PREVENTIVE OR THERAPEUTIC AGENT FOR AGE-RELATED MACULAR DEGENERATION

Abstract

To provide a new preventive or therapeutic agent for age-related macular degeneration.

The present invention relates to a preventive or therapeutic agent for age-related macular degeneration containing a BLT1 antagonist or a LTB.sub.4 biosynthesis inhibitor as an active ingredient. The administration form of the preventive or therapeutic agent for age-related macular degeneration of the present invention includes eye drops, injections, oral agents (tablets, granules, dispersions, capsules), ointments, and creams. The form of these pharmaceutical compositions can be formulated by combining with a pharmaceutically acceptable carrier.

Claims

1. An agent for age-related macular degeneration, comprising a BLT1 antagonist or a LTB.sub.4 biosynthesis inhibitor as an active ingredient.

2. The agent according to claim 1, comprising the BLT1 antagonist, which is a compound selected from the group consisting of a compound of following (1) through (6): ##STR00006## where R.sup.1 represents a hydrogen atom or a phenyl group, R.sup.2 represents a 2-carboxy-4-trifluoromethyl-phenyl group or a 1-carboxy-cyclopentyl group; ##STR00007## where l, m, and n each represent an integer of from 2 to 6, and R.sup.3 represents a C.sub.1 to C.sub.4 alkyl group; ##STR00008## where p represents an integer of from 2 to 6, q represents an integer of from 0 to 3, R.sup.4 and R.sup.5 each represent a C.sub.1 to C.sub.4 alkyl group or a cyclopropylmethyl group, and R.sup.6 represents an acetyl group, N-methylcarbamoyl group, or a thiazolyl group; ##STR00009## where R.sup.7 represents a 2H-1,3-benzodioxol-5-yl group, R.sup.8 represents a 2-thienyl group, and l, m, and n each represent an integer of from 2 to 6; ##STR00010## where r represents an integer of from 2 to 8, R.sup.9 represents a 3-carboxy-benzylthio group, 3-amino-phenylsulfinyl group, or a 2,6-dichlorophenylthio group, and R.sup.10 represents a hydrogen atom or a methoxy group; and (6) 4-[(3-[4-[2-(4-hydroxyphenyl)propan-2-yl]phenoxymethyl]phenyl)methoxy]benzene-2-carboximidamide (BIIL260), 4-[(3-[4-[2-(4-hydroxy phenyl)propan-2-yl]phenoxymethyl]phenyl)methoxy]benzene-2-N-ethoxycarbonyl-carboximidamide (amelubant), moxilubant maleate, 7-(4-(1-hydroxy-3Z-nonenyl)phenyl)-5S-hydroxy-6Z-heptenoic acid lithium salt (SL 45694), (5S)-6-[6-[(1E,3R,5Z)-3-hydroxyundeca-1,5-dienyl]pyridin-2-yl]hexane-1,5-diol (U 75302), 5-[2-(2-carboxyethyl)-3-[(E)-6-(4-methoxyphenyl)hex-5-enoxy]phenoxy]pentanoic acid (ONO-4057), (E)-7-carboxy-3-((6-(4-methoxy phenyl)-5-hexenyl)oxy)-9-oxo-9H-xanthene-4-propanoic acid (LY 210073), 2-[3-[3-[2-ethyl-4-(fluorophenyl)-5-hydroxyphenoxy]propoxy]-2-propylphenoxy]benzoic acid (etalocib), 1-(5-ethyl-2-hydroxy-4-[[6-methyl-6-(1H-tetrazol-5-yl)-heptyl]oxy]-phenyl]ethanone (LY 255283), 3-[[3-(2-carboxyethyl)-4-[[(5E)-6-(4-methoxyphenyl)hex-5-en-1-yl]oxy]phenyl]carbonyl]benzoic acid (LY 223982), 4,6-diphenyl-2-(3-(1H)tetrazolyl)pentyloxy-pyridine (CHEMBL 95799), and 2,2-dimethyl-7-[3-(3-phenylpropyl)thiophen-2-yl]heptanoic acid (RP 66153).

