ABSTRACT
PURPOSE: Poly(ADP-ribose) polymerase-1 (PARP-1) is a nuclear enzyme involved in the detection and repair of DNA damage. Studies have shown that inhibition of PARP and Tankyrase (TNKS) has significant antitumor effect in several types of cancers including BRCA-negative breast cancers. METHODS: Identification of ZYTP1, a novel PARP inhibitor, through a battery of in vitro assays and in vivo studies. PARP and TNKS inhibitory activity of ZYTP1 was assessed in cell-free kinase assay. In vitro cell killing potency of ZYTP1 was tested in a panel of cell lines including BRCA-negative cells. ZYTP1 was also tested in xenograft models in combination with temozolomide (TMZ). The pharmacokinetic profile of ZYTP1 was determined in rodent and non-rodent preclinical species. Safety of ZYTP1 was assessed in Wistar rats and Beagle dogs upon repeated dosing. RESULTS: ZYTP1 inhibited PARP1, PARP2, Tankyrase-1 and Tankyrase-2 with IC50 of 5.4, 0.7, 133.3 and 289.8 nM, respectively, and additionally trapped PARP1 onto damaged DNA. It also potentiated MMS-mediated killing of different cancer cell lines. Compound demonstrated good Caco-2 cell permeability. The oral bioavailability of ZYTP1 in mice, rats and dogs ranged between 40 and 79% and demonstrated efficacy in colon cancer xenograft model at a dose of 1-10 mg/kg in combination with TMZ. In a 28-day repeat dosing, oral toxicity study in rats, it was found to show > 10× safety margin. CONCLUSIONS: ZYTP1 is a novel PARP inhibitor that showed potential for development as a treatment for various solid tumors.
Subject(s)
Breast Neoplasms/drug therapy , Colonic Neoplasms/drug therapy , Poly(ADP-ribose) Polymerase Inhibitors/pharmacology , Animals , Apoptosis/drug effects , Biological Availability , Cell Line, Tumor , Cell Proliferation/drug effects , DNA Damage/drug effects , Dogs , Drug Monitoring/methods , Humans , Mice , Poly(ADP-ribose) Polymerases/metabolism , Rats , Rats, Wistar , Tankyrases/antagonists & inhibitors , Treatment Outcome , Xenograft Model Antitumor AssaysABSTRACT
Cannabinoid 1 (CB1) receptor antagonists reduce body weight and improve insulin sensitivity. Preclinical data indicates that an acute dose of CB1 antagonist rimonabant causes an increase in blood glucose. A stable analog of glucagon-like peptide 1 (GLP-1), exendin-4 improves glucose-stimulated insulin secretion in pancreas, and reduces appetite through activation of GLP-1 receptors in the central nervous system and liver. We hypothesized that the insulin secretagogue effect of GLP-1 agonist exendin-4 may synergize with the insulin-sensitizing action of rimonabant. Intraperitoneal as well as intracerebroventricular administration of rimonabant increased serum glucose upon glucose challenge in overnight fasted, diet-induced obese C57 mice, with concomitant rise in serum glucagon levels. Exendin-4 reversed the acute hyperglycemia induced by rimonabant. The combination of exendin-4 and rimonabant showed an additive effect in the food intake, and sustained body weight reduction upon repeated dosing. The acute efficacy of both the compounds was additive for inducing nausea-like symptoms in conditioned aversion test in mice, whereas exendin-4 treatment antagonized the effect of rimonabant on forced swim test upon chronic dosing. Thus, the addition of exendin-4 to rimonabant produces greater reduction in food intake owing to increased aversion, but reduces the other central nervous system side effects of rimonabant. The hyperglucagonemia induced by rimonabant is partially responsible for enhancing the antiobesity effect of exendin-4.
