ABSTRACT
The genome of pancreatic ductal adenocarcinoma (PDAC) is associated with frequent deletion of the tumor suppressor gene SMAD family member 4 (SMAD4) with collateral deletion of its chromosomal neighbor malic enzyme 2 (ME2). In SMAD4 -/- /ME2 -/- PDAC cells, ME3 takes over the function of the ME2 enzyme, and hence therapeutic targeting of ME3 is expected to arrest tumor growth. Hitherto no selective small molecule inhibitor of ME3 has been reported in the context of PDAC. Based on the molecular docking studies and structure-activity relationships with the reported ME1 inhibitor, several analogues of 6-piperazin-1-ylpyridin-3-ol amides have been synthesized and screened for their ME inhibition activity. Among them, compound 16b is identified as the most potent and selective ME3 inhibitor with an IC50 of 0.15 µM on ME3, and with 15- and 9-fold selectivity over ME1 and ME2, respectively. In the cell viability assay, compound 16b exhibited an IC50 of 3.5 µM on ME2-null PDAC cells, viz., BxPC-3.
ABSTRACT
TGR5 is a G protein-coupled receptor (GPCR), activation of which promotes secretion of glucagon-like peptide-1 (GLP-1) and modulates insulin secretion. The 2-thio-imidazole derivative 6g was identified as a novel, potent, and selective TGR5 agonist (hTGR5 EC50 = 57 pM, mTGR5 = 62 pM) with a favorable pharmacokinetic profile. The compound 6g was found to have potent glucose lowering effects in vivo during an oral glucose tolerance test in DIO C57 mice with ED50 of 7.9 mg/kg and ED90 of 29.2 mg/kg.
ABSTRACT
A series of novel aminomethyl-piperidones were designed and evaluated as potential DPP-IV inhibitors. Optimized analogue 12v ((4S,5S)-5-(aminomethyl)-1-(2-(benzo[d][1,3]dioxol-5-yl)ethyl)-4-(2,5-difluorophenyl)piperidin-2-one) showed excellent in vitro potency and selectivity for DPP-IV over other serine proteases. The lead compound 12v showed potent and long acting antihyperglycemic effects (in vivo), along with improved pharmacokinetic profile.
Subject(s)
Drug Design , Enzyme Activation/drug effects , Piperidones/chemical synthesis , Piperidones/pharmacology , Animals , Catalytic Domain , Dipeptidyl-Peptidase IV Inhibitors/chemical synthesis , Dipeptidyl-Peptidase IV Inhibitors/chemistry , Dipeptidyl-Peptidase IV Inhibitors/pharmacology , Hypoglycemic Agents/chemical synthesis , Hypoglycemic Agents/chemistry , Hypoglycemic Agents/pharmacology , Inhibitory Concentration 50 , Male , Mice , Mice, Inbred C57BL , Models, Molecular , Molecular Structure , Piperidones/chemistry , Pyrazines/chemistry , Pyrazines/pharmacology , Sitagliptin Phosphate , Triazoles/chemistry , Triazoles/pharmacologyABSTRACT
A series of peptidomimetic containing bidentate pTyr mimetics (9a-w) are reported as potent and selective PTP1B inhibitors. Compounds (9p and 9q) showed excellent selectivity towards PTP1B over various PTPs, including TCPTP (in vitro), which confirms discovery of highly potent and selective PTP1B inhibitors.