3. The agent according to claim 1, comprising the BLT1 antagonist, which is a compound selected from the group consisting of: 1-[(3 S,4R)-4-hydroxy-3-[(4-phenylphenyl)methyl]chroman-7-yl]cyclopentane-1-carboxylic acid (CP 105696), 2-[(3 S 4R)-4-hydroxy-3-(phenylmethyl)chroman-7-yl]-4-(trifluoromethyl)benzoic acid (CP 195543), 6-[2-(2-carboxyethyl)-3-[6-[(4-oxo-8-propyl-2,3-dihydrochromen-7-yl)oxy]hexyl]phenoxy]hexanoic acid (CHEMBL 86900), 5-[2(2-carboxyethyl)-3-[6-[(4-oxo-8-propyl-2,3-dihydrochromen-7-yl)oxy]hexyl]phenoxy]pentanoic acid (CHEMBL 95453), 3-[(2S)-7-[3-(2-cyclopropylmethyl)-3-methoxy-4-(methylcarbamoyl)phenoxy]propoxy]-8-propyl-3,4-dihydro-2H-chromen-2-yl]propanoic acid (CHEMBL 419948), 3-(7-[3-[2-cyclopropylmethyl]-3-methoxy-4-(methylcarbamoyl)phenoxy]propoxy]-8-propyl-3,4-dihydro-2H-chromen-2-yl)propanoic acid (CHEMBL 328492), 7-[3-[2-(cyclopropylmethyl)-3-methoxy-4-(1,3-thiazol-4-yl)phenoxy]propoxy]-8-propyl-3,4-dihydro-2H-chromen-2-carboxylic acid (SC 50605), 7-[3-(4-acetyl-3-methoxy-2-propylphenoxy)propoxy]-8-propylchroman-2-carboxylic acid (SC-41930), 4-(3-[6-[3-(2H-1,3-benzodioxol-5-yl)-5-(thiophen-3-yl)phenoxy]hexyl]-2-(2-carboxyethyl)phenoxy)butanoic acid (RO 5101576), ticolubant, (E)-3-((((6-(2-carboxyethenyl)-5-((8-(4-methoxyphenyl)octyl)oxy)-2-pyridinyl)methyl)thio)methyl)benzoic acid (CHEMBL 422598), (E)-3-[6-[(3-aminophenyl)sulfinylmethyl]-3-[8-(4-methoxyphenyl)octoxy]pyridin-2-yl]prop-2-enoic acid (SB 201146), 4-[(3-[4-[2-(4-hydroxyphenyl)propan-2-yl]phenoxymethyl]phenyl)methoxy]benzene-2-carboximidamide (BIIL260), 4-[(3-[4-[2-(4-hydroxyphenyl)propan-2-yl]phenoxymethyl]phenyl)methoxy]benzene-2-N-ethoxycarbonyl-carboximidamide (amelubant), moxilubant maleate, 7-(4-(1-hydroxy-3Z-nonenyl)phenyl)-5S-hydroxy-6Z-heptenoic acid lithium salt (SL 45694), (5S)-6-[6-[(1E,3R,5Z)-3-hydroxyundeca-1,5-dienyl]pyridin-2-yl]hexane-1,5-diol (U 75302), 5-[2-(2-carboxyethyl)-3-[(E)-6-(4-methoxyphenyl)hex-5-enoxy]phenoxy]pentanoic acid (ONO-4057), (E)-7-carboxy-3-((6-(4-methoxyphenyl)-5-hexenyl)oxy)-9-oxo-9H-xanthene-4-propanoic acid (LY 210073), 2-[3-[3-[2-ethyl-4-(fluorophenyl)-5-hydroxyphenoxy]propoxy]-2-propylphenoxy]benzoic acid (etalocib), 1-(5-ethyl-2-hydroxy-4-[[6-methyl-6-(1H-tetrazol-5-yl)-heptyl]oxy]-phenyl]ethanone (LY 255283), 3-[[3-(2-carboxyethyl)-4-[[(5E)-6-(4-methoxyphenyl)hex-5-en-1-yl]oxy]phenyl]carbonyl]benzoic acid (LY 223982), 4,6-diphenyl-2-(3-(1H)tetrazolyl)pentyloxy-pyridine (CHEMBL 95799), and 2,2-dimethyl-7-[3-(3-phenylpropyl)thiophen-2-yl]heptanoic acid (RP 66153).

