Design, Synthesis, and Biological Evaluation of Novel Matrix Metalloproteinase Inhibitors As Potent Antihemorrhagic Agents: From Hit Identification to an Optimized Lead
journal contributionposted on 12.03.2015, 00:00 by Josune Orbe, Juan A. Sánchez-Arias, Obdulia Rabal, José A. Rodríguez, Agustina Salicio, Ana Ugarte, Miriam Belzunce, Musheng Xu, Wei Wu, Haizhong Tan, Hongyu Ma, José A. Páramo, Julen Oyarzabal
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).
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thrombus dissolutionMMP inhibitionBiological EvaluationADMEphenotypic responseRacemic 19Drug Annotations seriesNovel Matrix Metalloproteinase Inhibitors0.85 mincandidate 5novel chemical seriessafety profilevivo efficacyOptimized LeadGrowing evidencenovel seriesPotent Antihemorrhagic Agentsstrategy29.28 minthrombus formationMMP inhibitorsmatrix metalloproteinases