JP2007538003A5

JP2007538003A5 -

Info

Publication number: JP2007538003A5
Application number: JP2006551601A
Authority: JP
Filing date: 2005-01-31
Publication date: 2008-03-21

Claims

A method for assessing human myocardial infarction (MI) susceptibility comprising the following steps:
Analyzing human nucleic acids for the presence or absence of 5-lipoxygenase activating protein (FLAP) haplotypes; and
Assessing myocardial infarction sensitivity based on the presence or absence of a FLAP haplotype whose presence correlates with increased myocardial infarction sensitivity;
The FLAP haplotype includes a step;
(a) SG13S25 (SEQ ID NO: 1, 165553), allele G; SG13S114 (SEQ ID NO: 1, 178096), allele T; SG13S89 (SEQ ID NO: 1, 159580), allele G And SG13S32 (SEQ ID NO: 1, position 198547), FLAP haplotype containing a marker for allele A,
(b) SG13S377 (SEQ ID NO: 1, position 169965), allele A; SG13S114 (SEQ ID NO: 1, position 178096), allele A; SG13S41 (SEQ ID NO: 1, position 202045), allele A And SG13S35 (SEQ ID NO: 1, position 206117), a FLAP haplotype containing an allele G marker,
(c) SG13S375 (SEQ ID NO: 1, 164874), a FLAP haplotype containing a marker for allele T, and
(d) SG13S25 (SEQ ID NO: 1, 165553), allele G; SG13S99 (DG00AAFIU), allele T (SEQ ID NO: 1, 138551); SG13S377 (DG00AAJFF) (SEQ ID NO: 1, 169965) ), Allele G; SG13S106 [SNP DG00AAHII] (SEQ ID NO: 1, position 176579), allele G; SG13S32 (SEQ ID NO: 1, position 198547), allele A; and SG13S35 (SEQ ID NO: 1, 206117), a FLAP haplotype containing a marker for allele G, and a method for evaluating the susceptibility of myocardial infarction, which is selected from the group consisting of:

The method of claim 1, wherein the analyzing step further comprises isolating nucleic acid from a biological sample collected from a human.

Use of a leukotriene synthesis inhibitor for the preparation of a medicament for prophylactic treatment of myocardial infarction (MI) in humans where a 5-lipoxygenase activating protein (FLAP) haplotype is detected, wherein the FLAP haplotype is;
(a) SG13S25 (SEQ ID NO: 1, 165553), allele G; SG13S114 (SEQ ID NO: 1, 178096), allele T; SG13S89 (SEQ ID NO: 1, 159580), allele G And SG13S32 (SEQ ID NO: 1, position 198547), FLAP haplotype containing a marker for allele A,
(b) SG13S377 (SEQ ID NO: 1, position 169965), allele A; SG13S114 (SEQ ID NO: 1, position 178096), allele A; SG13S41 (SEQ ID NO: 1, position 202045), allele A And SG13S35 (SEQ ID NO: 1, position 206117), a FLAP haplotype containing an allele G marker,
(c) SG13S375 (SEQ ID NO: 1, 164874), a FLAP haplotype containing a marker for allele T, and
(d) SG13S25 (SEQ ID NO: 1, 165553), allele G; SG13S99 (DG00AAFIU), allele T (SEQ ID NO: 1, 138551); SG13S377 (DG00AAJFF) (SEQ ID NO: 1, 169965) ), Allele G; SG13S106 [SNP DG00AAHII] (SEQ ID NO: 1, position 176579), allele G; SG13S32 (SEQ ID NO: 1, position 198547), allele A; and SG13S35 (SEQ ID NO: 1. Use of a leukotriene synthesis inhibitor, characterized in that it is selected from the group consisting of: a FLAP haplotype containing a marker for allele G.

The FLAP haplotype is SG13S25 (SEQ ID NO: 1, 165553), allele G; SG13S114 (SEQ ID NO: 1, 178096), allele T; allele T; SG13S89 (SEQ ID NO: 1, 159580) 4. Use according to claim 3, comprising allele G; and SG13S32 (SEQ ID NO: 1, position 198547), allele A marker.

