jm501940y_si_001.pdf (1.96 MB)
Design, Synthesis, and Biological Evaluation of Novel Matrix Metalloproteinase Inhibitors As Potent Antihemorrhagic Agents: From Hit Identification to an Optimized Lead
journal contribution
posted on 2015-03-12, 00:00 authored 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 OyarzabalGrowing
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
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