USE OF ISOQC INHIBITORS

The present invention relates in general to an inhibitor of a glutaminyl peptide cyclotransferase-like protein (QPCTL), and the use thereof for the treatment and/or prevention of an inflammatory disease or disorder selected from the group consisting of (a) chronic and acute inflammations, e.g. rheumatoid arthritis, atherosclerosis, restenosis, pancreatitis; (b) other inflammatory diseases, e.g. neuropathic pain, graft rejection/graft failure/graft vasculopathy, HIV infections/AIDS, gestosis, tuberous sclerosis, Guillain-Barré syndrome, chronic inflammatory demyelinising polyradiculoneuropathy and multiple sclerosis; (c) neuroinflammation; and (d) neurodegenerative diseases, e.g. mild cognitive impairment (MCI), Alzheimer's disease, neurodegeneration in Down Syndrome, Familial British Dementia, and Familial Danish Dementia, which may result from neuroinflammation.

IN VIVO SCREENING MODELS FOR TREATMENT OF QC-RELATED DISORDERS

A double transgenic non-human animal, in particular a transgenic mouse encoding Qpct proteins, which have been implicated in Qpct-related diseases, and Amyloid Precursor Protein (APP). Also provided are cells and cell lines comprising transgenes encoding for Qpct and APP. Also provided are methods and compositions for evaluating agents that affect Qpct, for use in compositions for the treatment of Qpct-related diseases. 1. A transgenic non-human animal for overexpressing amyloid precursor protein (APP) and glutaminyl cyclase (QC).2. The transgenic non-human animal of claim 1 , which overexpresses amyloid precursor protein (APP) and glutaminyl cyclase (QC).3. The transgenic non-human animal of claim 1 , which comprises cells containing one or more DNA transgenes encoding human APP and human QC.4. The transgenic non-human animal of claim 3 , wherein the human QC comprises the amino acid sequence of SEQ ID NO: 1 or an amino acid sequence having at least 75% sequence identity to the amino acid sequence of SEQ ID NO: 1 or a fragment or derivative of the amino acid sequence of SEQ ID NO: 1.5. The transgenic non-human animal of claim 3 , wherein the human QC consists of the amino acid sequence of SEQ ID NO: 1.6. The transgenic non-human animal of claim 3 , wherein the human APP comprises human APP695 or human APP770.7. The transgenic non-human animal of claim 6 , wherein the human APP comprises human APP695 as defined by the amino acid sequence of SEQ ID NO: 2 or an amino acid sequence having at least 75% sequence identity to the amino acid sequence of SEQ ID NO: 2 or a fragment or derivative of the amino acid sequence of SEQ ID NO: 2.8. The transgenic non-human animal of claim 7 , wherein the human APP695 consists of the amino acid sequence of SEQ ID NO: 2.9. The transgenic non-human animal of any of claim 3 , wherein the DNA transgene encoding QC comprises the nucleotide sequence of SEQ ID NO: 4 or substantially the same nucleotide sequence of SEQ ID NO: 4.10. The ...

Use of isoQC inhibitors in the treatment and prevention of inflammatory diseases or conditions

The present invention relates in general to an inhibitor of a glutaminyl peptide cyclotransferase-like protein (QPCTL), and the use thereof for the treatment and/or prevention of an inflammatory disease or disorder selected from the group consisting of (a) chronic and acute inflammations, e.g. rheumatoid arthritis, atherosclerosis, restenosis, pancreatitis; (b) other inflammatory diseases, e.g. neuropathic pain, graft rejection/graft failure/graft vasculopathy, HIV infections/AIDS, gestosis, tuberous sclerosis, Guillain-Barré syndrome, chronic inflammatory demyelinizing polyradiculoneuropathy and multiple sclerosis; (c) neuroinflammation; and (d) neurodegenerative diseases, e.g. mild cognitive impairment (MCI), Alzheimer's disease, neurodegeneration in Down Syndrome, Familial British Dementia, and Familial Danish Dementia, which may result from neuroinflammation.

Crystal structure of glutaminyl cyclase

A novel crystal structures of human and murine glutaminyl cyclase (QC, EC 2.3.2.5), methods of preparing the crystals, as well as the use of said crystal structures for identifying inhibitors of human and murine glutaminyl cyclase.

NOVEL INHIBITORS OF MEPRIN ALPHA AND BETA

The present invention relates to novel hydroxamic acid derivatives as inhibitors of meprin β and/or α, pharmaceutical compositions comprising such compounds, methods for treatment or prophylaxis of diseases or conditions, especially such that are related to meprin β and/or α, and compounds and pharmaceutical compositions for use in such methods.

