ABSTRACT
Whereas treatment of allergic diseases such as asthma relies largely on the targeting of dysregulated effector pathways, the conceptually attractive alternative of preventing them by a pharmaceutical, at-source intervention has been stymied until now by uncertainties about suitable targets and the challenges facing drug design. House dust mites (HDMs) are globally significant triggers of allergy. Group 1 HDM allergens, exemplified by Der p 1, are cysteine proteases. Their degradome has a strong disease linkage that underlies their status as risk and initiator allergens acting directly and through bystander effects on other allergens. Our objective was to test whether target-selective inhibitors of group 1 HDM allergens might provide a viable route to novel therapies. Using structure-directed design to optimize a series of pyruvamides, we undertook the first examination of whether pharmaceutically developable inhibitors of group 1 allergens might offer protection against HDM exposure. Developability criteria included durable inhibition of clinically relevant signals after a single aerosolized dose of the drug. The compounds suppressed acute airway responses of rats and mice when challenged with an HDM extract representing the HDM allergome. Inhibitory effects operated through a miscellany of downstream pathways involving, among others, IL-33, thymic stromal lymphopoietin, chemokines, and dendritic cells. IL-13 and eosinophil recruitment, indices of Th2 pathway activation, were strongly attenuated. The surprisingly expansive benefits arising from a unique at-source intervention suggest a novel approach to multiple allergic diseases in which HDMs play prominent roles and encourage exploration of these pharmaceutically developable molecules in a clinical setting.
ABSTRACT
Herein we describe the identification of 4-{[1,2,4]triazolo[1,5-a]pyridin-5-yl}benzonitrile-based inhibitors of the hypoxia-inducible factor prolylhydroxylase domain-1 (PHD-1) enzyme. These inhibitors were shown to possess a novel binding mode by X-ray crystallography, in which the triazolo N1 atom coordinates in a hitherto unreported monodentate interaction with the active site Fe2+ ion, while the benzonitrile group accepts a hydrogen-bonding interaction from the side chain residue of Asn315. Further optimization led to potent PHD-1 inhibitors with good physicochemical and pharmacokinetic properties.
Subject(s)
Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Hypoxia-Inducible Factor-Proline Dioxygenases/antagonists & inhibitors , Pyridines/chemistry , Pyridines/pharmacology , Triazoles/chemistry , Triazoles/pharmacology , Animals , Crystallography, X-Ray , Dogs , Enzyme Inhibitors/pharmacokinetics , Humans , Hypoxia-Inducible Factor-Proline Dioxygenases/chemistry , Hypoxia-Inducible Factor-Proline Dioxygenases/metabolism , Madin Darby Canine Kidney Cells , Mice , Mice, Inbred C57BL , Molecular Docking Simulation , Pyridines/pharmacokinetics , Triazoles/pharmacokineticsABSTRACT
Blocking the bioactivity of allergens is conceptually attractive as a small-molecule therapy for allergic diseases but has not been attempted previously. Group 1 allergens of house dust mites (HDM) are meaningful targets in this quest because they are globally prevalent and clinically important triggers of allergic asthma. Group 1 HDM allergens are cysteine peptidases whose proteolytic activity triggers essential steps in the allergy cascade. Using the HDM allergen Der p 1 as an archetype for structure-based drug discovery, we have identified a series of novel, reversible inhibitors. Potency and selectivity were manipulated by optimizing drug interactions with enzyme binding pockets, while variation of terminal groups conferred the physicochemical and pharmacokinetic attributes required for inhaled delivery. Studies in animals challenged with the gamut of HDM allergens showed an attenuation of allergic responses by targeting just a single component, namely, Der p 1. Our findings suggest that these inhibitors may be used as novel therapies for allergic asthma.
Subject(s)
Antigens, Dermatophagoides/chemistry , Arthropod Proteins/antagonists & inhibitors , Arthropod Proteins/chemistry , Asthma/drug therapy , Cysteine Endopeptidases/chemistry , Hypersensitivity/drug therapy , Administration, Oral , Allergens/immunology , Amino Acid Motifs , Animals , Chemistry, Pharmaceutical/methods , Drug Design , Humans , Inhibitory Concentration 50 , Molecular Weight , Peptides/chemistry , Protein Binding , Pyroglyphidae/immunologyABSTRACT
Optimization of the cellular and pharmacological activity of a novel series of PI3 kinase inhibitors targeting multiple isoforms is described.
Subject(s)
Benzoxazines/chemical synthesis , Benzoxazines/pharmacology , Phosphoinositide-3 Kinase Inhibitors , Pyrazoles/chemical synthesis , Pyrazoles/pharmacology , Administration, Oral , Animals , Benzoxazines/chemistry , Combinatorial Chemistry Techniques , Inhibitory Concentration 50 , Isoenzymes/antagonists & inhibitors , Male , Molecular Structure , Pyrazoles/chemistry , Rats , Rats, Wistar , Structure-Activity RelationshipABSTRACT
The SAR and pharmacokinetic profiles of a series of multi-isoform PI3K inhibitors based on a 3,4-dihydro-2H-benzo[1,4]oxazine scaffold are disclosed.
