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.
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, IC(50)=26 nM) demonstrated significant reduction of infarct volume in the rat model of permanent focal cerebral ischemia.
Ferraris
Dana
D
Guilford Pharmaceuticals Inc., 6611 Tributary Street, Baltimore, MD 21224, USA. ferrarisd@guilfordpharm.com
Ficco
Rica Pargas
RP
Dain
David
D
Ginski
Mark
M
Lautar
Susan
S
Lee-Wisdom
Kathy
K
Liang
Shi
S
Lin
Qian
Q
Lu
May X-C
MX
Morgan
Lisa
L
Thomas
Bert
B
Williams
Lawrence R
LR
Zhang
Jie
J
Zhou
Yinong
Y
Kalish
Vincent J
VJ
D000818:Animals; D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000737:chemistry; D001569:Benzodiazepines / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use*; D001665:Binding Sites; D002545:Brain Ischemia / Q000188:drug therapy*; D018938:Caco-2 Cells; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use*; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D051381:Rats; D013329:Structure-Activity Relationship
D001562:Benzimidazoles; D004791:Enzyme Inhibitors; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D001569:Benzodiazepines