The agent comprises an amount of a leukotriene synthesis inhibitor that effectively reduces the level of inflammatory markers in humans during prophylactic treatment, i.e., the level of C-reactive protein or myeloperoxidase (MPO). Use according to 3 or 4.

An amount of the agent that effectively reduces the level of leukotrienes in humans during prophylactic treatment, i.e., leukotriene levels in serum, plasma or urine collected from humans during prophylactic treatment Use according to claim 3 or 4, comprising a leukotriene synthesis inhibitor.

6. The use according to claim 5, wherein a blood sample collected from a human, i.e. a blood sample stimulated with a calcium ion permeable carrier, is analyzed ex vivo for a reduction in leukotriene levels prior to analysis of leukotriene production.

8. Use according to any of claims 3 to 7, wherein the agent comprises an amount of a leukotriene synthesis inhibitor that effectively reduces the level of leukotrienes to a level that is less than the average level of leukotrienes in humans.

A composition comprising a leukotriene synthesis inhibitor and a statin.

The composition of claim 9 further comprising a pharmaceutically acceptable carrier.

The leukotriene synthesis inhibitor is 5-lipoxygenase, 5-lipoxygenase activating protein (FLAP), leutocryen C4 synthase, leucryen A4 hydrase, arachidonic acid 4-lipoxygenase, leukotriene B4 12-hydroxydehydrogenase, leukotriene A4 receptor, leukotriene Group consisting of B4 receptor, leukotriene C4 receptor, leukotriene D4 receptor, leukotriene E4 receptor, leukotriene B4 receptor 1, leukotriene B4 receptor 2, cysteinyl leukotriene receptor 1, and cysteinyl leukotriene receptor 2 The composition according to claim 9 or 10, which is an inhibitor that inhibits the activity of a leukotriene synthesis pathway protein selected from:

The leukotriene synthesis inhibitor is 1-((4-chlorophenyl) methyl) -3-((1,1-dimethylethyl) thio) -α, α-dimethyl-5- (2-quinolinylmethoxy) -1H. -Indole-2-propionic acid, (R)-(+)-α-cyclopentyl-4- (2-quinolinylmethoxy) -benzeneacetic acid, 3- (3- (1,1-dimethylethylthio-5- (Quinolin-2-ylmethoxy) -1- (4-chloromethylphenyl) indol-2-yl) -2,2-dimethylpropionaldehyde oxime-0-2-acetic acid, zileuton, atreleuton, 6-((3- Fluoro-5- (terolahydro-4-methoxy-2H-pyran-4-yl) phenoxy) methyl) -1-methyl-2 (1H) -quinolinone, 1-((4-chlorophenyl) methyl) -3-((1 , 1 dimethylethyl) thio) -α, α-dimethyl-5- (2-quinolinylmethoxy) -1H-indole-2-propionic acid, and 4- (3- (4- (2- (2- Chill - imidazol-1-yl) - phenylsulfanyl) - phenyl) - Terorahidoro - composition according to claim 9 or 10 selected from the group consisting of pyran-4-carboxylic acid amide.

The composition according to any one of claims 9 to 12, wherein the leukotriene synthesis inhibitor is a FLAP inhibitor.

The FLAP inhibitor has the following formula:

Wherein R ¹ is a compound represented by the following formula:

Wherein R ² and R ³ are the same or different from each other and are hydrogen, a lower alkyl group, a phenyl group, a benzyl group, or the following formula:

Wherein R ⁴ is optionally substituted with a hydroxyl group, a carboxyl group, a lower alkoxycarbonyl group, a lower alkylthio group, a heteroaryl group or a carbamoyl group, hydrogen, a lower alkyl group, a phenyl group Or a benzyl group, R ⁵ is hydrogen, a lower alkyl group, a phenyl group or a benzyl group, R ⁶ is a group represented by the formula of —COR ⁵ or —CO ² R ⁵ , and R ⁷ is , Hydrogen, a lower alkyl group or a phenyl group, and Y represents the following formula:

Wherein R ⁸ is hydrogen, a lower alkyl group or a phenyl group, n is a number from 0 to 5, and Z is a norbornyl group or the following formula:

In which R ⁹ and R ¹⁰ are the same or different from each other and are hydrogen, a lower alkyl group, or a phenyl group, or R ⁹ and R ¹⁰ are combined together. Form a saturated carbocyclic structure having up to 6 carbon atoms, m is a number from 1 to 6, and A and B are the same or different from each other, and hydrogen, lower 14. A composition according to claim 13 comprising a compound of the formula or a pharmaceutically acceptable salt thereof which is an alkyl group or halogen, or a pharmaceutically acceptable salt thereof.

