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New use 938

New use 938 description/claims

The present invention relates to the use of Myeloperoxidase (MPO) inhibitors or pharmaceutically acceptable salts thereof for the treatment of multiple system atrophy (MSA). The present invention further relates to the use of Myeloperoxidase (MPO) inhibitors or pharmaceutically acceptable salts thereof for the treatment of Huntington's disease (HD). The present invention also relates to the use of Myeloperoxidase (MPO) inhibitors or pharmaceutically acceptable salts thereof for neuroprotection.

Myeloperoxidase (MPO) is a heme-containing enzyme found predominantly in polymorphonuclear leukocytes (PMNs). MPO is one member of a diverse protein family of mammalian peroxidases that also includes eosinophil peroxidase, thyroid peroxidase, salivary peroxidase, lactoperoxidase, prostaglandin H synthase, and others. The mature enzyme is a dimer of identical halves. Each half molecule contains a covalently bound heme that exhibits unusual spectral properties responsible for the characteristic green colour of MPO. Cleavage of the disulphide bridge linking the two halves of MPO yields the hemi-enzyme that exhibits spectral and catalytic properties indistinguishable from those of the intact enzyme. The enzyme uses hydrogen peroxide to oxidize chloride to hypochlorous acid. Other halides and pseudohalides (like thiocyanate) are also physiological substrates to MPO.

PMNs are of particular importance for combating infections. These cells contain MPO, with well-documented microbicidal action. PMNs act non-specifically by phagocytosis to engulf microorganisms, incorporate them into vacuoles, termed phagosomes, which fuse with granules containing myeloperoxidase to form phagolysosomes. In phagolysosomes the enzymatic activity of the myeloperoxidase leads to the formation of hypochlorous acid, a potent bactericidal compound. Hypochlorous acid is oxidizing in itself, and reacts most avidly with thiols and thioethers, but also converts amines into chloramines, and chlorinates aromatic amino acids. Macrophages are large phagocytic cells, which, like PMNs, are capable of phagocytosing microorganisms. Macrophages can generate hydrogen peroxide and upon activation also produce myeloperoxidase. MPO and hydrogen peroxide can also be released to the outside of the cells where the reaction with chloride can induce damage to adjacent tissue.

Linkage of myeloperoxidase activity to disease has been implicated in neurological diseases with a neuroinflammatory response including multiple sclerosis, Alzheimer's disease and Parkinson's disease.

MPO positive cells are immensely present in the circulation and in tissue undergoing inflammation. More specifically MPO containing macrophages, microglia, astrocytes and/or neurons have been documented in the CNS during disease; multiple sclerosis (Nagra R M, et al. Journal of Neuroimmunology 1997; 78(1-2):97-107; Marik C, et al. Brain. 2007; 130: 2800-15; Gray E, et al. Brain Pathology. 2008; 18: 86-95), Parkinson's disease (Choi D-K. et al. J. Neurosci. 2005; 25(28):6594-600) and Alzheimer's disease (Reynolds W F, et al. Experimental Neurology. 1999; 155:31-41; Green P S. et al. Journal of Neurochemistry. 2004; 90(3):724-33). It is supposed that some aspects of a chronic ongoing inflammation result in an overwhelming destruction where agents from MPO reactions have an important role.

