ABSTRACT
A series of inhibitors of mammalian 15-lipoxygenase (15-LO) based on a 3,4,5-tri-substituted pyrazole scaffold is described. Replacement of a sulfonamide functionality in the lead series with a sulfamide group resulted in improved physicochemical properties generating analogs with enhanced inhibition in cell-based and whole blood assays.
Subject(s)
Amides/chemistry , Arachidonate 15-Lipoxygenase/chemistry , Lipoxygenase Inhibitors/chemistry , Pyrazoles/chemistry , Amides/chemical synthesis , Amides/pharmacology , Animals , Arachidonate 15-Lipoxygenase/metabolism , CHO Cells , Cricetinae , Cricetulus , Humans , Hydroxyeicosatetraenoic Acids/blood , Lipoxygenase Inhibitors/chemical synthesis , Lipoxygenase Inhibitors/pharmacology , Rabbits , Structure-Activity Relationship , Sulfonamides/chemical synthesis , Sulfonamides/chemistry , Sulfonamides/pharmacologyABSTRACT
A series of 2,4,5-tri-substituted imidazoles has proven to be highly potent in inhibiting mammalian 15-lipoxygenase (15-LO) with excellent selectivity over human isozymes 5- and P-12-LO. Non-symmetrical sulfamides (e.g., 21a-n) were found to be suitable replacements for the earlier arylsulfonamide-containing members of this series (e.g., 2, 14a-p). Several members of these series also demonstrated potent inhibition of human 15-LO in a cell-based assay.
Subject(s)
Imidazoles/pharmacology , Lipoxygenase Inhibitors , Lipoxygenase Inhibitors/pharmacology , Animals , CHO Cells , Cricetinae , Cricetulus , Humans , Imidazoles/chemistry , Lipoxygenase Inhibitors/chemistry , Male , Rats , Rats, Sprague-DawleyABSTRACT
A series of inhibitors of mammalian 15-lipoxygenase based on tryptamine and homotryptamine scaffolds is described. Compounds with aryl substituents at C-2 of the indole core of tryptamine and homotryptamine sulfonamides (e.g., 37a-p) proved to be potent inhibitors of the isolated enzyme. Selected compounds also demonstrated desirable inhibition selectivities over isozymes 5- and P-12-LO.
Subject(s)
Enzyme Inhibitors/pharmacology , Lipoxygenase Inhibitors , Sulfonamides/pharmacology , Tryptamines/chemistry , Animals , Enzyme Inhibitors/chemistry , Molecular Structure , Structure-Activity Relationship , Sulfonamides/chemistryABSTRACT
A series of substituted spirobenzazepines was prepared and evaluated as V(1a) and V(2) dual vasopressin receptor antagonists. Compounds 7p and 7q have been shown to be not only potent inhibitors of vasopressin receptors, but also have exhibited an excellent overall pharmaceutical suitability profile.
Subject(s)
Antidiuretic Hormone Receptor Antagonists , Benzazepines/chemical synthesis , Animals , Benzazepines/metabolism , Benzazepines/pharmacology , Cell Line , Drug Evaluation, Preclinical/methods , Humans , Rats , Receptors, Vasopressin/metabolismABSTRACT
A novel series of spirobenzazepines was synthesized and evaluated for V1a and V2 receptor antagonist activity. Compounds 8b, 8i, and 8k have shown selective V1a receptor antagonist activity. Compounds 8p and 8q were shown to be dual V1a/V2 receptor antagonists.
Subject(s)
Antidiuretic Hormone Receptor Antagonists , Benzazepines/pharmacology , Spiro Compounds/pharmacology , Benzazepines/chemical synthesis , Cell Line , Cyclic AMP/analysis , Humans , Inhibitory Concentration 50 , Ligands , Protein Binding , Spiro Compounds/chemical synthesis , Structure-Activity RelationshipABSTRACT
Inhibition of the sodium hydrogen exchanger isoform-1 (NHE-1) has been shown to limit damage to the myocardium under ischemic conditions in animals. While most known NHE-1 inhibitors are acylguanidines, this report describes the design and synthesis of a series of heterocyclic inhibitors of NHE-1 including aminoimidazoles with undiminished in vitro activity and oral bioavailability.
Subject(s)
Cation Transport Proteins/antagonists & inhibitors , Guanidines/administration & dosage , Imidazoles/administration & dosage , Membrane Proteins/antagonists & inhibitors , Sodium-Hydrogen Exchangers/antagonists & inhibitors , Administration, Oral , Biological Availability , Cation Transport Proteins/metabolism , Cell Line , Guanidines/chemistry , Guanidines/pharmacokinetics , Humans , Imidazoles/chemistry , Imidazoles/pharmacokinetics , Membrane Proteins/metabolism , Protein Isoforms/antagonists & inhibitors , Protein Isoforms/metabolism , Sodium-Hydrogen Exchanger 1 , Sodium-Hydrogen Exchangers/metabolism , StereoisomerismABSTRACT
A series of benzoxazinones has been synthesized and tested for PPARgamma agonist activity. Synthetic approaches were developed to provide either racemic or chiral compounds. In vitro functional potency could be measured through induction of the aP2 gene, a target of PPARgamma. These studies revealed that compounds with large aliphatic chains at the nitrogen of the benzoxazinone were the most potent. Substitution of the chain was tolerated and in many cases enhanced the in vitro potency of the compound. Select compounds were further tested for metabolic stability, oral bioavailability in rats, and efficacy in db/db mice after 11 days of dosing. In vivo analysis with 13 and 57 demonstrated that the series has potential for the treatment of type 2 diabetes.
Subject(s)
Amides/chemical synthesis , Diabetes Mellitus, Type 2/drug therapy , Oxazines/chemical synthesis , Receptors, Cytoplasmic and Nuclear/agonists , Transcription Factors/agonists , Amides/chemistry , Amides/pharmacology , Animals , Biological Availability , Cytochrome P-450 Enzyme System/metabolism , Drug Stability , Female , Humans , In Vitro Techniques , Mice , Microsomes, Liver/metabolism , Oxazines/chemistry , Oxazines/pharmacology , Rats , Stereoisomerism , Structure-Activity RelationshipABSTRACT
A series of benzoxazinones was synthesized as PPARgamma agonists. The compounds were obtained in seven steps, and SAR was developed by variations to the core shown below. The compounds were tested as functional agonists in the induction of the aP2 gene in preadipocytes, and the most potent compound in the series has an EC(50)=0.51 microM. The potency was further confirmed through a PPAR-Gal4 construct. Efficacy has been demonstrated in the db/db mouse model of hyperglycemia.