The FLAP inhibitor is 2- [4- (quinolin-2-yl-methoxy) phenyl] -2-cyclopentylacetic acid, 2- [4- (quinolin-2-yl-methoxy) phenyl] -2-cyclohexylacetic acid, And [+)-of 2- [4- (quinolin-2-yl-methoxy) phenyl] -2-cycloheptylacetic acid, 2- [4- (quinolin-2-yl-methoxy) phenyl] -2-cyclopentylacetic acid Selected from the group consisting of the enantiomers, the 2- (4- (quinolin-2-yl-methoxy) phenyl] -2-cyclopentylacetic acid (-)-enantiomer, and pharmaceutically acceptable salts thereof. 14. A composition according to claim 13 comprising a compound.

14. The composition of claim 13, wherein the FLAP inhibitor comprises BAY-X-1005 or a physiologically acceptable salt, formulation or prodrug thereof.

The composition according to claim 13, wherein the leukotriene synthesis inhibitor is (R)-(+)-α-cyclopentyl-4- (2-quinolinylmethoxy) -benzeneacetic acid.

18. The composition according to any one of claims 9 to 17, wherein the statin is selected from the group consisting of lobvastatin, fluvastatin, atorvastatin, lovastatin, simvastatin, pravastatin or pitavastatin.

19. A composition according to any of claims 9 to 18 comprising an amount of a leukotriene synthesis inhibitor that effectively reduces human serum C-reactive protein (CRP).

20. A composition according to any of claims 9 to 19 comprising an amount of a statin that effectively reduces human low density lipoprotein cholesterol (LDL) and serum CRP.

21. A composition according to any of claims 9 to 20, comprising a leukotriene synthesis inhibitor and a statin in an amount that effectively and synergistically reduces human serum C-reactive protein.

The composition according to any one of claims 9 to 21, comprising a unit dose for administration to a human.

The composition according to any one of claims 9 to 22, which is in the form of a pill or a capsule.

24. A composition according to any of claims 9 to 23 comprising 50 to 750 mg of FLAP inhibitor.

24. A composition according to any one of claims 9 to 23 comprising 250 to 375 mg of FLAP inhibitor.

26. A composition according to any one of claims 9 to 25 comprising 1 to 200 mg of statin.

27. A composition according to any one of claims 9 to 26 comprising 5 to 80 mg of FLAP inhibitor.

28. Use of a composition according to any of claims 9 to 27 for the manufacture of a medicament that reduces human serum LDL, serum leukotrienes and serum C-reactive protein (CRP).

29. The use of claim 28, wherein the human is at risk for a disease or condition selected from the group consisting of myocardial infarction, acute coronary syndrome, stroke, and peripheral arterial occlusive disease.

A method for monitoring the effects of a prophylactic treatment of human myocardial infarction (MI), ie, a prophylactic treatment comprising administering to a human a leukotriene synthesis inhibitor, the following steps:
Analyzing the myeloperoxidase (MPO) contained in samples taken from humans before and during prophylactic treatment and monitoring the effectiveness of the treatment, and an effective prophylactic treatment is prophylactic A method for monitoring the effect of a prophylactic treatment of myocardial infarction, characterized in that the MPO level during the treatment is decreased as compared with the MPO level prior to the treatment.

32. The method of claim 30, further comprising monitoring at least one inflammatory marker in a sample taken from a human undergoing prophylactic treatment.

32. The method of claim 31, wherein the inflammatory marker is C-reactive protein (CRP).

33. The method of any one of claims 30 to 32, further comprising monitoring leukotriene levels in serum, plasma or urine in humans prior to and during prophylactic treatment that effectively reduces leukotriene levels. Method.

