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
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.
Subject(s)
Aza Compounds/chemical synthesis , Brain Ischemia/drug therapy , Enzyme Inhibitors/chemical synthesis , Myocardial Ischemia/drug therapy , Naphthyridines/chemical synthesis , Phenanthridines/chemical synthesis , Piperazines/chemical synthesis , Piperidines/chemical synthesis , Poly(ADP-ribose) Polymerase Inhibitors , Animals , Aza Compounds/chemistry , Aza Compounds/pharmacology , Dogs , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Haplorhini , Humans , In Vitro Techniques , Injections, Intravenous , Male , Microsomes, Liver/metabolism , Naphthyridines/chemistry , Naphthyridines/pharmacology , Phenanthridines/chemistry , Phenanthridines/pharmacology , Piperazines/chemistry , Piperazines/pharmacology , Piperidines/chemistry , Piperidines/pharmacology , Rats , Rats, Sprague-Dawley , Rats, Wistar , Solubility , Structure-Activity Relationship , Tissue Distribution , WaterABSTRACT
Effects of pocket gopher (Geomys attwateri) mound-building activity on plant community composition and soil nutrient concentrations were investigated in south Texas on both burned and unburned coastal prairie sites. Pocket gophers deposited large amounts of soil which were lower in nutrient content than randomly-collected samples. Above-ground plant biomass was greater around mounds than in random samples mainly because of increased dicots around mounds on the burned area when compared with random samples on the same area. Pocket gophers may have concentrated their activities (and therefore, mounds) in areas with higher dicot biomass on the burned area since they prefer perennial dicots as food, or the presence of mounds may have ameliorated the apparent negative effect of fire on dicots.
