Design, Synthesis, and Biological Evaluation of Novel Matrix Metalloproteinase Inhibitors As Potent Antihemorrhagic Agents: From Hit Identification to an Optimized Lead

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 synt...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2015-03, Vol.58 (5), p.2465-2488
Main Authors: Orbe, Josune, Sánchez-Arias, Juan A, Rabal, Obdulia, Rodríguez, José A, Salicio, Agustina, Ugarte, Ana, Belzunce, Miriam, Xu, Musheng, Wu, Wei, Tan, Haizhong, Ma, Hongyu, Páramo, José A, Oyarzabal, Julen
Format: Article
Language:English
Subjects:
Animals
Benzamides - chemical synthesis
Benzamides - pharmacology
Cell Membrane Permeability - drug effects
Drug Design
Hemorrhage - drug therapy
Humans
Hydroxamic Acids - chemical synthesis
Hydroxamic Acids - chemistry
Hydroxamic Acids - pharmacology
Male
Matrix Metalloproteinase Inhibitors - chemistry
Matrix Metalloproteinase Inhibitors - pharmacology
Matrix Metalloproteinases - chemistry
Matrix Metalloproteinases - metabolism
Mice
Mice, Inbred C57BL
Models, Molecular
Molecular Structure
Structure-Activity Relationship
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Summary: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, α-spiropiperidine hydroxamates, of potent and soluble (>75 μg/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, 10.1021/jm501939z ).
ISSN:0022-2623
1520-4804
DOI:10.1021/jm501940y