Crystal structure of isoglutaminyl cyclase

A crystal comprising human isoglutaminyl cyclase having a characterized space group of P1211 and unit cell dimensions of +/5% of a=126.51 , b=109.68 , c=159.53 , =90.0°, =104.9° and =90.0°.

Crystal structure of glutaminyl cyclase

Novel crystal structures of human and murine glutaminyl cyclase (QC, EC 2.3.2.5), methods of preparing the crystals, as well as the use of said crystal structures for identifying inhibitors of human and murine glutaminyl cyclase.

CRYSTAL STRUCTURE OF GLUTAMINYL CYCLASE

Novel crystal structures of human and murine glutaminyl cyclase (QC, EC 2.3.2.5), methods of preparing the crystals, as well as the use of said crystal structures for identifying inhibitors of human and murine glutaminyl cyclase.

CRYSTAL STRUCTURE OF ISOGLUTAMINYL CYCLASE

A crystal comprising human isoglutaminyl cyclase having a characterised space group of P1211 and unit cell dimensions of +/5% of a=126.51 , b=109.68 , c=159.53 , =90.0°, =104.9° and =90.0°.

Inhibitors of meprin α and β

The present invention relates to novel hydroxamic acid derivatives as inhibitors of meprin β and/or α, pharmaceutical compositions comprising such compounds, methods for treatment or prophylaxis of diseases or conditions, especially such that are related to meprin β and/or α, and compounds and pharmaceutical compositions for use in such methods.

NOVEL INHIBITORS OF MEPRIN ALPHA AND BETA

The present invention relates to novel hydroxamic acid derivatives as inhibitors of meprin β and/or α, pharmaceutical compositions comprising such compounds, methods for treatment or prophylaxis of diseases or conditions, especially such that are related to meprin β and/or α, and compounds and pharmaceutical compositions for use in such methods. 3. The compound according to claim 1 , wherein Ris H.4. (canceled)5. The compound according to claim 1 , wherein Ris selected from the group consisting of arylmethyl claim 1 , (alkoxyaryl)methyl claim 1 , (hydroxyaryl)methyl claim 1 , (carboxyaryl)methyl claim 1 , (alkoxyheteroaryl)methyl claim 1 , (heteroarylaryl)methyl claim 1 , (hydroxyheteroaryl)methyl and (carboxyheteroaryl)methyl claim 1 , each of which can be optionally substituted.7. The compound according to claim 1 , wherein Ris selected from the group consisting of (1 claim 1 ,3-benzodioxol-5-yl)methyl claim 1 , (3-carboxyphenyl)methyl claim 1 , and (4-carboxyphenyl)methyl.8. The compound according to claim 1 , wherein Ris selected from the group consisting of aryl claim 1 , alkoxyaryl claim 1 , carboxyaryl claim 1 , cyanoaryl claim 1 , haloaryl claim 1 , hydroxyaryl claim 1 , alkoxyheteroaryl claim 1 , cyanoheteroaryl claim 1 , haloheteroaryl claim 1 , heteroarylaryl claim 1 , hydroxyheteroaryl and carboxyheteroaryl claim 1 , each of which can be optionally substituted.10. The compound according to claim 1 , wherein Ris selected from the group consisting of 1 claim 1 ,3-benzodioxol-5-yl claim 1 , 3-carboxyphenyl claim 1 , 1 claim 1 ,3-benzodioxol-5-yl claim 1 , 3-carboxyphenyl claim 1 , 4-carboxyphenyl claim 1 , 3-carboxy-4-methoxyphenyl claim 1 , 3 claim 1 ,5-dichloro-4-hydroxyphenyl claim 1 , 4-chlorophenyl claim 1 , 4-cyanophenyl claim 1 , 4-fluorophenyl claim 1 , 2 claim 1 ,6-difluoro-4-methoxyphenyl claim 1 , 3-fluoro-4-methoxyphenyl claim 1 , 3-methoxyphenyl claim 1 , 4-methoxyphenyl claim 1 , 4-chlorophenyl claim 1 , and 4-methylphenyl.11. The compound ...

CRYSTAL STRUCTURE OF GLUTAMINYL CYCLASE

A novel crystal structures of human and murine glutaminyl cyclase (QC, EC 2.3.2.5), methods of preparing the crystals, as well as the use of said crystal structures for identifying inhibitors of human and murine glutaminyl cyclase.