Subject(s)
Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Peptidomimetics , Protein Tyrosine Phosphatase, Non-Receptor Type 1/antagonists & inhibitors , Acetates/chemistry , Amides/chemistry , Dipeptides/chemistry , Dose-Response Relationship, Drug , Enzyme Inhibitors/chemical synthesis , Humans , Models, Molecular , Molecular Structure , Piperidines/chemistry , Protein Tyrosine Phosphatase, Non-Receptor Type 1/metabolism , Structure-Activity Relationship , Substrate SpecificityABSTRACT
A novel series of potent and efficacious factor Xa inhibitors which possesses sulfoximine moiety as novel S4 binding element in anthranilamide chemotype has been identified. Lead optimization at this novel P4 group led to many potent factor Xa inhibitors with excellent anticoagulant activity in human plasma. Selected compounds were dosed orally in rats and checked for their ex vivo prothrombin time prolonging activity, which resulted in identification of compound 5-chloro-N-(5-chloropyridin-2-yl)-2-(4-(N-(2-(diethylamino)acetyl)-S-methylsulfonimidoyl)benzamido)benzamide (18f). The detailed pharmacokinetic evaluation and subsequent metabolism study of 18f suggested the presence of an active metabolite. The compound 18f and its active metabolite 18b demonstrated excellent in vivo efficacy in both arterial and venous thrombosis model in rats and were found to be highly selective against related serine proteases. Based on this promising profile, compound 18f was selected for further evaluation.
Subject(s)
Anticoagulants/pharmacology , Factor Xa Inhibitors , Imines/chemistry , Serine Proteinase Inhibitors/pharmacology , Sulfoxides/chemistry , ortho-Aminobenzoates/pharmacology , Animals , Anticoagulants/administration & dosage , Anticoagulants/chemical synthesis , Anticoagulants/metabolism , Binding Sites/drug effects , Disease Models, Animal , Dose-Response Relationship, Drug , Humans , Male , Models, Molecular , Molecular Structure , Rats , Rats, Wistar , Reference Values , Serine Proteases/metabolism , Serine Proteinase Inhibitors/administration & dosage , Serine Proteinase Inhibitors/chemical synthesis , Serine Proteinase Inhibitors/metabolism , Structure-Activity Relationship , Venous Thrombosis/drug therapy , Venous Thrombosis/metabolism , ortho-Aminobenzoates/administration & dosage , ortho-Aminobenzoates/chemical synthesis , ortho-Aminobenzoates/metabolismABSTRACT
Series of benzyl-phenoxybenzyl amino-phenyl acid derivatives (8a-q) are reported as non-steroidal GR antagonist. Compound 8g showed excellent h-GR binding and potent antagonistic activity (in vitro). The lead compound 8g exhibited significant oral antidiabetic and antihyperlipidemic effects (in vivo), along with liver selectivity. These preliminary results confirm discovery of potent and liver selective passive GR antagonist for the treatment of T2DM.
Subject(s)
Benzyl Compounds/pharmacology , Diabetes Mellitus, Type 2/drug therapy , Drug Discovery , Hypoglycemic Agents/pharmacology , Liver/chemistry , Receptors, Glucocorticoid/antagonists & inhibitors , Administration, Oral , Animals , Benzyl Compounds/administration & dosage , Benzyl Compounds/chemistry , Blood Glucose/drug effects , Dose-Response Relationship, Drug , Focal Adhesion Protein-Tyrosine Kinases/antagonists & inhibitors , Gene Products, tat/antagonists & inhibitors , Humans , Hypoglycemic Agents/administration & dosage , Hypoglycemic Agents/chemistry , Liver/drug effects , Liver/metabolism , Male , Mice , Mice, Obese , Models, Molecular , Molecular Structure , Rats , Rats, Sprague-Dawley , Structure-Activity RelationshipABSTRACT
Pyrrolidine based peptidomimetics are reported as potent and selective DPP-IV inhibitors for the treatment of T2DM. Compounds 16c and 16d showed excellent in vitro potency and selectivity towards DPP-IV and the lead compound 16c showed sustained antihyperglycemic effects, along with improved pharmacokinetic profile.
