ABSTRACT
Herein we report the discovery of a novel series of vasopressin 1b (V1b) receptor antagonists, starting from potent but metabolically labile oxindole SSR149415. Masking the proline N,N-dimethyl amide moiety as an oxazole and attaching a benzylic amine moiety to the northern phenyl ring resulted in potent and selective V1b receptor antagonists with improved metabolic stability and improved pharmacokinetic properties in rat. Compound 18c was found to be efficacious in a rat model of anti-depressant activity.
Subject(s)
Antidepressive Agents/chemical synthesis , Antidepressive Agents/pharmacokinetics , Antidiuretic Hormone Receptor Antagonists , Indoles/chemical synthesis , Indoles/pharmacokinetics , Animals , Antidepressive Agents/chemistry , Antidepressive Agents/pharmacology , Disease Models, Animal , Indoles/chemistry , Indoles/pharmacology , Molecular Structure , Oxindoles , Protein Binding/drug effects , RatsABSTRACT
We have developed a series of cyclic amine-containing benzimidazole carboxamide poly(ADP-ribose)polymerase (PARP) inhibitors, with good PARP-1 enzyme potency, as well as cellular potency. These efforts led to the identification of a lead preclinical candidate, 10b, 2-(1-propylpiperidin-4-yl)-1H-benzimidazole-4-carboxamide (A-620223). 10b displayed very good potency against both the PARP-1 enzyme with a K(i) of 8nM and in a whole cell assay with an EC(50) of 3nM. 10b is aqueous soluble, orally bioavailable across multiple species, and demonstrated good in vivo efficacy in a B16F10 subcutaneous murine melanoma model in combination with temozolomide (TMZ) and in an MX-1 breast xenograph model in combination with cisplatin.
Subject(s)
Benzimidazoles/chemistry , Benzimidazoles/pharmacology , Breast Neoplasms/drug therapy , Melanoma, Experimental/drug therapy , Poly(ADP-ribose) Polymerase Inhibitors , Animals , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Cisplatin/therapeutic use , Dacarbazine/analogs & derivatives , Dacarbazine/therapeutic use , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Humans , Mice , Structure-Activity Relationship , Temozolomide , Transplantation, Heterologous , Xenograft Model Antitumor AssaysABSTRACT
The synthesis and SAR of novel and selective dopamine D(3)-receptor antagonists based on a 3,4-dihydro-1H-quinolin-2-one, a 1,3,4,5-tetrahydro-benzo[b]azepin-2-one, 1H-quinoline-2,4-dione or a 3,4-dihydro-1H-benzo[b]azepine-2,5-dione scaffold are discussed. A706149 (2.15mg/kg, po) antagonizes PD 128907-induced huddling deficits in rat, a social interaction paradigm.
Subject(s)
Benzazepines/chemical synthesis , Dopamine Antagonists/chemical synthesis , Quinolones/chemical synthesis , Receptors, Dopamine D3/antagonists & inhibitors , Animals , Benzazepines/pharmacology , Dopamine Antagonists/pharmacology , Models, Molecular , Molecular Structure , Quinolones/pharmacology , Rats , Structure-Activity RelationshipABSTRACT
Two novel calpain inhibitors (A-705239 and A-705253) were studied in isolated perfused rabbit hearts subjected to 60-min occlusion of the ramus interventricularis of the left coronary artery (below the origin of the first diagonal branch), followed by 120 min of reperfusion. The inhibitors were added to the perfusion fluid in various final concentrations from the beginning of the experiments before the coronary artery was blocked. Hemodynamic monitoring and biochemical analysis of perfusion fluid from the coronary outflow were carried out. Myocardial infarct size and the area at risk (transiently non-perfused myocardium) were determined from left ventricular slices after a special staining procedure with Evans blue and 2,3,5-triphenyltetrazolium chloride. The infarcted area (dead myocardium) was 77.9+/-2.3% of the area at risk in untreated controls ( n =12). The infarct size was significantly reduced in the presence of both calpain inhibitors. The best effect was achieved with 10 -8 M A-705253 ( n =8), which reduced ( p <0.001) the infarcted area to 49.3+/-3.9% of the area at risk, corresponding to an infarct reduction of 61.8%. No statistical difference was observed between the experimental groups in coronary perfusion, left ventricular pressure, and in the release of lactate dehydrogenase and creatine kinase from heart muscle.
