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).