Subject(s)
Benzoxazines/chemistry , Chemistry, Pharmaceutical/methods , Oxazines/chemical synthesis , Oxazines/pharmacology , Phosphatidylinositol 3-Kinases/metabolism , Area Under Curve , Benzoxazines/pharmacology , Crystallography, X-Ray/methods , Drug Design , Humans , Inflammation , Inhibitory Concentration 50 , Models, Chemical , Molecular Structure , Protein Isoforms , Structure-Activity RelationshipABSTRACT
Following the identification of a potent IRAK inhibitor through routine project cross screening, a novel class of IRAK-4 inhibitor was established. The SAR of imidazo[1,2-a]pyridino-pyridines and benzimidazolo-pyridines was explored.
Subject(s)
Interleukin-1 Receptor-Associated Kinases/antagonists & inhibitors , Protein Kinase Inhibitors/pharmacology , Pyridines/pharmacology , Drug Evaluation, Preclinical , Molecular Structure , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Pyridines/chemical synthesis , Pyridines/chemistry , Stereoisomerism , Structure-Activity RelationshipABSTRACT
A potent IRAK-4 inhibitor was identified through routine project cross screening. The binding mode was inferred using a combination of in silico docking into an IRAK-4 homology model, surrogate crystal structure analysis and chemical analogue SAR.
Subject(s)
Drug Design , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Imidazoles/chemical synthesis , Imidazoles/pharmacology , Interleukin-1 Receptor-Associated Kinases/antagonists & inhibitors , Models, Molecular , Pyridines/chemical synthesis , Pyridines/pharmacology , Binding Sites , Crystallography, X-Ray , Enzyme Inhibitors/chemistry , Imidazoles/chemistry , Molecular Conformation , Molecular Structure , Pyridines/chemistry , Structure-Activity RelationshipABSTRACT
The synthesis and profile of a series of amides are described. Some of these compounds were potent IRAK-4 inhibitors and two examples were evaluated in vivo.
Subject(s)
Amides/chemical synthesis , Amides/pharmacology , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Interleukin-1 Receptor-Associated Kinases/antagonists & inhibitors , Models, Biological , Pyridines/chemical synthesis , Pyridines/pharmacology , Small Molecule Libraries/chemical synthesis , Small Molecule Libraries/pharmacology , Amides/chemistry , Drug Design , Enzyme Inhibitors/chemistry , Humans , Molecular Structure , Pyridines/chemistry , Small Molecule Libraries/chemistry , Structure-Activity RelationshipABSTRACT
A recent metabolic scaling theory predicts that plants minimize resistance to hydraulic conduction in the bulk transport network by narrowing the diameter of xylem conduits distally. We hypothesized that trees growing at high altitude or on nutrient-depleted soils would prioritize survival over minimizing hydraulic resistance, and that their vascular systems would be structured differently from those of trees growing under more benign conditions. In fact, conduits were observed to narrow towards the periphery of vascular system within all 45 trees of three species we investigated, and scaling relationships were indistinguishable across a range of environments. Thus, conduit tapering relationships appear to be invariant with respect to environmental conditions.
Subject(s)
Altitude , Ecosystem , Soil , Trees/anatomy & histology , Xylem/anatomy & histology , Fagaceae/anatomy & histology , Picea/anatomy & histology , Pinus sylvestris/anatomy & histologyABSTRACT
The study of non-oxazole containing indole fragments as inhibitors of inosine monophosphate dehydrogenase (IMPDH) is described. The synthesis and in vitro inhibitory values for IMPDH II are discussed.
Subject(s)
Enzyme Inhibitors/pharmacology , IMP Dehydrogenase/antagonists & inhibitors , Indoles/pharmacology , Carbamates/chemistry , Carbamates/pharmacology , Crystallography, X-Ray , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Hydrogen Bonding , Indoles/chemical synthesis , Indoles/chemistry , Models, Molecular , Molecular Structure , Molecular Weight , Oxazoles/pharmacology , Phenylurea Compounds/chemistry , Phenylurea Compounds/pharmacology , Sensitivity and Specificity , Structure-Activity RelationshipABSTRACT
The elaboration of previously reported indole fragments as inhibitors of inosine monophosphate dehydrogenase (IMPDH) is described. The synthesis, in vitro inhibitory values for IMPDH II, PBMC proliferation and physicochemical properties are discussed.
Subject(s)
Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , IMP Dehydrogenase/antagonists & inhibitors , Indoles/chemical synthesis , Indoles/pharmacology , Biological Transport, Active/drug effects , Caco-2 Cells , Cell Proliferation/drug effects , Drug Evaluation, Preclinical , Enzyme Activation/drug effects , Enzyme Inhibitors/chemistry , Humans , In Vitro Techniques , Indoles/chemistry , Leukocytes, Mononuclear/drug effects , Molecular Structure , Molecular Weight , Structure-Activity RelationshipABSTRACT
This work describes the preparation of approximately 13,000 compounds for rapid identification of hits in high-throughput screening (HTS). These compounds were designed as potential serine/threonine or tyrosine kinase inhibitors. The library consists of various scaffolds, e.g., purines, oxindoles, and imidazoles, whereby each core scaffold generally includes the hydrogen bond acceptor/donor properties known to be important for kinase binding. Several of these are based upon literature kinase templates, or adaptations of them to provide novelty. The routes to their preparation are outlined. A variety of automation techniques were used to prepare >500 compounds per scaffold. Where applicable, scavenger resins were employed to remove excess reagents and when necessary, preparative high performance liquid chromatography (HPLC) was used for purification. These compounds were screened against an 'in-house' kinase panel. The success rate in HTS was significantly higher than the corporate compound collection.