TY - JOUR
T1 - Design and synthesis of poly(ADP-ribose) polymerase-1 (PARP-1) inhibitors. Part 4
T2 - Biological evaluation of imidazobenzodiazepines as potent PARP-1 inhibitors for treatment of ischemic injuries
AU - Ferraris, Dana
AU - Ficco, Rica Pargas
AU - Dain, David
AU - Ginski, Mark
AU - Lautar, Susan
AU - Lee-Wisdom, Kathy
AU - Liang, Shi
AU - Lin, Qian
AU - Lu, May X C
AU - Morgan, Lisa
AU - Thomas, Bert
AU - Williams, Lawrence R.
AU - Zhang, Jie
AU - Zhou, Yinong
AU - Kalish, Vincent J.
PY - 2003/8/15
Y1 - 2003/8/15
N2 - A class of poly(ADP-ribose) polymerase (PARP-1) inhibitors, the imidazobenzodiazepines, are presented in this text. Several derivatives were designed and synthesized with ionizable groups (i.e., tertiary amines) in order to promote the desired pharmaceutical characteristics for administration in ischemic injury. Within this series, several compounds have excellent in vitro potency and our computational models accurately justify the structure-activity relationships (SARs) and highlight essential hydrogen bonding residues and hydrophobic pockets within the catalytic domain of PARP-1. Administration of these compounds (5q, 17a and 17e) in the mouse model of streptozotocin-induced diabetes results in maintainance of glucose levels. Furthermore, one such inhibitor (5g, IC50=26 nM) demonstrated significant reduction of infarct volume in the rat model of permanent focal cerebral ischemia.
AB - A class of poly(ADP-ribose) polymerase (PARP-1) inhibitors, the imidazobenzodiazepines, are presented in this text. Several derivatives were designed and synthesized with ionizable groups (i.e., tertiary amines) in order to promote the desired pharmaceutical characteristics for administration in ischemic injury. Within this series, several compounds have excellent in vitro potency and our computational models accurately justify the structure-activity relationships (SARs) and highlight essential hydrogen bonding residues and hydrophobic pockets within the catalytic domain of PARP-1. Administration of these compounds (5q, 17a and 17e) in the mouse model of streptozotocin-induced diabetes results in maintainance of glucose levels. Furthermore, one such inhibitor (5g, IC50=26 nM) demonstrated significant reduction of infarct volume in the rat model of permanent focal cerebral ischemia.
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U2 - 10.1016/S0968-0896(03)00333-X
DO - 10.1016/S0968-0896(03)00333-X
M3 - Article
C2 - 12901915
AN - SCOPUS:12444286415
SN - 0968-0896
VL - 11
SP - 3695
EP - 3707
JO - Bioorganic and Medicinal Chemistry
JF - Bioorganic and Medicinal Chemistry
IS - 17
ER -