IN VIVO SCREENING MODELS FOR TREATMENT OF ALZHEIMER'S DISEASE AND OTHER QPCT-RELATED DISORDERS

A transgenic non-human animal, in particular a transgenic mouse, encoding Qpct proteins which have been implicated in Qpct-related diseases. Also disclosed are cells and cell lines comprising transgenes encoding for Qpct. Further disclosed are methods and compositions for evaluating agents that affect Qpct, for use in compositions for the treatment of Qpct-related diseases.

Crystal structure of isoglutaminyl cyclase

In vivo screening models for treatment of alzheimer's disease and other qpct-related disorders

Transgenična neljudska životinja koja hipereksprimira glutaminil-ciklazu, naznačena time što joj stanice sadrže DNA transgena koji kodira glutaminil-ciklazu. Patent sadrži još 22 patentna zahtjeva. A transgenic non-human animal that hyperexpresses glutaminyl cyclase, wherein its cells contain the DNA of a transgene encoding glutaminyl cyclase. The patent contains 22 more patent claims.

Novel alpha and beta meprin inhibitors

Un compuesto representado por la siguiente fórmula I, sus enantiómeros individuales, sus diastereoisómeros individuales, sus hidratos, sus solvatos, sus formas de cristal, sus tautómeros individuales o una sal farmacéuticamente aceptable del mismo, **(Ver fórmula)** en la que: n = 1-3, preferiblemente 1 o 2; R1 se selecciona del grupo que consiste en arilo, arilalquilo, heteroarilo y heteroarilalquilo, cada uno de los cuales puede estar opcionalmente sustituido; R3 y R4 se seleccionan independientemente de H y el grupo que consiste en alquilo, arilo, arilalquilo, heteroarilo y heteroarilalquilo, cada uno de los cuales puede estar opcionalmente sustituido; R2 se selecciona del grupo que consiste en arilo, arilalquilo, heteroarilo y heteroarilalquilo, cada uno de los cuales está sustituido; en la que dos cualesquiera de R1, R2, R3 y R4 pueden unirse juntos para formar un anillo; R4 es preferiblemente H; y X es -CH2-. A compound represented by the following formula I, its individual enantiomers, its individual diastereoisomers, its hydrates, its solvates, its crystal forms, its individual tautomers or a pharmaceutically acceptable salt thereof, **(See formula)** in which : n = 1-3, preferably 1 or 2; R1 is selected from the group consisting of aryl, arylalkyl, heteroaryl, and heteroarylalkyl, each of which may be optionally substituted; R3 and R4 are independently selected from H and the group consisting of alkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl, each of which may be optionally substituted; R2 is selected from the group consisting of aryl, arylalkyl, heteroaryl, and heteroarylalkyl, each of which is substituted; wherein any two of R1, R2, R3, and R4 can be joined together to form a ring; R4 is preferably H; and X is -CH2-.

Crystal structure of isoglutaminyl cyclase

The invention relates to novel crystal structures of isoglutaminyl cyclase, methods of preparing the crystals, as well as the use of said crystal structures for identifying inhibitors of isoglutaminyl cyclase.

Use of isoQC inhibitors

The present invention relates in general to an inhibitor of a glutaminyl peptide cyclotransferase-like protein (QPCTL), and the use thereof for the treatment and/or prevention of an inflammatory disease or disorderselected from the group consisting of a.chronic and acute inflammations, e.g. rheumatoid arthritis, atherosclerosis, restenosis, pancreatitis, b.other inflammatory diseases, e.g. neuropathic pain, graft rejection/graft failure/graft vasculopathy, HIV infections/AIDS, gestosis, tuberous sclerosis, Guillain-Barr syndrome, chronic inflammatory demyelinising polyradiculoneuropathy and multiple sclerosis, c.neuroinflammation, and d.neurodegenerative diseases, e.g. mild cognitive impairment (MCI), Alzheimer's disease, neurodegeneration in Down Syndrome, Familial British Dementia, and Familial Danish Dementia, which may result from neuroinflammation.

Novel inhibitors of meprin alpha and beta

The present invention relates to hydroxamic acid derivatives of Formula I as inhibitors of meprin .BETA. and/or .ALPHA., pharmaceutical compositions comprising such compounds, use for treatment or prophylaxis of diseases or conditions. R1, R2, R3, R4 and X can represent various different groups and n can represent various different integers.