Subject(s)
Dipeptidyl-Peptidase IV Inhibitors/pharmacology , Hypoglycemic Agents/pharmacology , Peptidomimetics/pharmacology , Animals , Dipeptidyl-Peptidase IV Inhibitors/pharmacokinetics , Mice , Mice, Inbred C57BL , Peptidomimetics/pharmacokineticsABSTRACT
A novel series of pTyr mimetics containing triaryl-sulfonamide derivatives (5a-r) are reported as potent and selective PTP1B inhibitors. Some of the test compounds (5o and 5p) showed excellent selectivity towards PTP1B over various PTPs, including TCPTP (in vitro). The lead compound 5o showed potent antidiabetic activity (in vivo), along with improved pharmacokinetic profile. These preliminary results confirm discovery of highly potent and selective PTP1B inhibitors for the treatment of T2DM.
Subject(s)
Diabetes Mellitus/drug therapy , Drug Discovery , Enzyme Inhibitors/pharmacology , Hypoglycemic Agents/pharmacology , Protein Tyrosine Phosphatase, Non-Receptor Type 1/antagonists & inhibitors , Sulfonamides/pharmacology , Administration, Oral , Animals , Biological Availability , Drug Evaluation, Preclinical , Enzyme Inhibitors/administration & dosage , Enzyme Inhibitors/chemistry , Hypoglycemic Agents/administration & dosage , Hypoglycemic Agents/chemistry , Male , Mice , Mice, Inbred C57BL , Models, Molecular , Molecular Structure , Protein Tyrosine Phosphatase, Non-Receptor Type 1/metabolism , Structure-Activity Relationship , Sulfonamides/administration & dosage , Sulfonamides/chemistryABSTRACT
Two novel series of 5-nitro-2-phenoxybenzoic acid derivatives are designed as potent PAI-1 inhibitors using hybridization and conformational restriction strategy in the tiplaxtinin and piperazine chemo types. The lead compounds 5a, 6c, and 6e exhibited potent PAI-1 inhibitory activity and favorable oral bioavailability in the rodents.
Subject(s)
Benzoates/chemistry , Benzoates/pharmacology , Drug Design , Drug Discovery , Phenyl Ethers/chemistry , Plasminogen Activator Inhibitor 1/metabolism , Administration, Oral , Animals , Benzoates/pharmacokinetics , Biological Availability , Disease Models, Animal , Drug Evaluation, Preclinical , Indoleacetic Acids/chemistry , Indoleacetic Acids/pharmacology , Male , Molecular Structure , Phenyl Ethers/pharmacokinetics , Phenyl Ethers/pharmacology , Piperazine , Piperazines/chemistry , Rats , Rats, Wistar , Structure-Activity Relationship , Thrombosis/chemically induced , Thrombosis/drug therapySubject(s)
Diabetes Mellitus/drug therapy , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/therapeutic use , Hypoglycemic Agents/chemistry , Hypoglycemic Agents/therapeutic use , Protein Tyrosine Phosphatase, Non-Receptor Type 1/antagonists & inhibitors , Triazoles/chemistry , Triazoles/therapeutic use , Administration, Oral , Animals , Enzyme Inhibitors/pharmacokinetics , Enzyme Inhibitors/pharmacology , Humans , Hypoglycemic Agents/pharmacokinetics , Hypoglycemic Agents/pharmacology , Male , Mice , Mice, Inbred C57BL , Models, Molecular , Protein Binding , Protein Tyrosine Phosphatase, Non-Receptor Type 1/metabolism , Rats , Rats, Wistar , Structure-Activity Relationship , Triazoles/pharmacokinetics , Triazoles/pharmacologyABSTRACT
A novel series of oxime containing benzyl-1,3-dioxane-r-2-carboxylic acid derivatives (6a-k) were designed as selective PPARα agonists, through bioisosteric modification in the lipophilic tail region of PPARα/γ dual agonist. Some of the test compounds (6a, 6b, 6c and 6f) showed high selectivity towards PPARα over PPARγ in vitro. Further, highly potent and selective PPARα agonist 6c exhibited significant antihyperglycemic and antihyperlipidemic activity in vivo, along with its improved pharmacokinetic profile. Favorable in-silico interaction of 6c with PPARα binding pocket correlate its in vitro selectivity profile toward PPARα over PPARγ. Together, these results confirm discovery of novel series of oxime based selective PPARα agonists for the safe and effective treatment of various metabolic disorders.