Subject(s)
Anti-Obesity Agents/pharmacology , Glucagon-Like Peptide 1/agonists , Glucagon/metabolism , Obesity/drug therapy , Peptides/pharmacology , Piperidines/pharmacology , Pyrazoles/pharmacology , Receptor, Cannabinoid, CB1/antagonists & inhibitors , Venoms/pharmacology , Animals , Anti-Obesity Agents/therapeutic use , Blood Glucose/metabolism , Body Weight/drug effects , Diet, High-Fat , Drug Synergism , Eating/drug effects , Exenatide , Glucagon-Like Peptide 1/metabolism , Insulin Resistance , Male , Mice, Inbred C57BL , Mice, Obese , Obesity/metabolism , Obesity/physiopathology , Peptides/therapeutic use , Piperidines/therapeutic use , Pyrazoles/therapeutic use , Receptor, Cannabinoid, CB1/metabolism , Rimonabant , Venoms/therapeutic useABSTRACT
A few thienyl substituted pyrazole derivatives were synthesized to aid in the characterization of the cannabinoid receptor antagonist and also to serve as potentially useful antiobesity agent. Structural requirements for selective CB1 receptor antagonistic activity of 5-thienyl pyrazole derivatives included the structural similarity with potent, specific antagonist rimonabant 1. Compound 3 has been identified as a hair growth stimulator and an antiobesity agent in animal models.
Subject(s)
Chemistry, Pharmaceutical/methods , Hair/drug effects , Obesity/drug therapy , Piperidines/chemical synthesis , Pyrazoles/chemical synthesis , Receptor, Cannabinoid, CB1/antagonists & inhibitors , Animals , Benzoxazines/pharmacology , CHO Cells , Cricetinae , Cricetulus , Cyclic AMP/metabolism , Drug Design , Inhibitory Concentration 50 , Models, Chemical , Morpholines/pharmacology , Naphthalenes/pharmacology , Piperidines/pharmacology , Pyrazoles/pharmacology , RimonabantABSTRACT
Design, synthesis and conformational analysis of few imidazole and oxazole as bioisosters of 4S-(-)-3-(4-chlorophenyl)-N-methyl-N'-[(4-chlorophenyl)-sulfonyl]-4-phenyl-4,5-dihydro-1H-pyrazole-1-caboxamidine (SLV-319) 2 is reported. Computer assisted conformational analysis gave a direct clue for the loss of CB1 antagonistic activity of the ligands without a fine docking simulation for the homology model.
Subject(s)
Imidazoles/chemistry , Imidazoles/pharmacology , Models, Molecular , Oxazoles/chemistry , Oxazoles/pharmacology , Pyrazoles/chemistry , Pyrazoles/pharmacology , Receptor, Cannabinoid, CB1/antagonists & inhibitors , Sulfonamides/chemistry , Sulfonamides/pharmacology , Animals , Combinatorial Chemistry Techniques , Cricetinae , Cricetulus , Drug Design , Humans , Imidazoles/chemical synthesis , Molecular Structure , Oxazoles/chemical synthesis , Pyrazoles/chemical synthesis , Structure-Activity Relationship , Sulfonamides/chemical synthesisABSTRACT
Design and synthesis of novel piperazinylaryloxazolidinones possessing heteroaryl groups are described and their in vitro antibacterial activities have been evaluated by MIC assay. Compounds (S)-N-[3-{3-fluoro-4-[4-[3-(5-nitrofuran-2-yl)-acryloyl]-piperazin-1-yl]-phenyl}-2-oxo-oxazolidin-5-yl-methyl] acetamide (6o), (S)-N-[3-{3-fluoro-4-[4-[3-(5-nitrothien-2-yl)-acryloyl]-piperazin-1-yl]-phenyl}-2-oxo-oxazolidin-5-yl-methyl] acetamide (6p) and N-oxide of (S)-N-[3-{3-fluoro-4-[4-[3-(5-nitrofuran-2-yl)-acryloyl]-piperazin-1-yl]-phenyl}-2-oxo-oxazolidin-5-yl-methyl] acetamide (9) showed superior antibacterial activities than linezolid and also active against the linezolid resistant Staphylococcus aureus strains.
