Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 58, Issue 5, Pages 2465-2488Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jm501940y
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Funding
- Foundation for Applied Medical Research
- University of Navarra (Pamplona, Spain)
- Ministerio de Economia y Competitividad [FIS PI12/00710]
- FSE (Inncorpora-Torres Quevedo grant) [PTQ-11-04781, PTQ-12-05641]
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Growing evidence suggests that matrix metalloproteinases (MMP) are involved in thrombus dissolution; then, considering that new therapeutic strategies are required for controlling hemorrhage, we hypothesized that MMP inhibition may reduce bleeding by delaying fibrinolysis. Thus, we designed and synthesized a novel series of MMP inhibitors to identify potential candidates for acute treatment of bleeding. Structure-based and knowledge-based strategies were utilized to design this novel chemical series, alpha-spiropiperidine hydroxamates, of potent and soluble (>75 mu g/mL) pan-MMP inhibitors. The initial hit, 12, was progressed to an optimal lead 19d. Racemic 19d showed a remarkable in vitro phenotypic response and outstanding in vivo efficacy; in fact, the mouse bleeding time at 1 mg/kg was 0.85 min compared to 29.28 min using saline. In addition, 19d displayed an optimal ADME and safety profile (e.g., no thrombus formation). Its corresponding enantiomers were separated, leading to the preclinical candidate 5 (described in Drug Annotations series, J. Med. Chem. 2015,).
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