2. Academic Validation
  3. Several non-salt and solid thienopyridine derivatives as oral P2Y12 receptor inhibitors with good stability

Several non-salt and solid thienopyridine derivatives as oral P2Y12 receptor inhibitors with good stability

  • Bioorg Med Chem Lett. 2022 Nov 1:75:128969. doi: 10.1016/j.bmcl.2022.128969.
Lei Liu 1,  Lingjun Li 1,  Jing Yuan 1,  Wei Liu 1,  Yuquan Li 1,  Shijun Zhang 1,  Changjiang Huang 2
Affiliations

Affiliations

  • 1 Tianjin Key Laboratory of Molecular Design and Drug Discovery, Tianjin Institute of Pharmaceutical Research, 306 Huiren Road, Tianjin 300301, PR China; State Key Laboratory of Drug Delivery Technology and Pharmacokinetics, Tianjin Institute of Pharmaceutical Research, 306 Huiren Road, Tianjin 300301, PR China.
  • 2 Tianjin Key Laboratory of Molecular Design and Drug Discovery, Tianjin Institute of Pharmaceutical Research, 306 Huiren Road, Tianjin 300301, PR China; State Key Laboratory of Drug Delivery Technology and Pharmacokinetics, Tianjin Institute of Pharmaceutical Research, 306 Huiren Road, Tianjin 300301, PR China. Electronic address: huangcj@tipr.com.cn.
PMID: 36058469 DOI: 10.1016/j.bmcl.2022.128969
Abstract

A series of novel thienopyridine derivatives were designed and synthesized as P2Y12 receptor inhibitors. Several solid compounds were assessed for inhibitory effect where they exhibited stronger potency than clopidogrel. Compound 6b and 6g were evaluated for metabolism to verify that they could overcome clopidogrel resistance and for toxicity where they showed lower toxicity than prasugrel. Compound 6b exhibited lower risk of bleeding than prasugrel and showed good stability under stress testing. Overall, as a promising antiplatelet agent, representative compound 6b showed the following advantages: (1) no drug resistance for CYP2C19 poor metabolizers; (2) higher potency than clopidogrel; (3) lower toxicity than prasugrel; (4) lower risk of bleeding than prasugrel; (5) good stability as a non-salt solid.

Keywords

Clopidogrel resistance; Hygroscopicity; P2Y(12) receptor inhibitors; Prodrug design; Stability; Thienopyridine derivatives.

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