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/pharmacology , Oxazolidinones/chemical synthesis , Oxazolidinones/pharmacology , Staphylococcus aureus/drug effects , Acetamides/pharmacology , Anti-Bacterial Agents/chemistry , Drug Design , Linezolid , Microbial Sensitivity Tests , Molecular Structure , Oxazolidinones/chemistry , Structure-Activity RelationshipABSTRACT
A number of analogues of diaryl dihydropyrazole-3-carboxamides have been synthesized. Their activities were evaluated for appetite suppression and body weight reduction in animal models. Depending on the chemical modification of the selected dihydropyrazole scaffold, the lead compounds--the bisulfate salt of (+/-)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4,5-dihydro-1H-pyrazole-3-carboxylic acid morpholin-4-ylamide 26 and the bisulfate salt of (-)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4,5-dihydro-1H-pyrazole-3-carboxylic acid morpholin-4-ylamide 30--showed significant body weight reduction in vivo, which is attributed to their CB1 antagonistic activity and exhibited a favorable pharmacokinetic profile. The molecular modeling studies also showed interactions of two isomers of (+/-)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4,5-dihydro-1H-pyrazole-3-carboxylic acid morpholin-4-ylamide 9 with CB1 receptor in the homology model similar to those of N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-3-pyrazole-carboxamide (rimonabant) 1 and 4S-(-)-3-(4-chlorophenyl)-N-methyl-N'-[(4-chlorophenyl)-sulfonyl]-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamidine (SLV-319) 2.
Subject(s)
Amides/chemical synthesis , Anti-Obesity Agents/chemical synthesis , Pyrazoles/chemical synthesis , Amides/pharmacokinetics , Amides/pharmacology , Animals , Anti-Obesity Agents/pharmacokinetics , Anti-Obesity Agents/pharmacology , Appetite Depressants/chemical synthesis , Appetite Depressants/pharmacokinetics , Appetite Depressants/pharmacology , Body Weight/drug effects , Female , Models, Molecular , Morpholines/chemical synthesis , Morpholines/pharmacokinetics , Morpholines/pharmacology , Piperidines/chemistry , Pyrazoles/chemistry , Pyrazoles/pharmacokinetics , Pyrazoles/pharmacology , Rats , Rats, Zucker , Receptor, Cannabinoid, CB1/antagonists & inhibitors , Rimonabant , Stereoisomerism , Structure-Activity Relationship , Sulfonamides/chemistryABSTRACT
Design and synthesis of a few novel methylamino piperidinyl substituted oxazolidinones are reported. Their antibacterial activities have been evaluated in a MIC assay against broader panel of both susceptible and resistant Gram-positive strains. (S)-N-{3-[3-Fluoro-4-(methyl-{1-[3-(5-nitrofuran-2-yl)-acryloyl]-piperidin-4-yl}-amino)-phenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide 4i has shown comparable antibacterial activity to linezolid and eperezolid in the MIC assay, additionally compound 4i showed good antibacterial activity with an in vitro MIC value of 2-4 microg/mL against linezolid resistant Staphylococcus aureus (linezolid 16 microg/mL).
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/pharmacology , Oxazolidinones/chemical synthesis , Oxazolidinones/pharmacology , Piperidines/chemistry , Anti-Bacterial Agents/chemistry , Microbial Sensitivity Tests , Oxazolidinones/chemistryABSTRACT
Synthesis and antibacterial activity of a number of substituted 4,5,6,7-tetrahydro-thieno[3,2-c]pyridine quinolones is reported. The antibacterial activities were evaluated in standard in vitro MIC assay method. Some of the compounds showed in vitro (MIC) antibacterial activity comparable to those of Gatifloxacin, Ciprofloxacin, and Sparfloxacin.
