75 results about "Blood brain barrier penetration" patented technology

The present invention relates to a method for regulating the permeability of the blood brain barrier by administering a NOS-3 inhibitor to reduce the increased permeability of the blood brain barrier caused by a pathological condition or by administering a NOS-3 activator or nitric oxide donor to increase the permeability of the blood brain barrier. By increasing the permeability of the blood barrier, a therapeutic or diagnostic compound can be delivered across this barrier into the central nervous system.

Novel blood-brain barrier permeant amyloid-targeting peptides and peptide conjugates are described. The peptide conjugates include a radioisotope or other label in a stable complex that translocates across brain capillary endothelial cell monolayers. The labeled peptide conjugate binds to amyloid plaques (Aβ) associated with Alzheimer's disease, and is useful for the targeted delivery of therapeutic and diagnostic molecules into the brain.

A purine derivative or analogue comprises a 9-atom bicyclic moiety, moiety A, linked through a linker L to a moiety B, where B is a carboxylic acid, a carboxylic acid ester, or a moiety of the structure N(Y1)-D, where Y1 can be one of a variety of substituents, including hydrogen or alkyl, and D is a moiety that enhances the pharmacological effects, promotes absorption or blood-brain barrier penetration of the derivative or analogue. The moiety A has a six-membered ring fused to a five-membered ring. The moiety A can have one, two, or three nitrogen atoms in the five membered ring and has two nitrogen atoms in the six-membered ring. The moiety A can be a purine moiety. The moiety B can be one of a variety of moieties, including moieties having nootropic activity or other biological or physiological activity.

Compounds, compositions and methods are contemplated in which senile plaques and / or neurofibrillary tangles are labeled using compounds with improved permeability across the blood brain barrier and improved selective binding to senile plaques and / or neurofibrillary tangles. Contemplated compounds are derivatives of FDDNP or curcumin, which most preferably have improved solubility in aqueous solvents. Labeling is typically performed using a PET detectable label, and especially 11C and 18F.

A tetrahydroindolone derivative or analogue comprises a 9-atom bicyclic moiety, moiety A, linked through a linker L to a moiety B, where B is a carboxylic acid, a carboxylic acid ester, or a moiety of the structure N(Y1)-D, where Y1 can be one of a variety of substituents, including hydrogen or alkyl, and D is a moiety that enhances the pharmacological effects, promotes absorption or blood-brain barrier penetration of the derivative or analogue. The moiety A has a six-membered ring fused to a five-membered ring. The moiety A can have one, two, or three nitrogen atoms in the five membered ring. The moiety A can be a tetrahydroindolone moiety. The moiety B can be one of a variety of moieties, including moieties having nootropic activity or other biological or physiological activity.

This invention relates to compositions, methods and kits for enhancing the permeability of the blood-brain barrier. Particularly, compositions comprising 5-phosphodiesterase inhibitors, such as sildenafil, vardenafil, or tadalafil, when administered to a mammal, will selectively enhance the permeability of the blood-brain barrier in abnormal brain tissue. This selective enhancement allows for selective delivery of therapeutic agents to treat the abnormal brain tissue; for example, a brain tumor.

Novel blood-brain barrier permeant amyloid-targeting peptides and peptide conjugates are described. The peptide conjugates include a radioisotope or other label in a stable complex that translocates across brain capillary endothelial cell monolayers. The labeled peptide conjugate binds to amyloid plaques (Aβ) associated with Alzheimer's disease, and is useful for the targeted delivery of therapeutic and diagnostic molecules into the brain.

