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

  • J Med Chem. 2024 Jul 5. doi: 10.1021/acs.jmedchem.4c00626.
Peng Wang  1 ,  Huajian Zhu  1 ,  Jia-Sheng Tian  2 ,  Wenjian Zhu  1 ,  Shengtao Xu  1 ,  Hong Yao  1 ,  Jie Liu  1 ,  Zheying Zhu  3 ,  Chao-Yu Miao  2 ,  Jinyi Xu  1
Affiliations
  • 1. State Key Laboratory of Natural Medicines and Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, China.
  • 2. Department of Pharmacology, Second Military Medical University/Naval Medical University, Shanghai 200433, China.
  • 3. Division of Molecular Therapeutics & Formulation, School of Pharmacy, The University of Nottingham, Nottingham NG7 2RD, U.K.
PMID: 38968440 DOI: 10.1021/acs.jmedchem.4c00626
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.

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