Design and synthesis of poly(ADP-ribose) polymerase-1 (PARP-1) inhibitors. Part 4: Biological evaluation of imidazobenzodiazepines as potent PARP-1 inhibitors for treatment of ischemic injuries

被引：56

作者：

Ferraris, D ^{[1
]}

Ficco, RP ^{[1
]}

Dain, D ^{[1
]}

Ginski, M ^{[1
]}

Lautar, S ^{[1
]}

Lee-Wisdom, K ^{[1
]}

Liang, S ^{[1
]}

Lin, Q ^{[1
]}

Lu, MXC ^{[1
]}

Morgan, L ^{[1
]}

Thomas, B ^{[1
]}

Williams, LR ^{[1
]}

Zhang, J ^{[1
]}

Zhou, YN ^{[1
]}

Kalish, VJ ^{[1
]}

机构：

[1] Guilford Pharmaceut Inc, Baltimore, MD 21224 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2003年 / 11卷 / 17期

关键词：

D O I：

10.1016/S0968-0896(03)00333-X

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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. (C) 2003 Elsevier Ltd. All rights reserved.

引用

页码：3695 / 3707

页数：13

共 42 条

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