
• Deposit Date: Jul 13, 2024
• Publicly Available Date: Jul 6, 2025
• Journal: Journal of Medicinal Chemistry
• Print ISSN: 0022-2623
• Electronic ISSN: 1520-4804
• Publisher: American Chemical Society
• Peer Reviewed: Peer Reviewed
• Volume: 67
• Issue: 18
• Pages: 16128-16144
• DOI: https://doi.org/10.1021/acs.jmedchem.4c00626
• Public URL: https://nottingham-repository.worktribe.com/output/37283463
• Publisher URL: https://pubs.acs.org/doi/10.1021/acs.jmedchem.4c00626