title: Design, synthesis, and biological evaluation of novel matrix metalloproteinase inhibitors as potent antihemorrhagic agents: from hit identification to an optimized lead.
abstract: 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, ).
authors: Atherosclerosis Research Laboratory, ‡Small Molecule Discovery Platform, Molecular Therapeutics Program, Center for Applied Medical Research (CIMA), University of Navarra , Avenida Pio XII 55, E-31008 Pamplona, Spain.
authors: Josune
authors: J
authors: Orbe
authors: Juan A
authors: JA
authors: Sánchez-Arias
authors: Obdulia
authors: O
authors: Rabal
authors: José A
authors: JA
authors: Rodríguez
authors: Agustina
authors: A
authors: Salicio
authors: Ana
authors: A
authors: Ugarte
authors: Miriam
authors: M
authors: Belzunce
authors: Musheng
authors: M
authors: Xu
authors: Wei
authors: W
authors: Wu
authors: Haizhong
authors: H
authors: Tan
authors: Hongyu
authors: H
authors: Ma
authors: José A
authors: JA
authors: Páramo
authors: Julen
authors: J
authors: Oyarzabal
mesh_terms: D000818:Animals; D001549:Benzamides / Q000138:chemical synthesis* / Q000494:pharmacology*; D002463:Cell Membrane Permeability / Q000187:drug effects; D015195:Drug Design; D006470:Hemorrhage / Q000188:drug therapy*; D006801:Humans; D006877:Hydroxamic Acids / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D008297:Male; D061965:Matrix Metalloproteinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D020782:Matrix Metalloproteinases / Q000737:chemistry* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D015394:Molecular Structure; D013329:Structure-Activity Relationship
chemical_list: C000598576:4-(4-((3-(hydroxycarbamoyl)-8-azaspiro(4.5)decan-3-yl)sulfonyl)phenoxy)-N-methylbenzamide; D001549:Benzamides; D006877:Hydroxamic Acids; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases