ABSTRACT
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.
Subject(s)
Benzimidazoles/chemical synthesis , Benzodiazepines/chemical synthesis , Benzodiazepines/therapeutic use , Brain Ischemia/drug therapy , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/therapeutic use , Poly(ADP-ribose) Polymerase Inhibitors , Animals , Benzimidazoles/chemistry , Benzodiazepines/chemistry , Binding Sites , Caco-2 Cells , Diabetes Mellitus, Experimental/drug therapy , Drug Design , Enzyme Inhibitors/chemistry , Humans , Mice , Models, Molecular , Rats , Structure-Activity RelationshipABSTRACT
The 1,3,4,5-tetrahydro-benzo[c][1,6]- and [c][1,7]-napthyridin-6-ones are presented as a potent class of PARP-1 inhibitors. Derivatives of these partially saturated aza-5[H]-phenanthridin-6-ones were designed and synthesized with tertiary amines for salt formation, thus enhancing aqueous solubility, iv formulation and their potential use in acute ischemic injuries (i.e., myocardial ischemia and stroke). We found that partial saturation of the C-ring results in derivatives that are several times more potent than the aromatic C-ring derivatives. The general synthetic routes are presented herein as well as thorough in vitro potencies and SAR discussion for selected derivatives.
Subject(s)
Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Naphthyridines/chemical synthesis , Poly(ADP-ribose) Polymerase Inhibitors , Chemical Phenomena , Chemistry, Physical , Indicators and Reagents , Naphthyridines/pharmacology , Solubility , Structure-Activity RelationshipABSTRACT
A series of aza-5[H]-phenanthridin-6-ones were synthesized and evaluated as inhibitors of poly ADP-ribose polymerase-1 (PARP-1). Inhibitory potency of the unsubstituted aza-5[H]-phenanthridin-6-ones (i.e., benzonaphthyridones) was dependent on the position of the nitrogen atom within the core structure. The A ring nitrogen analogues (7-, 8-, and 10-aza-5[H]-phenanthridin-6-ones) were an order of magnitude less potent than C ring nitrogen analogues (1-, 2-, 3-, and 4-aza-5[H]-phenanthridin-6-ones). Preliminary stroke results from 1- and 2-aza-5[H]-phenanthridin-6-one prompted structure-activity relationships to be established for several 2- and 3-substituted 1-aza-5[H]-phenanthridin-6-ones. The 2-substituted 1-aza-5[H]-phenanthridin-6-ones were designed to improve the solubility and pharmacokinetic profiles for this series of PARP-1 inhibitors. Most importantly, three compounds from this series demonstrated statistically significant protective effects in rat models of stroke and heart ischemia.