ABSTRACT
A potent series of substituted 2-phenyl-2H-indazole-7-carboxamides were synthesized and evaluated as inhibitors of poly (ADP-ribose) polymerase (PARP). This extensive SAR exploration culminated with the identification of substituted 5-fluoro-2-phenyl-2H-indazole-7-carboxamide analog 48 which displayed excellent PARP enzyme inhibition with IC(50)=4nM, inhibited proliferation of cancer cell lines deficient in BRCA-1 with CC(50)=42nM and showed encouraging pharmacokinetic properties in rats compared to the lead 6.
Subject(s)
Amides/chemical synthesis , Antineoplastic Agents/chemical synthesis , Azetidines/chemical synthesis , Enzyme Inhibitors/chemical synthesis , Indazoles/chemical synthesis , Poly(ADP-ribose) Polymerase Inhibitors , Amides/chemistry , Amides/pharmacology , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Azetidines/chemistry , Azetidines/pharmacology , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , HeLa Cells , Humans , Indazoles/chemistry , Indazoles/pharmacology , Poly(ADP-ribose) Polymerases/metabolism , Rats , Structure-Activity Relationship , Ubiquitin-Protein Ligases/deficiency , Ubiquitin-Protein Ligases/genetics , Ubiquitin-Protein Ligases/metabolismABSTRACT
A SAR study was conducted on chromane-2-carboxylic acid toward selective PPARalpha agonisim. As a result, highly potent, and selective PPARalpha agonists were discovered. The optimized compound 43 exhibited robust lowering of total cholesterol levels in hamster and dog animal models.
Subject(s)
Carboxylic Acids/pharmacology , Chromans/pharmacology , Hypolipidemic Agents/pharmacology , PPAR alpha/agonists , Animals , Carboxylic Acids/administration & dosage , Carboxylic Acids/chemical synthesis , Chromans/administration & dosage , Chromans/chemical synthesis , Cricetinae , Dogs , Dose-Response Relationship, Drug , Drug Design , Drug Evaluation, Preclinical , Humans , Hypolipidemic Agents/administration & dosage , Hypolipidemic Agents/chemical synthesis , Macaca mulatta , Male , Molecular Structure , Rats , Rats, Sprague-Dawley , Species Specificity , Structure-Activity RelationshipABSTRACT
A series of chromane-2-carboxylic acid derivatives was synthesized and evaluated for PPAR agonist activities. A structure-activity relationship was developed toward PPARalpha/gamma dual agonism. As a result, (2R)-7-(3-[2-chloro-4-(4-fluorophenoxy)phenoxy]propoxy)-2-ethylchromane-2-carboxylic acid (48) was identified as a potent, structurally novel, selective PPARalpha/gamma dual agonist. Compound 48 exhibited substantial antihyperglycemic and hypolipidemic activities when orally administered in three different animal models: the db/db mouse type 2 diabetes model, a Syrian hamster lipid model, and a dog lipid model.
Subject(s)
Benzopyrans/chemical synthesis , Chromans/chemical synthesis , Hypoglycemic Agents/chemical synthesis , Hypolipidemic Agents/chemical synthesis , Phenyl Ethers/chemical synthesis , Receptors, Cytoplasmic and Nuclear/agonists , Transcription Factors/agonists , Animals , Benzopyrans/chemistry , Benzopyrans/pharmacokinetics , Benzopyrans/pharmacology , Chromans/chemistry , Chromans/pharmacokinetics , Chromans/pharmacology , Cricetinae , Diabetes Mellitus, Type 2/drug therapy , Diabetes Mellitus, Type 2/genetics , Dogs , Humans , Hypoglycemic Agents/chemistry , Hypoglycemic Agents/pharmacokinetics , Hypoglycemic Agents/pharmacology , Hypolipidemic Agents/chemistry , Hypolipidemic Agents/pharmacokinetics , Hypolipidemic Agents/pharmacology , Macaca mulatta , Male , Mesocricetus , Mice , Phenyl Ethers/chemistry , Phenyl Ethers/pharmacokinetics , Phenyl Ethers/pharmacology , Rats , Rats, Sprague-Dawley , Receptors, Cytoplasmic and Nuclear/genetics , Receptors, Cytoplasmic and Nuclear/metabolism , Stereoisomerism , Structure-Activity Relationship , Trans-Activators/chemical synthesis , Trans-Activators/chemistry , Trans-Activators/pharmacology , Transcription Factors/genetics , Transcription Factors/metabolismABSTRACT
A series of N-acridin-9-yl-butane-1,4-diamines were found to be high-affinity ligands of the alpha(2)delta subunit of voltage gated calcium channels. The SAR studies of butane-1,4-diamine side chain resulted in the identification of compound 10 (IC(50)=9 nM), which is more potent than gabapentin (IC(50)=27 nM). Partial saturation of the acridine ring was also pursued and provided a compound with higher binding affinity than 1.
Subject(s)
Amines , Calcium Channels/physiology , Cyclohexanecarboxylic Acids , Diamines/chemistry , Diamines/pharmacology , Protein Subunits/physiology , gamma-Aminobutyric Acid , Acetates/pharmacology , Binding, Competitive/drug effects , Calcium Channels/drug effects , Diamines/chemical synthesis , Gabapentin , Ligands , Molecular Structure , Protein Binding/drug effects , Protein Binding/physiology , Protein Subunits/drug effects , Structure-Activity RelationshipABSTRACT
A series of 5-aryl thiazolidine-2,4-diones containing 4-phenoxyphenyl side chains was designed, synthesized, and evaluated for PPAR agonist activities. One such compound 28 exhibited comparable levels of glucose correction to rosiglitazone in the db/db mouse type 2 diabetes animal model.