Subject(s)
Benzamides/pharmacology , Calpain/antagonists & inhibitors , Enzyme Inhibitors/pharmacology , Heart/drug effects , Myocardial Infarction/prevention & control , Animals , Female , In Vitro Techniques , Male , Potassium/metabolism , RabbitsABSTRACT
Novel benzoylalanine-derived ketoamides were prepared and evaluated for calpain I inhibition. Derivatives carrying vinylbenzyl amino residues in the P(2)-P(3) region inhibited calpain in nanomolar concentrations and thus represent a novel class of nonpeptidic calpain inhibitors. Selected examples exhibited an improved pharmacokinetic profile including improved water-solubility and metabolic stability. In particular, these calpain inhibitors showed oral bioavailability in rats as demonstrated by N-(1-benzyl-2-carbamoyl-2-oxoethyl)-2-[E-2-(4-diethylaminomethylphenyl)ethen-1-yl]benzamide (5d). The closely related derivative N-(1-carbamoyl-1-oxohex-1-yl)-2-[E-2-(4-dimethylaminomethylphenyl)-ethen-1-yl]benzamide (5b) was evaluated for neuroprotective efficacy after experimental traumatic brain injury in a fluid percussion model in rats. When administered after injury, 5b reduced the number of damaged neurons by 41%, and this result would be in line with the suggested neuroprotective efficacy of calpain inhibition.
Subject(s)
Alanine/analogs & derivatives , Alanine/chemical synthesis , Benzene Derivatives/chemical synthesis , Calpain/antagonists & inhibitors , Cysteine Proteinase Inhibitors/chemical synthesis , Neuroprotective Agents/chemical synthesis , Vinyl Compounds/chemical synthesis , Administration, Oral , Alanine/pharmacokinetics , Alanine/pharmacology , Animals , Benzene Derivatives/pharmacokinetics , Benzene Derivatives/pharmacology , Biological Availability , Blood Platelets/drug effects , Blood Platelets/metabolism , Brain Injuries/drug therapy , Brain Injuries/pathology , Cell Survival/drug effects , Cysteine Proteinase Inhibitors/pharmacokinetics , Cysteine Proteinase Inhibitors/pharmacology , Dentate Gyrus/drug effects , Dentate Gyrus/pathology , Humans , In Vitro Techniques , Male , Neuroprotective Agents/pharmacokinetics , Neuroprotective Agents/pharmacology , Proto-Oncogene Proteins pp60(c-src)/metabolism , Rats , Rats, Sprague-Dawley , Solubility , Stereoisomerism , Structure-Activity Relationship , Vinyl Compounds/pharmacokinetics , Vinyl Compounds/pharmacology , WaterABSTRACT
The effects of the novel calpain inhibitor A-705239 were studied in isolated perfused rabbit hearts subjected to 45 min of global ischemia, followed by 60 min of reperfusion. During 15 min of perfusion the inhibitor accumulated in myocardial tissue up to 16 times the concentration in the perfusate. Almost complete recovery and survival of heart function (90%) was seen with an inhibitor concentration of 10(-8) M in the perfusion fluid when the compound was administered prior to ischemia. Left ventricular pressure amplitude and coronary flow showed significantly higher values during reperfusion in the presence of the inhibitor. A-705239 significantly reduced the release of creatine kinase, from 166+/-49 U/l in untreated hearts to 44+/-10 U/l, and diminished the release of lactate dehydrogenase from 118+/-20 U/l in untreated hearts to 63+/-4 U/l. Mitochondrial dysfunction following ischemia and reperfusion was markedly attenuated by the inhibitor. Thus, the state 3 respiration rate only decreased to 4.2 in contrast to 2.6 nmol O2/(min x mg s.w.) in untreated hearts, reflecting a reduced damage of oxidative phosphorylation. Furthermore, in the presence of the inhibitor the inner mitochondrial membranes became less permeable as indicated by a smaller leak respiration. The excellent properties of A-705239 should make this compound a valuable tool for further pharmacological studies.