Disclosed are methods for delivering an enzyme to a subject's brain or bone. The methods include administering a hyaluronidase to the subject and administering the enzyme to the subject. The hyaluronidase and the enzyme are administered to the subject under conditions effective to deliver the enzyme to the subject's brain or bone. Compositions and kits which include hyaluronidase and an enzyme are also disclosed, as are methods for increasing blood-brain barrier permeability in a subject. Also disclosed are methods, compositions, and kits for delivering genes or other nucleic acid molecules to a subject's brain or bone, as well as methods, compositions, and kits for delivering enzymes to a subject's tissues. The methods, compositions, and kits are disclosed as being useful in treating or preventing a variety of enzyme deficiency diseases, such as those affecting brain and / or bone, e.g., as Canavan's disease, Fabry disease, Gaucher's disease, various forms of mucopolysaccharidosis (e.g., Hurler's syndrome, Scheie syndrome, Hurler-Scheie syndrome, Sanfillippo A syndrome, Morquio A syndrome, Morquio B syndrome, etc.), Niemann-Pick disease, Schindler disease, and Pompe disease.

The invention provides a substituted phenyl pyrazolone derivative and specifically relates to a 2-phenyl-pyrazoline-3-one compound as well as a pharmaceutically-acceptable salt and solvate thereof. Atarget compound is prepared by carrying out a reflux reaction on substituted ethyl acetoacetate and benzyloxyphenylhydrazine in a sodium hydroxide aqueous solution, then, carrying out hydrogenolysis on a benzyl group under the actions of palladium / carbon and hydrogen to obtain phenylpyrazolone phenol, then, making phenylpyrazolone phenol react with bromochloroalkane to obtain a chloride, and finally, carrying out condensation on the chloride and secondary amine. The substituted phenyl pyrazolone derivative provided by the invention shows good free radial scavenging capability in vitro, has relatively strong H3 receptor inhibiting activity, shows good blood brain barrier penetration capability and has unique double activities so as to have a unique clinic effect on treating neurodegenerative diseases such as cerebral apoplexy, presenile dementia, parkinsonism and amyotrophic lateral sclerosis. The compound provided by the invention is applied to preparation of drugs for treating centralsystem related diseases and inflammatory diseases. A structure of a general formula is shown as the specification.

This invention relates to methods and kits for enhancing the permeability of the blood-brain barrier of abnormal brain tissue or the blood-tumor barrier. Particularly, methods comprising the administration of 5-phosphodiesterase inhibitors, such as sildenafil and vardenafil, to selectively enhance the permeability of the blood-brain barrier of abnormal brain tissue or the blood-tumor barrier are described. This selective enhancement allows for selective delivery of therapeutic agents or imaging to treat the abnormal brain tissue or a tumor, including brain tumors and non-central nervous system tumors.

The invented inositol and trehalose derivatives, prepared by introducing multiple units of the guanidine group to the backbone molecules, show excellent blood-brain barrier permeability, and accordingly, it can be easily transported to the brain tissues and utilized for the treatment of neurodegenerative diseases such as Alzheimer's disease and Huntington's disease.

The invention relates to a series of compounds represented as the formula (I), or pharmaceutically acceptable salts thereof, which can be used as new-generation Wee1 selective inhibitor. Compared withexisting Wee1 inhibitor, the compound has a higher selectivity on Wee1 kinase, so that the compound is safer and is higher in treatment index, and also has higher blood brain barrier permeability. The compound has better safety and a larger applicable range, and can be applied to treatment on various tumors, including brain tumor.

The invention discloses a preparation method of an RGD (Arg-Gly-Asp) and PEG (Polyethylene Glycol) co-modified PAMAM (Polyamide-Amne Dendrimer) arsenic trioxide-loaded medicine delivery system. The preparation method comprises the following steps: enabling a sulfydryl group of an RGD cyclopeptide to react with a maleimide group of MAL-PEG-NHS, thus generating RGD-PEG-NHS; then reacting with a surface amino group of PAMAM, thus generating RGD-PEG-PAMAM; enabling the RGD-PEG-PAMAM to react with mPEG-NHS, thus preparing RGD-PEG-PAMAM-mPEG; enabling an arsenic trioxide solution to react with the RGD-PEG-PAMAM-mPEG, thus preparing the RGD and PEG co-modified PAMAM arsenic trioxide-loaded medicine delivery system. According to the preparation method disclosed by the invention, highly toxic traditional Chinese medicine-arsenic trioxide is firstly loaded in PAMAM; compared with an original medicine, a certain slow release action can be reflected, and the problems that ATO is poor in fat solubility, the blood-brain barrier penetration is difficult, body distribution is lack of specificity, and the like are solved; RGD is used for modifying the PAMAM, so that cellular uptake of tumor cells on the PAMAM is further increased; mPEG is used for modifying residual amino groups on the PAMAM, so that the cytotoxicity of a carrier can be further reduced.