4. The agent according to claim 1, comprising the LTB.sub.4 biosynthesis inhibitor, which is zileuton, bestatin, MK-886, caffeic acid, licofelone, 3,4-dihydroxyphenyl ethanol, CAY10649, or captopril.

5.-12. (canceled)

13. A method for treating age-related macular degeneration, the method comprising administering an effective amount of a BLT1 antagonist or a LTB.sub.4 biosynthesis inhibitor.

14. The method according to claim 13, wherein the BLT1 antagonist is used and the BLT1 antagonist is a compound selected from the group consisting of a compound of following (1) through (6): ##STR00011## where R.sup.1 represents a hydrogen atom or a phenyl group, R.sup.2 represents a 2-carboxy-4-trifluoromethyl-phenyl group or a 1-carboxy-cyclopentyl group; ##STR00012## where l, m, and n each represent an integer of from 2 to 6, and R.sup.3 represents a C.sub.1 to C.sub.4 alkyl group; ##STR00013## where p represents an integer of from 2 to 6, q represents an integer of from 0 to 3, R.sup.4 and R.sup.5 each represent a C.sub.1 to C.sub.4 alkyl group or a cyclopropylmethyl group, and R.sup.6 represents an acetyl group, N-methylcarbamoyl group, or a thiazolyl group; ##STR00014## where R.sup.7 represents a 2H-1,3-benzodioxol-5-yl group, R.sup.8 represents a 2-thienyl group, and 1, m, and n each represent an integer of from 2 to 6; ##STR00015## where r represents an integer of from 2 to 8, R.sup.9 represents a 3-carboxy-benzylthio group, 3-amino-phenylsulfinyl group, or a 2,6-dichlorophenylthio group, and R.sup.10 represents a hydrogen atom or a methoxy group; and (6) 4-[3-[4-[2-(4-hydroxyphenyl)propan-2-yl]phenoxymethyl]phenyl)methoxy]benzene-2-carboximidamide (BIIL260), 4-[(3-[4-[2-(4-hydroxy phenyl)propan-2-yl]phenoxymethyl]phenyl)methoxy]benzene-2-N-ethoxycarbonyl-carboximidamide (amelubant), moxilubant maleate, 7-(4-(1-hydroxy-3Z-nonenyl)phenyl)-5S-hydroxy-6Z-heptenoic acid lithium salt (SL 45694), (5S)-6-[6-[(1E,3R,5Z)-3-hydroxyundeca-1,5-dienyl]pyridin-2-yl]hexane-1,5-diol (U 75302), 5-[2-(2-carboxyethyl)-3-[(E)-6-(4-methoxyphenyl)hex-5-enoxy]phenoxy]pentanoic acid (ONO-4057), (E)-7-carboxy-3-((6-(4-methoxy phenyl)-5-hexenyl)oxy)-9-oxo-9H-xanthene-4-propanoic acid (LY 210073), 2-[3-[3-[2-ethyl-4-(fluorophenyl)-5-hydroxyphenoxy]propoxy]-2-propylphenoxy]benzoic acid (etalocib), 1-(5-ethyl-2-hydroxy-4-[[6-methyl-6-(1H-tetrazol-5-yl)-heptyl]oxy]-phenyl]ethanone (LY 255283), 3-[[3-(2-carboxyethyl)-4-[[(5E)-6-(4-methoxyphenyl)hex-5-en-1-yl]oxy]phenyl]carbonyl]benzoic acid (LY 223982), 4,6-diphenyl-2-(3-(1H)tetrazolyl)pentyloxy-pyridine (CHEMBL 95799), and 2,2-dimethyl-7-[3-(3-phenylpropyl)thiophen-2-yl]heptanoic acid (RP 66153).

