The present invention provides benzothiadiazine and chroman derivatives and particularly diazoxide and cromakalim derivatives for use in treating glaucoma, retinopathy, treating age related macular degeneration, treating, stabilizing and/or inhibiting blood and lymph vascularization, and reducing intraocular pressure by administering a pharmaceutically effective amount of a prodrug disposed in an ophthalmically acceptable carrier to the eye, wherein the prodrug specifically modulates a KATP channel to reduce an intraocular pressure.

The present invention provides benzothiadiazine and chroman derivatives and particularly diazoxide and cromakalim derivatives for use in treating glaucoma, retinopathy, treating age related macular degeneration, treating, stabilizing and/or inhibiting blood and lymph vascularization, and reducing intraocular pressure by administering a pharmaceutically effective amount of a prodrug disposed in an ophthalmically acceptable carrier to the eye, wherein the prodrug specifically modulates a KATP channel to reduce an intraocular pressure.

The present invention provides benzothiadiazine and chroman derivatives and particularly diazoxide and cromakalim derivatives for use in treating glaucoma, retinopathy, treating age related macular degeneration, treating, stabilizing and/or inhibiting blood and lymph vascularization, and reducing intraocular pressure by administering a pharmaceutically effective amount of a prodrug disposed in an ophthalmically acceptable carrier to the eye, wherein the prodrug specifically modulates a K.sub.ATP channel to reduce an intraocular pressure.

The present invention provides benzothiadiazine and chroman derivatives and particularly diazoxide and cromakalim derivatives for use in treating glaucoma, retinopathy, treating age related macular degeneration, treating, stabilizing and/or inhibiting blood and lymph vascularization, and reducing intraocular pressure by administering a pharmaceutically effective amount of a prodrug disposed in an ophthalmically acceptable carrier to the eye, wherein the prodrug specifically modulates a K.sub.ATP channel to reduce an intraocular pressure.

Pharmaceutical compositions of the invention comprise functionalized N,N-dialkylamino phenyl ethers derivatives having a disease-modifying action in the treatment of diseases associated with lysosomal storage dysfunction that include Gaucher's disease, and any disease or condition involving lysosomal storage dysfunction.

Senescent cell medicine encompasses the paradigm that many conditions that are associated with aging or tissue damage are caused or mediated by senescent cells. This disclosure shows that HSP90, pI3-kinase, proteasome, HDAC, and p97 pathways are all active in senescent cells, and can be used as an effective means for removing senescent cells from a target tissue. Exemplary inhibitors of each of these pathways are provided. Also provided is a new genus of p97 inhibitor molecules. The structure includes a core 4 amino pyrimidine ring system, substituted at the 2 position with a nitrogen atom of an amino substituent or a N heterocycle. The 4 amino substituent of the core ring system is optionally linked to a substituted phenyl group. Any of the inhibitors referred to in this disclosure can be screened for senolytic activity and developed for the treatment of conditions such as osteoarthritis, ophthalmic disease, pulmonary disease, and atherosclerosis.

The proteasome inhibitors of this invention include peptide-based compounds with a short linear sequence of amino acids. An oxo or thio group is attached to the N-terminal amino acid. A protein-reactive electrophilic group such as an epoxyketone, an aziridinylketone, or a beta-lactone is attached to the C-terminal amino acid. Upon contact with a proteasome complex in a target cell, the electrophilic group reacts with a functional group in or near a binding pocket or active site of the proteasome, forming a covalent bond and thereby inactivating the proteasome. These and other proteasome inhibitors can be screened for binding affinity and an ability to selectively eliminate senescent cells or cancer cells. Compounds that selectively remove senescent cells can be developed for the treatment of conditions such as osteoarthritis, ophthalmic disease, pulmonary disease, and atherosclerosis.

The proteasome inhibitors of this invention include peptide-based compounds with a short linear sequence of amino acids. An oxo or thio group is attached to the N-terminal amino acid. A protein-reactive electrophilic group such as an epoxyketone, an aziridinylketone, or a beta-lactone is attached to the C-terminal amino acid. Upon contact with a proteasome complex in a target cell, the electrophilic group reacts with a functional group in or near a binding pocket or active site of the proteasome, forming a covalent bond and thereby inactivating the proteasome. These and other proteasome inhibitors can be screened for binding affinity and an ability to selectively eliminate senescent cells or cancer cells. Compounds that selectively remove senescent cells can be developed for the treatment of conditions such as osteoarthritis, ophthalmic disease, pulmonary disease, and atherosclerosis.

Novel compounds of the structural formula (I), and the pharmaceutically acceptable salts thereof, are agonists of G-protein coupled receptor 40 (GPR40) and may be useful in the treatment, prevention and suppression of diseases mediated by the G-protein-coupled receptor 40. The compounds of the present invention may be useful in the treatment of Type 2 diabetes mellitus, and of conditions that are often associated with this disease, including obesity and lipid disorders, such as mixed or diabetic dyslipidemia, hyperlipidemia, hypercholesterolemia, and hypertriglyceridemia. ##STR00001##

Novel compounds of the structural formula (I), and the pharmaceutically acceptable salts thereof, are agonists of G-protein coupled receptor 40 (GPR40) and may be useful in the treatment, prevention and suppression of diseases mediated by the G-protein-coupled receptor 40. The compounds of the present invention may be useful in the treatment of Type 2 diabetes mellitus, and of conditions that are often associated with this disease, including obesity and lipid disorders, such as mixed or diabetic dyslipidemia, hyperlipidemia, hypercholesterolemia, and hypertriglyceridemia. ##STR00001##