Described herein is a microphysiological system for models of disease. Specifically, induced pluripotent stem cells (iPSCs) and iPSC-derived cells, including those obtained from disease patients, are seeded onto microfluidic “chip” devices to study cellular development and disease pathogenesis. Herein, neurodegenerative disease modeling, including Parkinson's Disease (PD) is shown to reproduce key PD pathology in a vascularized human model that contains neurons relating to PD pathology. Such compositions and methods are used for research for PD biomarkers, patient screening for PD risk assessment, and therapeutic discovery and testing. A panel of biomarkers are generated through analysis of living PD-chips by neural activity, whole transcriptomic, proteomic, and metabolomic analysis, and functional enzyme tests of media and tissue. Introducing therapeutics through a vasculature channel, coupled with blood brain barrier penetration studies can be assessed for efficacy in the human neural cells present in the PD-Chip.

The invented inositol and trehalose derivatives, prepared by introducing multiple units of the guanidine group to the backbone molecules, show excellent blood-brain barrier permeability, and accordingly, it can be easily transported to the brain tissues and utilized for the treatment of neurodegenerative diseases such as Alzheimer's disease and Huntington's disease.

There is provided a composition comprising a compound represented by general formula (I), wherein R 1 represents a 5-iodothiophen-2-yl group or the like, and R 2 represents a 4-dimethylaminophenyl group or the like. This composition is useful for diagnosis of an amyloid-related disease such as Alzheimer's disease because the compound has high binding specificity to amyloid protein, high permeability through the blood-brain barrier, and a property of being rapidly eliminated from sites other than senile plaques in the brain.

The invention designs a carrier based on mesoporous silicon, wherein the surface of the mesoporous silicon is modified with G-rich sequence DNA, paclitaxel is loaded, the tetrahedral structure is formed through DNA self-assembly, a C-rich sequence protruding from the tetrahedron is hybridized with the G-rich sequence on the mesoporous silicon surface, and holes are sealed. DNA modified with aminois reacted with polypeptide to form a DNA-polypeptide chimera, and the polypeptide has the function of mediating blood-brain barrier penetration. The structure of the C-rich sequence can be changed ina slightly acidic environment of tumor, the seal of the tetrahedron DNA is open, the G-rich sequence has the function of targeting glioma, and the paclitaxel has the treatment effect.

Tricyclic pyrone compounds having high oral bioavailability, excellent blood-brain barrier permeability, and low toxicity are presented. Administration of the compounds to Alzheimer's Disease transgenic models resulted in substantially reduced soluble and insoluble Aβ species in the brain without affecting general behavior and motor coordination. Furthermore, in addition to blocking the toxicity and formation of both intraneuronal and extracellular Aβ aggregates, the compounds also increase cellular cholesterol efflux, restore axonal trafficking, and enhance hippocampal synaptic plasticity.

The invention provides a borneol derivative. The chemical name of the derivative is (+)-monobornyl maleinate, and the chemical structure is shown as the formula (I). The derivative can be prepared by reacting maleic anhydride with (+)-borneol through esterification, has the effects of easing pains and penetrating blood brain barriers and can be used for preparing pain easing medicaments or blood brain barrier penetration promoters.