34. The method of claim 33, wherein the monitoring step analyzes ex vivo on a blood sample collected from a human, i.e., a blood sample stimulated with a calcium ion permeable carrier prior to analysis of leukotriene production.

35. The method of claim 33 or 34, wherein the prophylactic treatment comprises administration of an agent that inhibits FLAP activity.

The human is a FLAP haplotype, ie;
(a) SG13S25 (SEQ ID NO: 1, 165553), allele G; SG13S114 (SEQ ID NO: 1, 178096), allele T; SG13S89 (SEQ ID NO: 1, 159580), allele G And SG13S32 (SEQ ID NO: 1, position 198547), FLAP haplotype containing a marker for allele A,
(b) SG13S377 (SEQ ID NO: 1, position 169965), allele A; SG13S114 (SEQ ID NO: 1, position 178096), allele A; SG13S41 (SEQ ID NO: 1, position 202045), allele A And SG13S35 (SEQ ID NO: 1, position 206117), a FLAP haplotype containing an allele G marker,
(c) SG13S375 (SEQ ID NO: 1, 164874), a FLAP haplotype containing a marker for allele T, and
(d) SG13S25 (SEQ ID NO: 1, 165553), allele G; SG13S99 (DG00AAFIU), allele T (SEQ ID NO: 1, 138551); SG13S377 (DG00AAJFF) (SEQ ID NO: 1, 169965) ), Allele G; SG13S106 [SNP DG00AAHII] (SEQ ID NO: 1, position 176579), allele G; SG13S32 (SEQ ID NO: 1, position 198547), allele A; and SG13S35 (SEQ ID NO: 36. A method according to any one of claims 33 to 35, wherein the method comprises a FLAP haplotype selected from the group consisting of: an FLAP haplotype comprising a marker for allele G, No. 1, 206117).

Use of a leukotriene synthesis inhibitor to prepare a drug for prophylactic treatment of human myocardial infarction (MI), wherein the drug inhibits leukotriene synthesis in an amount that effectively inhibits leukotriene synthesis in vivo. Use of a leukotriene synthesis inhibitor, characterized in that it reduces the level of human myeloperoxidase (MPO) in the course of a prophylactic treatment comprising an agent.

A kit comprising a reagent used in carrying out the method according to any one of claims 1, 2, and 30 to 36.

SG13S377 (SEQ ID NO: 1, position 169965), allele A; SG13S114 (SEQ ID NO: 1, position 178096), allele A; SG13S41 (SEQ ID NO: 1, 202045), allele A; and SG13S35 (SEQ ID NO: 1, 206117), a reagent comprising an allele G marker.

A reagent used for analyzing a FLAP haplotype contained in a sample, comprising SG13S375 (SEQ ID NO: 1, No. 164874) and comprising an allele T marker.

40. The reagent of claim 39, wherein the haplotype further comprises SG13S25 (SEQ ID NO: 1, position 165553), an allele G marker.

42. The reagent according to claim 41, wherein the haplotype further comprises a marker of SG13S32 (SEQ ID NO: 1, position 176579), allele A.

43. The reagent of claim 42, wherein the haplotype further comprises a marker of SG13S106 (SEQ ID NO: 1, position 198547), allele G or A.

A reagent used for analyzing a FLAP haplotype contained in a sample, comprising SG13S25 (SEQ ID NO: 1, 165553), allele G; SG13S114 (SEQ ID NO: 1, 178096), allele T; SG13S89 (SEQ ID NO: 1, 159580), allele G; and SG13S32 (SEQ ID NO: 1, 198547), a reagent comprising allele A marker.

A reagent kit used to analyze a FLAP haplotype contained in a sample, each of which is contained in a separate container, (a) includes a label that hybridizes to the marker of the FLAP haplotype and is detectable 45. A reagent kit comprising one or more reagents according to any one of claims 39 to 44, which is a probe, and (b) a reagent for detecting the label.

A reagent kit used to analyze a FLAP haplotype contained in a sample, each of which is contained in a separate container, (a) a partial region of a FLAP nucleic acid containing at least one marker of the FLAP haplotype 45. One or more reagents according to any of claims 39 to 44, and (b) a reagent for amplifying a partial region of the FLAP nucleic acid. Reagent kit characterized.