15. The method according to claim 13, wherein the BLT1 antagonist is used and the BLT1 antagonist is a compound selected from the group consisting of: 1-[(3S,4R)-4-hydroxy-3-[(4-phenylphenyl)methyl]chroman-7-yl]cyclopentane-1-carboxylic acid (CP 105696), 2-[(3 S 4R)-4-hydroxy-3-(phenylmethyl)chroman-7-yl]-4-(trifluoromethyl)benzoic acid (CP 195543), 6-[2-(2-carboxyethyl)-3-[6-[(4-oxo-8-propyl-2,3-dihydrochromen-7-yl)oxy]hexyl]phenoxy]hexanoic acid (CHEMBL 86900), 5-[2(2-carboxyethyl)-3-[6-[(4-oxo-8-propyl-2,3-dihydrochromen-7-yl)oxy]hexyl]phenoxy]pentanoic acid (CHEMBL 95453), 3-[(2S)-7-[3-(2-cyclopropylmethyl)-3-methoxy-4-(methylcarbamoyl)phenoxy]propoxy]-8-propyl-3,4-dihydro-2H-chromen-2-yl]propanoic acid (CHEMBL 419948), 3-(7-[3-[2-cyclopropylmethyl]-3-methoxy-4-(methylcarbamoyl)phenoxy]propoxy]-8-propyl-3,4-dihydro-2H-chromen-2-yl)propanoic acid (CHEMBL 328492), 7-[3-[2-(cyclopropylmethyl)-3-methoxy-4-(1,3-thiazol-4-yl)phenoxy]propoxy]-8-propyl-3,4-dihydro-2H-chromen-2-carboxylic acid (SC 50605), 7-[3-(4-acetyl-3-methoxy-2-propylphenoxy)propoxy]-8-propylchroman-2-carboxylic acid (SC-41930), 4-(3-[6-[3-(2H-1,3-benzodioxol-5-yl)-5-(thiophen-3-yl)phenoxy]hexyl]-2-(2-carboxyethyl)phenoxy)butanoic acid (RO 5101576), ticolubant, (E)-3-((((6-(2-carboxyethenyl)-5-((8-(4-methoxyphenyl)octyl)oxy)-2-pyridinyl)methyl)thio)methyl)benzoic acid (CHEMBL 422598), (E)-3-[6-[(3-aminophenyl)sulfinylmethyl]-3-[8-(4-methoxyphenyl)octoxy]pyridin-2-yl]prop-2-enoic acid (SB 201146), 4-[(3-[4-[2-(4-hydroxyphenyl)propan-2-yl]phenoxymethyl]phenyl)methoxy]benzene-2-carboximidamide (BIIL260), 4-[(3-[4-[2-(4-hydroxyphenyl)propan-2-yl]phenoxymethyl]phenyl)methoxy]benzene-2-N-ethoxycarbonyl-carboximidamide (amelubant), moxilubant maleate, 7-(4-(1-hydroxy-3Z-nonenyl)phenyl)-5S-hydroxy-6Z-heptenoic acid lithium salt (SL 45694), (5S)-6-[6-[(1E,3R,5Z)-3-hydroxyundeca-1,5-dienyl]pyridin-2-yl]hexane-1,5-diol (U 75302), 5-[2-(2-carboxyethyl)-3-[(E)-6-(4-methoxyphenyl)hex-5-enoxy]phenoxy]pentanoic acid (ONO-4057), (E)-7-carboxy-3-((6-(4-methoxyphenyl)-5-hexenyl)oxy)-9-oxo-9H-xanthene-4-propanoic acid (LY 210073), 2-[3-[3-[2-ethyl-4-(fluorophenyl)-5-hydroxyphenoxy]propoxy]-2-propylphenoxy]benzoic acid (etalocib), 1-(5-ethyl-2-hydroxy-4-[[6-methyl-6-(1H-tetrazol-5-yl)-heptyl]oxy]-phenyl]ethanone (LY 255283), 3-[[3-(2-carboxyethyl)-4-[[(5E)-6-(4-methoxyphenyl)hex-5-en-1-yl]oxy]phenyl]carbonyl]benzoic acid (LY 223982), 4,6-diphenyl-2-(3-(1H)tetrazolyl)pentyloxy-pyridine (CHEMBL 95799), and 2,2-dimethyl-7-[3-(3-phenylpropyl)thiophen-2-yl]heptanoic acid (RP 66153).