In vivo screening models for treatment of Alzheimer's disease and other Qpct-related disorders

The present invention provides a transgenic non-human animal, in particular a transgenic mouse encoding Qpct proteins, which have been implicated in Qpct-related diseases. The present invention additionally provides cells and cell lines comprising transgenes encoding for Qpct. The present invention further provides methods and compositions for evaluating agents that affect Qpct, for use in compositions for the treatment of Qpct-related diseases.

Novel inhibitors of meprin alpha and beta

In vivo screening models for treatment of Alzheimer's disease and other QPCT-related disorders

The present invention provides a transgenic non-human animal, in particular a transgenic mouse encoding Qpct proteins, which have been implicated in Qpct-related diseases. The present invention additionally provides cells and cell lines comprising transgenes encoding for Qpct. The present invention further provides methods and compositions for evaluating agents that affect Qpct, for use in compositions for the treatment of Qpct-related diseases.

Use of isoqc inhibitors

Anti-transthyretin (ttr) binding proteins and uses thereof

Transthyretin amyloidosis is characterized by progressive deposition of the plasma protein transthyretin in the myocardium, peripheral nerves and/or other tissues, which can ultimately lead to congestive heart failure, polyneuropathy and death. The present invention provides binding proteins that can specifically bind to an isoaspartate residue in a transthyretin protein as well as their therapeutic, diagnostic and prognostic uses.

In-vivo-screening-modelle zur behandlung der alzheimer-krankheit und anderer erkrankungen in zusammenhang mit dem qpct-gen

メプリンアルファ及びベータの新規な阻害剤

【課題】本発明は、メプリンβ及び/又はαの阻害剤としての新規なヒドロキサム酸誘導体、このような化合物を含む医薬組成物、特にメプリンβ及び/又はαに関連する疾患又は状態を処置又は予防するための方法、並びに、このような方法において使用するための化合物及び医薬組成物に関する。【解決手段】上記に説明した課題に対する解決策として、本発明は、式Iによって表される化合物、その個々のエナンチオマー、その個々のジアステレオマー、その水和物、その溶媒和物、その結晶形、その個々の互変異性体、又はその薬学的に許容可能な塩を提供する。【選択図】なし

Anti-transthyretin (ttr) binding proteins and uses thereof

Transthyretin amyloidosis is characterized by progressive deposition of the plasma protein transthyretin in the myocardium, peripheral nerves and/or other tissues, which can ultimately lead to congestive heart failure, polyneuropathy and death. The present invention provides binding proteins that can specifically bind to an isoaspartate residue in a transthyretin protein as well as their therapeutic, diagnostic and prognostic uses.

Crystal structure of glutaminyl cyclase

The invention relates to novel crystal structures of human and murine glutaminyl cyclase (QC, EC 2.3.2.5), methods of preparing the crystals, as well as the use of said crystal structures for identifying inhibitors of human and murine glutaminyl cyclase.

Continuous spectrometric assays for measuring meprin activity using an auxiliary enzyme

The present invention relates to assays for measuring meprin activity. More particularly, the assays concern rapid, sensitive, reliable and robust assays for measuring meprin activity comprising a coupled enzyme assay suitable for high-throughput screening. In particular, the invention relates to methods for 1) for assaying meprin catalytic activity; 2) identifying inhibitors of meprin activity; 3) methods for measuring the IC50 of a test compound inhibiting meprin activity; 4) methods for differentiating a competitive inhibitor meprin from a non-competitive inhibitor of meprin; and 5) methods for identifying specific inhibitors for meprin α and meprin β. Further provided is a kit, which can be used to perform the methods of the invention.

Continuous spectrometric assays for measuring meprin activity using an auxiliary enzyme

The present invention relates to assays for measuring meprin activity. More particularly, the assays concern rapid, sensitive, reliable and robust assays for measuring meprin activity comprising a coupled enzyme assay suitable for high-throughput screening. In particular, the invention relates to methods for 1) for assaying meprin catalytic activity; 2) identifying inhibitors of meprin activity; 3) methods for measuring the IC50 of a test compound inhibiting meprin activity; 4) methods for differentiating a competitive inhibitor meprin from a non-competitive inhibitor of meprin; and 5) methods for identifying specific inhibitors for meprin α and meprin β. Further provided is a kit, which can be used to perform the methods of the invention.

Kontinuerlige spektrometriske assays til måling af meprin-aktivitet ved anvendelse af et hjælpeenzym