ABSTRACT
The synthesis, evaluation, and structure-activity relationships of a set of related constrained diaminopropane inhibitors of BACE-1 are described. The full in vivo profile of an optimized inhibitor in both normal and P-gp deficient mice is compared with data generated in normal rats.
Subject(s)
Amyloid Precursor Protein Secretases/antagonists & inhibitors , Amyloid Precursor Protein Secretases/metabolism , Diamines/chemistry , Diamines/pharmacology , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , ATP Binding Cassette Transporter, Subfamily B, Member 1/genetics , Alzheimer Disease/drug therapy , Animals , Aspartic Acid Endopeptidases/antagonists & inhibitors , Aspartic Acid Endopeptidases/metabolism , Crystallography, X-Ray , Diamines/chemical synthesis , Diamines/pharmacokinetics , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacokinetics , HEK293 Cells , Humans , Mice , Mice, Knockout , Models, Molecular , Rats , Structure-Activity RelationshipABSTRACT
We have developed a simple and effective route for the high yield extraction of sugars from cellulosic based biomass. This process uses a combination of a cellulose decrystallization step with a mixture of phosphoric and sulfuric acid, followed by a hydrolysis step producing sugars (xylose and glucose) with yields of approximately 90%.
Subject(s)
Biomass , Carbohydrates/chemistry , Phosphoric Acids/chemistry , Sulfuric Acids/chemistry , CrystallizationABSTRACT
The synthesis, evaluation, and structure-activity relationships of a series of succinoyl lactam inhibitors of the Alzheimer's disease gamma-secretase are described. Beginning with a screening hit with broad proteinase activity, optimization provided compounds with both high selectivity for inhibition of gamma-secretase and high potency in cellular assays of A beta reduction. The SAR and early in vivo properties of this series of inhibitors will be presented.
Subject(s)
Caprolactam/chemistry , Endopeptidases/drug effects , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Succinates/chemistry , Alzheimer Disease/drug therapy , Alzheimer Disease/enzymology , Amyloid Precursor Protein Secretases , Animals , Aspartic Acid Endopeptidases , Caprolactam/analogs & derivatives , Cell Line , Dogs , Drug Design , Drug Evaluation, Preclinical , Endopeptidases/chemistry , Enzyme Inhibitors/chemistry , Humans , Molecular Conformation , Stereoisomerism , Structure-Activity RelationshipABSTRACT
Starting with our previously described(20) class of CC chemokine receptor-3 (CCR3) antagonist, we improved the potency by replacing the phenyl linker of 1 with a cyclohexyl linker and by replacing the 4-benzylpiperidine with a 3-benzylpiperidine. The resulting compound, 32, is a potent and selective antagonist of CCR3. SAR studies showed that the 3-acetylphenyl urea of 32 could be replaced with heterocyclic ureas or heterocyclic-substituted phenyl ureas and still maintain the potency (inhibition of eotaxin-induced chemotaxis) of this class of compounds in the low-picomolar range (IC(50) = 10-60 pM), representing some of the most potent CCR3 antagonists reported to date. The potency of 32 for mouse CCR3 (chemotaxis IC(50) = 41 nM) and its oral bioavailability in mice (20% F ) were adequate to assess the efficacy in animal models of allergic airway inflammation. Oral administration of 32 reduced eosinophil recruitment into the lungs in a dose-dependent manner in these animal models. On the basis of its overall potency, selectivity, efficacy, and safety profile, the benzenesulfonate salt of 32, designated DPC168, entered phase I clinical trials.
Subject(s)
Cyclohexanes/chemical synthesis , Phenylurea Compounds/chemical synthesis , Piperidines/chemical synthesis , Receptors, Chemokine/antagonists & inhibitors , Animals , Biological Availability , CHO Cells , Caco-2 Cells , Calcium/metabolism , Chemotaxis, Leukocyte/drug effects , Cricetinae , Cyclohexanes/chemistry , Cyclohexanes/pharmacology , Eosinophils/drug effects , Eosinophils/physiology , Female , Humans , Hypersensitivity/drug therapy , Hypersensitivity/immunology , In Vitro Techniques , Inflammation/drug therapy , Male , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Permeability , Phenylurea Compounds/chemistry , Phenylurea Compounds/pharmacology , Piperidines/chemistry , Piperidines/pharmacology , Receptors, CCR3 , Stereoisomerism , Structure-Activity Relationship , Urea/analogs & derivatives , Urea/chemical synthesis , Urea/chemistry , Urea/pharmacologyABSTRACT
Factor Xa (fXa) is an important serine protease in the blood coagulation cascade. Inhibition of fXa has emerged as an attractive target for potential therapeutic applications in the treatments of both arterial and venous thrombosis. Herein, we describe a series of non-benzamidine isoxazoline derivatives as fXa inhibitors. The chloroaniline group was found to be the most potent benzamidine mimic in this series. Chloroaniline 1 (ST368) has a K(i) value of 1.5 nM against fXa and is highly selective for fXa relative to thrombin and trypsin.
Subject(s)
Factor Xa Inhibitors , Isoxazoles/chemical synthesis , Isoxazoles/pharmacology , Animals , Biological Availability , Chromatography, High Pressure Liquid , Dogs , Fibrinolytic Agents/chemical synthesis , Fibrinolytic Agents/pharmacokinetics , Fibrinolytic Agents/pharmacology , Half-Life , Humans , In Vitro Techniques , Indicators and Reagents , Isoxazoles/pharmacokinetics , Kinetics , Models, Molecular , RabbitsABSTRACT
Factor Xa (fXa) is an important serine protease that holds the central position linking the intrinsic and extrinsic activation mechanisms in the blood coagulation cascade. Therefore, inhibition of fXa has potential therapeutic applications in the treatments of both arterial and venous thrombosis. Herein we describe a series of tetrazole fXa inhibitors containing benzamidine mimics as the P(1) substrate, of which the aminobenzisoxazole moiety was found to be the most potent benzamidine mimic. SR374 (12) inhibits fXa with a K(i) value of 0.35 nM and is very selective for fXa over thrombin and trypsin.
