10.1021/jm501940y.s001 Josune Orbe Josune Orbe Juan A. Sánchez-Arias Juan A. Sánchez-Arias Obdulia Rabal Obdulia Rabal José A. Rodríguez José A. Rodríguez Agustina Salicio Agustina Salicio Ana Ugarte Ana Ugarte Miriam Belzunce Miriam Belzunce Musheng Xu Musheng Xu Wei Wu Wei Wu Haizhong Tan Haizhong Tan Hongyu Ma Hongyu Ma José A. Páramo José A. Páramo Julen Oyarzabal Julen Oyarzabal Design, Synthesis, and Biological Evaluation of Novel Matrix Metalloproteinase Inhibitors As Potent Antihemorrhagic Agents: From Hit Identification to an Optimized Lead American Chemical Society 2015 thrombus dissolution MMP inhibition Biological Evaluation ADME phenotypic response Racemic 19 Drug Annotations series Novel Matrix Metalloproteinase Inhibitors 0.85 min candidate 5 novel chemical series safety profile vivo efficacy Optimized LeadGrowing evidence novel series Potent Antihemorrhagic Agents strategy 29.28 min thrombus formation MMP inhibitors matrix metalloproteinases 2015-03-12 00:00:00 Journal contribution https://acs.figshare.com/articles/journal_contribution/Design_Synthesis_and_Biological_Evaluation_of_Novel_Matrix_Metalloproteinase_Inhibitors_As_Potent_Antihemorrhagic_Agents_From_Hit_Identification_to_an_Optimized_Lead/2186701 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, <b>12</b>, was progressed to an optimal lead <b>19d</b>. Racemic <b>19d</b> 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, <b>19d</b> displayed an optimal ADME and safety profile (e.g., no thrombus formation). Its corresponding enantiomers were separated, leading to the preclinical candidate <b>5</b> (described in Drug Annotations series, J. Med. Chem. 2015, 10.1021/jm501939z).