The invention discloses application of cinnamon essential oil. The cinnamon essential oil can be used for preparing medicine for treating or preventing brain function diseases or disordered brain function diseases and health products for relieving brain function diseases or disordered brain function diseases. The novel purpose of the cinnamon essential oil on medicine or great health products showing activity in experiment animal brain function diseases or disordered brain function diseases is discovered for the first time; the condition that the cinnamon essential oil or composition containing cinnamon essential oil or free cinnamon essential oil compositions can relieve the brain function or disordered brain function animal diseases such as senile dementia, depression and anxiety in animal in vivo models is discovered for the first time. Compared with the existing medicine for treating brain functions and disordered brain functions, the cinnamon essential oil and free compositions ofthe cinnamon essential oil have the mechanism of multimolecular cooperated action on multiple points of inhibiting choline esterase, regulating neurotransmitters and the like; good pharmacokinetics parameters are realized; the blood brain barrier penetration is easy, so that the cinnamon essential oil has the characteristics of high toxicology safety, stable metabolism, long half-time and small side effects.

This invention relates to: (a) compounds of formula (I) (with R1 to R5, n and A as defined herein) and pharmaceutically acceptable salts or solvates thereof that are useful as dopamine-β-hydroxylase inhibitors; (b) pharmaceutical compositions comprising such compounds, salts or solvates; (c) the use of such compounds, salts or solvates in therapy; (d) therapeutic methods of treatment using such compounds, salts or solvates; and (e) processes and intermediates useful for the synthesis of such compounds.

The invention relates to application of a black phosphorus nanosheet in preparation of a medicine for treating the Parkinson's disease. The black phosphorus nanosheet is a black phosphorus nanosheet of which the surface is modified with polyethylene glycol. The black phosphorus nanosheet has photothermal conversion performance, can improve blood-brain barrier permeability through a photothermal effect, and can improve the brain-targeted delivery efficiency of the black phosphorus nanosheet. In addition, the black phosphorus nanosheet also has oxidation resistance, can remove excessive active oxygen in the Parkinson's disease pathological state, has a nano biological effect of resisting the Parkinson's disease, and has a wide application prospect in future clinical practice.

The invention relates to a mono-propargylamine modified thiouracil compound, and applications thereof. The structure of the mono-propargylamine modified thiouracil compound is novel; the mono-propargylamine modified thiouracil compound possesses cholinesterase inhibition activity, monoamine oxidase activity, and metal ion chelating properties, is capable of inhibiting generation of metal ion-induced free radicals, and inhibiting metal ion-induced Abeta aggregation, is low in cytotoxicity, and is high in blood brain barrier penetration rate in vitro experiment. Preparation technology is simple; preparation cost is low; and it is promising to prepare multifunctional drugs used for treating, improving and / or preventing Alzheimer disease from the mono-propargylamine modified thiouracil compound.

The invention discloses an analogue obtained by disulfide bond cyclization of opium and neuropeptide FF receptor multi-target molecule BN-9. By adopting BN-9 as a chemical template to introduce a sidechain thiol-containing amino acid residue for multi-site substitution modifications, and through cyclization modification, a series of disulfide bond cyclization analogues are obtained. The inventionalso discloses a preparation method and application of the analogues obtained by disulfide bond cyclization of opium and neuropeptide FF receptor multi-targeted molecule BN-9. These analogs simultaneously activate opium and the neuropeptide FF receptor, mediate high-efficiency, and have analgesic effects free from tolerance. Half-life period, blood-brain barrier penetration, and in vivo analgesiatime of the cyclized analogues of BN-9 are greatly improved relative to the matrix. Thus, the disulfide cyclized analogues of the BN-9 can be used for preparing analgesic drugs.

Provided are polyethylene glycol drug conjugates of general formula (I), (II) or (III) and pharmaceutical compositions and a use thereof. The conjugates are formed by combining low molecular weight polyethylene glycol with 2-4 drug molecules. The conjugates can interact with receptor dimers or polymers, thereby improving the in vivo distribution of the drug, changing the oil and water distribution coefficient, enhancing the pharmacological activity, reducing the blood-brain barrier permeability of the drug, and improving the bioavailability of the drug.