Inhibitors of nitric oxide synthase
AssigneeMUSC Foundation for Research Development
InventorInderjit Singh
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Abstract
The current invention discloses novel methods for the inhibition of inducible nitric oxide synthesis (iNOS) and the production of NO. Methods of inhibiting the induction of proinflammatory cytokines are also described. Methods of treating various disease states, such as X-linked adrenoleukodystrophy, multiple sclerosis, Alzheimer's and septic shock using inhibitors of iNOS and cytokine induction are disclosed. The inhibitors include the exemplary compounds lovastatin, a sodium salt of phenylacetic acid (NaPA), FPT inhibitor II, N-acetyl cysteine (NAC), and cAMP.
Claims75
A method for suppressing the induction of inducible nitric oxide synthase in a cell comprising contacting said cell with an effective amount of at least one induction suppressor of inducible nitric oxide synthase or a proinflammatory cytokine, wherein said induction suppressor is selected from the group consisting of an inhibitor of mevalonate synthesis, an inhibitor of Ras/Raf/MAP kinase pathway, an inhibitor of the farnesylation of Ras, an inhibitor of NF-kβ activation, an antioxidant, an enhancer of intracellular cAMP, an enhancer of protein kinase A (PKA) or a stimulator of AMP-activated protein kinase.
12 The method of claim 11, wherein said inhibitor of the farnesylation of Ras is FPT inhibitor II.
A method for suppressing the induction of inducible nitric oxide synthase in a cell comprising contacting said cell with an effective amount of at least one induction suppressor of inducible nitric oxide synthase, wherein said induction suppressor of inducible nitric oxide synthase is selected from the group consisting of lovastatin, mevastatin, FPT inhibitor II, forskolin, rolipram, phenylacetate, N-acetyl cysteine, PDTC, 4-phenylbutyrate (4PBA), 5-aminoimmidazole-4-carboxamide ribonucleoside (AICAR), theophylline, papaverine, cAMP, 8-bromo-cAMP and (S)-cAMP.
A method of identifying a candidate induction suppressor of inducible nitric oxide synthase inhibitor, comprising preparing a cell capable of inducible nitric oxide synthase activity and testing said candidate induction suppressor for the ability to inhibit said inducible nitric oxide synthase activity, wherein said candidate induction suppressor of inducible nitric oxide synthase is an inhibitor of mevalonate synthesis, an inhibitor of Ras/Raf/MAP kinase pathway, an inhibitor of the farnesylation of Ras, an inhibitor of NF-kβ activation, an antioxidant, an enhancer of intracellular cAMP, an enhancer of protein kinase A (PKA) or a stimulator of AMP-activated protein kinase, and wherein said ability to inhibit said inducible nitric oxide synthase activity is indicative of a candidate induction suppressor of inducible nitric oxide synthase.
A method of suppressing the accumulation of very long chain fatty acids in a cell, comprising administering a biologically effective amount of at least one induction suppressor of inducible nitric oxide synthase.
A method of treating a nitric oxide or cytokine mediated disorder in a cell, comprising administering a biologically effective amount of at least one induction suppressor of inducible nitric oxide synthase.
A method for treatment of septic shock, comprising administering a biologically effective amount of at least one induction suppressor of inducible nitric oxide synthase.
A method for inhibiting apoptosis of a cell comprising contacting said cell with an effective amount of at least one induction suppressor of inducible nitric oxide synthase.
A method for enhancing the production of an inducible nitric oxide synthatase or a proinflammatory cytokine in a cell comprising comprising providing a biologically effective amount of a inducible nitric oxide synthatase stimulator, wherein said stimulator is a PKA inhibitor or enhancer of intracellular cAMP.
Dependencies are inferred from the claim text.