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Chemistry, Pharmaceutical/methods , Pyridines/chemistry , Quinolones/chemistry , Quinolones/chemical synthesis , Anti-Bacterial Agents/pharmacology , Anti-Infective Agents/pharmacology , Ciprofloxacin/pharmacology , Drug Design , Drug Evaluation, Preclinical , Drug Resistance, Microbial , Fluoroquinolones/pharmacology , Gatifloxacin , Microbial Sensitivity Tests , Models, Chemical , Molecular ConformationABSTRACT
Three-dimensional QSAR studies for N-4-arylacryloylpiperazin-1-yl-phenyl-oxazolidinones were conducted using TSAR 3.3. The in vitro activities (MICs) of the compounds against Staphylococcus aureus ATCC 25923 exhibited a strong correlation with the prediction made by the model developed in the present study.
Subject(s)
Anti-Bacterial Agents/pharmacology , Oxazolidinones/chemistry , Oxazolidinones/pharmacology , Piperazines/chemistry , Piperazines/pharmacology , Staphylococcus aureus/drug effects , Anti-Bacterial Agents/chemistry , Microbial Sensitivity Tests , Quantitative Structure-Activity RelationshipABSTRACT
A few substituted piperazinylphenyloxazolidinone compounds 6-13 having substitution on the distant nitrogen atom of piperazine ring scaffold have been synthesized and evaluated for their antibacterial activity in Gram-positive bacteria. A few compounds showed superior in vitro antibacterial activity against Staphylococcus aureus, Staphylococcus epidermidis, Enterococcus faecalis, and Streptococcus pyogenes than linezolid and eperezolid.
Subject(s)
Anti-Bacterial Agents , Gram-Positive Bacteria/drug effects , Oxazolidinones , Piperazines/chemistry , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Enterococcus faecalis/drug effects , Enterococcus faecalis/growth & development , Gram-Positive Bacteria/growth & development , Microbial Sensitivity Tests , Oxazolidinones/chemical synthesis , Oxazolidinones/chemistry , Oxazolidinones/pharmacology , Piperazine , Staphylococcus aureus/drug effects , Staphylococcus aureus/growth & development , Staphylococcus epidermidis/drug effects , Staphylococcus epidermidis/growth & development , Streptococcus pyogenes/drug effects , Streptococcus pyogenes/growth & developmentABSTRACT
A few Mannich ketones of piperazinyl oxazolidinone derivatives have been synthesized and their antibacterial activity in various Gram-positive organisms such as Bacillus subtilis, Staphylococcus aureus, Staphylococcus epidermidis and Enterococcus faecalis were evaluated by MIC determination. Compound 12 showed comparable activity (MIC) to linezolid and superior to eperezolid.
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Ketones/chemical synthesis , Oxazolidinones/chemical synthesis , Piperazines/chemical synthesis , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Bacillus subtilis/drug effects , Enterococcus faecalis/drug effects , Ketones/chemistry , Ketones/pharmacology , Microbial Sensitivity Tests , Oxazolidinones/chemistry , Oxazolidinones/pharmacology , Piperazines/chemistry , Piperazines/pharmacology , Staphylococcus aureus/drug effects , Staphylococcus epidermidis/drug effectsABSTRACT
Synthesis of a number of 4,5,6,7-tetrahydro-thieno[3,2-c]pyridine substituted oxazolidinones have been reported. They have been screened against a panel of Gram-positive pathogens including methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus faecalis. A SAR has been developed. Compound 15 showed comparable activity (MIC) to linezolid and superior to eperezolid.
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Enterococcus faecalis/drug effects , Oxazoles/chemical synthesis , Pyridines/chemical synthesis , Staphylococcus aureus/drug effects , Acetamides/pharmacology , Anti-Bacterial Agents/pharmacology , Drug Resistance, Microbial , Linezolid , Methicillin/pharmacology , Microbial Sensitivity Tests , Oxazoles/pharmacology , Oxazolidinones/chemistry , Oxazolidinones/pharmacology , Pyridines/pharmacology , Structure-Activity Relationship , Vancomycin/pharmacologyABSTRACT
A number of substituted piperazinyl oxazolidinone derivatives have been synthesized and their antibacterial activities were evaluated by MIC determination. A systematic SAR was carried out to get highly potent oxazolidinone derivatives.