The enzyme is released both extracellularly as well as into phagolysosomes in the neutrophils (Hampton M B, Kettle A J, Winterboum C C. Blood 1998; 92(9):3007-17). A prerequisite for the MPO activity is the presence of hydrogen peroxide, generated by NADPH oxidase and a subsequent superoxide dismutation. The oxidized enzyme is capable to use a plethora of different substrates of which chloride is most recognized. From this reaction the strong non-radical oxidant—hypochlorous acid (HOCl)—is formed. HOCl oxidizes sulphur containing amino acids like cysteine and methionine very efficiently (Peskin A V, Winterbourn C C. Free Radical Biology and Medicine 2001; 30(5):572-9). It also forms chloramines with amino groups, both in proteins and other biomolecules (Peskin A V. et al. Free Radical Biology and Medicine 2004; 37(10):1622-30). It chlorinates phenols (like tyrosine) (Hazen S L. et al. Mass Free Radical Biology and Medicine 1997; 23(6):909-16) and unsaturated bonds in lipids (Albert C J. et al. J. Biol. Chem. 2001; 276(26):23733-41), oxidizes iron centers (Rosen H, Klebanoff S J. Journal of Biological Chemistry 1982; 257(22):13731-354) and crosslinks proteins (Fu X, Mueller D M, Heinecke J W. Biochemistry 2002; 41(4):1293-301). Various compounds that are MPO inhibitors are disclosed in WO 01/85146, J. Heterocyclic Chemistry, 1992, 29, 343-354, J. Chem. Soc., 1962, 1863, WO03/089430 and WO2006/062465.

Multiple system atrophy (MSA) is a neurodegenerative disorder presenting with autonomic failure and with motor impairment resulting from L-dopa-unresponsive parkinsonism, cerebellar ataxia and pyramidal signs. Histologically, there is neuron loss in the striatum, substantia nigra pars compacta, cerebellum, pons, inferior olives and intermediolateral column of the spinal cord. Glial pathology includes astrogliosis, microglial activation and α-synuclein containing oligodendroglial cytoplasmic inclusions. The pronounced neuroinflammation with activated microglia contribution as well as cytoplasmic inclusion bodies, containing aggregated and oxidatively modified proteins, makes it intriguing to consider a significant contribution of MPO activity in the progressive neurodegeneration characterizing the MSA pathology.

Support for MPO inhibition in an MSA-like pathology can be generated through the use of preclinical disease models for MSA, like transgenic mice with oligodendroglial overexpression of human α-synuclein with or without a toxin addition like 3-nitropropionic acid.

Huntington's disease (HD) is a hereditary progressive neurodegenerative disorder characterized clinically by motor and psychiatric disturbances and pathologically by neuronal loss and gliosis (reactive astrocytosis) particularly in the striatum and cerebral cortex. HD is a neurodegenerative disorder caused by expansion of a CAG repeat in the HD gene, coding for polyglutamine in the huntingtin protein. Explanations to the pathological mechanisms include oxidative stress, impaired energy metabolism, and abnormal protein-protein interactions. Such mechanisms are possible to link to MPO activity, which might be manifested through its observed overexpression in pathological HD tissue (Choi D-K. et al. J. Neurosci. 2005; 25(28):6594-600).

Support for MPO inhibition in an HD-like pathology can be generated through the use of preclinical disease models for HD. Such models might be mice or rats treated with mitochondrial toxins like 3-nitropropionic acid or malonate (Matthews R T. et al J. Neurosci. 1998; 18:156-63). Useful models might also be transgenic mice expressing mutants of the huntingtin protein with or without a toxin addition like 3-nitropropionic acid (Bogdanov M B. et al. J. Neurochem. 1998; 71:2642-44).

There is a large unmet need for medications that can be used for the treatment of Huntington's disease, for the treatment of multiple system atrophy and/or for neuroprotection.

FIG. 1 is a graph depicting the mean daily motor score of MSA mice treated with AZD (compound I) and vehicle.

FIG. 2 is a graph depicting the rearing and open field activity of MSA mice treated with AZD (compound I) and vehicle.

FIG. 3 is a graph depicting stride length of the left and right hindlimbs of MSA mice treated with AZD (compound I) and vehicle.

FIG. 4A is a graph depicting the number of TH immunopositive cells in the substantia nigra pars compacta (SNc) of MSA mice treated with AZD (compound I) and vehicle.

FIG. 4B is a graph depicting the dopaminergic terminals in striatum of MSA mice treated with AZD (compound I) and vehicle.

FIG. 4C is a graph depicting the number of neurons in the striatum of MSA mice treated with AZD (compound I) and vehicle.

FIG. 5A is a graph depicting the total number of neurons in the inferior olivary complex in the cerebellum of MSA mice treated with AZD (compound I) and vehicle.

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