16. The method according to claim 13, wherein the LTB.sub.4 biosynthesis inhibitor is used and the LTB.sub.4 biosynthesis inhibitor is zileuton, bestatin, MK-886, caffeic acid, licofelone, 3,4-dihydroxyphenyl ethanol, CAY10649, or captopril.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0015] FIG. 1 The volume of choroidal neovascularization (CNV) generated from the choroid plexus to the retinal lower layer was measured after laser irradiation of the eyes of young and old BLT1 wild (BLT1.sup.+/+) and BLT1 deficient (BLT1.sup.−/−) mice. The figure shows that CNV that increases with age was suppressed by a deficiency of BLT1.

[0016] FIG. 2 The figure shows the suppressive effect of a BLT1 antagonist (CP105696) and LTB.sub.4 biosynthesis inhibitors (zileuton, bestatin, and MK886) on AMD onset.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0017] The active ingredient of the preventive or therapeutic agent for AMD of the present invention is a BLT1 antagonist or a LTB.sub.4 biosynthesis inhibitor.

[0018] The first receptor of LTB.sub.4 is BLT1, and this is a receptor identified by the present inventors (Yokomizo, Nature, 1997, 387, 620-624). The present inventors also studied the pathophysiological role of BLT1, and discovered that the pathological condition of a BLT1 deficient mouse was milder than a wild mouse in models of contact dermatitis, bronchial asthma, multiple sclerosis, and the like (Toda, Biochemie, 2010, 92, 682-691, Terawaki, J. Immunol. 2005, 175, 4217-4225, Kihara, BBRC, 2010, 394, 673-624).

[0019] However, there are no reports concerning the relationship between BLT1 and eye diseases.

[0020] The BLT1 antagonist is not particularly restricted, so long as binding of LTB.sub.4 to BLT1 is hindered, and examples include the compounds of the following groups (1) through (6).

##STR00001##

(in the formula, R.sup.1 represents a hydrogen atom or a phenyl group, R.sup.2 represents a 2-carboxy-4-trifluoromethyl-phenyl group or a 1-carboxy-cyclopentyl group)

##STR00002##

(in the formula, l, m, and n each represent an integer of from 2 to 6, and R.sup.3 represents a C.sub.1 to C.sub.4 alkyl group)

##STR00003##

(in the formula, p represents an integer of from 2 to 6, q represents an integer of from 0 to 3, R.sup.4 and R.sup.5 each represent a C.sub.1 to C.sub.4 alkyl group or a cyclopropylmethyl group, and R.sup.6 represents an acetyl group, N-methylcarbamoyl group, or a thiazolyl group)

##STR00004##

(in the formula, R.sup.7 represents a 2H-1,3-benzodioxol-5-yl group, R.sup.8 represents a 2-thienyl group, and 1, m, and n each represent an integer of from 2 to 6)

##STR00005##

(in the formula, r represents an integer of from 2 to 8, R.sup.9 represents a 3-carboxy-benzylthio group, 3-amino-phenyl sulfinyl group, or a 2,6-dichlorophenylthio group, and R.sup.10 represents a hydrogen atom or a methoxy group)
(6) [0021] 4-[(3-[4-[2-(4-hydroxyphenyl)propan-2-yl]phenoxymethyl]phenyl)methoxy]benzene-2-carboximidamide (BIIL260), [0022] 4-[(3-[4-[2-(4-hydroxyphenyl)propan-2-yl]phenoxymethyl]phenyl)methoxy]benzene-2-N-ethoxycarbonyl-carboximidamide (amelubant), moxilubant maleate, [0023] 7-(4-(1-hydroxy-3Z-nonenyl)phenyl)-5S-hydroxy-6Z-heptenoic acid lithium salt (SL 45694), [0024] (5S)-6-[6-[(1E,3R,5Z)-3-hydroxyundeca-1,5-dienyl]pyridin-2-yl]hexane-1,5-diol (U 75302), [0025] 5-[2-(2-carboxyethyl)-3-[(E)-6-(4-methoxyphenyl)hex-5-enoxy]phenoxy]pentanoic acid (ONO-4057), [0026] (E)-7-carboxy-3-(( 6-(4-methoxyphenyl)-5-hexenyl)oxy)-9-oxo-9H-xanthene-4-propanoic acid (LY 210073), [0027] 2-[3-[3-[2-ethyl-4-(fluorophenyl)-5-hydroxyphenoxy]propoxy]-2-propylphenoxy]benzoic acid (etalocib), [0028] 1-(5-ethyl-2-hydroxy-4-[[6-methyl-6-(1H-tetrazol-5-yl)-heptyl]oxy]-phenyl]ethanone (LY 255283), [0029] 3-[[3-(2-carboxyethyl)-4-[[(5E)-6-(4-methoxyphenyl)hex-5-en-1-yl]oxy]phenyl]carbonyl]benzoic acid (LY 223982), 4,6-diphenyl-2-(3-(1H)tetrazolyl)pentyloxy-pyridine (CHEMBL 95799), and 2,2-dimethyl-7-[3-(3-phenylpropyl)thiophen-2-yl]heptanoic acid (RP 66153).