Subject(s)
Carboxylic Acids/pharmacology , Dioxanes/pharmacology , Hypoglycemic Agents/pharmacology , Hypolipidemic Agents/pharmacology , Oximes/pharmacology , PPAR alpha/agonists , Animals , Carboxylic Acids/chemistry , Carboxylic Acids/pharmacokinetics , Carboxylic Acids/therapeutic use , Cell Line , Dioxanes/chemistry , Dioxanes/pharmacokinetics , Dioxanes/therapeutic use , Humans , Hypoglycemic Agents/chemistry , Hypoglycemic Agents/pharmacokinetics , Hypoglycemic Agents/therapeutic use , Hypolipidemic Agents/chemistry , Hypolipidemic Agents/pharmacokinetics , Hypolipidemic Agents/therapeutic use , Male , Mice , Models, Molecular , Oximes/chemistry , Oximes/pharmacokinetics , Oximes/therapeutic use , PPAR alpha/metabolism , PPAR gamma/agonists , PPAR gamma/metabolism , Rats , Rats, Sprague-Dawley , Rats, Wistar , Structure-Activity RelationshipABSTRACT
Oxazole containing glycine and oximinobutyric acid derivatives were synthesized as PPARalpha agonists by incorporating polymethylene spacer as a replacement of commonly used phenylene group that connects the acidic head with lipophilic tail. Compound 13a was found to be a selective and potent PPARalpha agonist. Further 1,3-dioxane-2-carboxylic acid derivative 20 was synthesized by replacing the tetramethylene spacer of NS-220, a selective PPARalpha agonist with phenylene group and found to exhibit PPARalpha/gamma dual agonism. These results suggest that compounds possessing polymethylene spacer between pharmacophore and lipophilic tail exhibit predominantly PPARalpha agonism whereas those with an aromatic phenylene spacer shows PPARalpha/gamma dual agonism.
Subject(s)
Chemistry, Pharmaceutical/methods , PPAR alpha/chemistry , Peroxisome Proliferator-Activated Receptors/chemistry , Butyrates/chemistry , Dioxanes/chemistry , Drug Design , Glycine/analogs & derivatives , Glycine/chemistry , Humans , Hydrogen/chemistry , Hydrogen Bonding , Ligands , Models, Chemical , Oxazoles/chemistry , PPAR alpha/metabolism , Transcriptional ActivationABSTRACT
Facile synthesis of biaryl pyrazole sulfonamide derivative of 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxylic acid piperidin-1-ylamide (SR141716, 1) and an investigation of the effect of replacement of the -CO group in the compound 1 by the -SO(2) group in the aminopiperidine region is reported. Primary ex-vivo pharmacological testing and in vitro screening of sulfonamide derivative 2 showed the loss of CB1 receptor antagonism.
Subject(s)
Piperidines/pharmacology , Pyrazoles/pharmacology , Receptor, Cannabinoid, CB1/antagonists & inhibitors , Sulfonamides/chemistry , Animals , Chemistry, Pharmaceutical/methods , Drug Design , Inhibitory Concentration 50 , Mice , Models, Chemical , Molecular Conformation , Piperidines/chemistry , 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
Thromboxane A(2) receptor antagonists have attracted much attention in recent times in the design of new agents that could be active against diseases such as thrombosis, asthma and myocardial ischemia. 3D-QSAR studies have been performed on a series of [[1-aryl(or benzyl)-1-(benzenesulphonamido)methyl] phenyl] alkanoic acid derivatives by using the receptor surface analysis (RSA) method. The RSA analysis was carried out on 31 analogues of which 25 were used in the training set and the rest considered for the test set. This study produced reasonably good predictive models with good cross-validated and conventional r(2) values in both the models.