[0030] Specific examples of the BLT1 antagonist include [0031] 1-[(3S,4R)-4-hydroxy-3-[(4-phenyl phenyl)methyl]chroman-7-yl]cyclopentane-1-carboxylic acid (CP 105696), [0032] 2-[(3S,4R)-4-hydroxy-3-(phenylmethyl)chroman-7-yl]-4-(trifluoromethyl)benzoic acid (CP 195543), [0033] 6-[2-(2-carboxyethyl)-3-[6-[(4-oxo-8-propyl-2,3-dihydrochromen-7-yl)oxy]hexyl]phenoxy]hexanoic acid (CHEMBL 86900), [0034] 5-[2-(2-carboxyethyl)-3-[6-[(4-oxo-8-propyl-2,3-dihydrochromen-7-yl)oxy]hexyl]phenoxy]pentanoic acid (CHEMBL 95453), [0035] 3-[(2 S)-7-[3-(2-cyclopropylmethyl)-3-methoxy-4-(methylcarbamoyl)phen oxy]propoxy]-8-propyl-3,4-dihydro-2H-chromen-2-yl]propanoic acid (CHEMBL 419948), [0036] 3-(7-[3-[2-cyclopropylmethyl]-3-methoxy-4-(methylcarbamoyl)phenoxy]propoxy]-8-propyl-3,4-dihydro-2H-chromen-2-yl)propanoic acid (CHEMBL 328492), [0037] 7-[3-[2-(cyclopropylmethyl)-3-methoxy-4-(1,3-thiazol-4-yl)phenoxy]propoxy]-8-propyl-3,4-dihydro-2H-chromen-2-carboxylic acid (SC 50605), [0038] 7-[3-(4-acetyl-3-methoxy-2-propylphenoxy)propoxy]-8-propylchroman-2-carboxylic acid (SC-41930), [0039] 4-(3-[6-[3-(2H-1,3-benzodioxol-5-yl)-5-(thiophen-3-yl)phenoxy]hexyl]-2-(2-carboxyethyl)phenoxy)butanoic acid (RO 5101576), ticolubant, [0040] (E)-3-((((6-(2-carboxyethenyl)-5-((8-(4-methoxyphenyl)octyl)oxy)-2-pyridinyl)methyl)thio)methyl)benzoic acid (CHEMBL 422598), [0041] (E)-3-[6-[(3-aminophenyl)sulfinylmethyl]-3-[8-(4-methoxyphenyl)octoxy]pyridin-2-yl]prop-2-enoic acid (SB 201146), [0042] 4-[(3-[4-[2-(4-hydroxyph enyl)propan-2-yl]phenoxymethyl]phenyl)methoxy]benzene-2-carboximidamide (BIIL260), [0043] 4-[(3-[4-[2-(4-hydroxyph enyl)propan-2-yl]phenoxymethyl]phenyl)methoxy]benzene-2-N-ethoxycarbonyl-carboximidamide (amelubant), moxilubant maleate, [0044] 7-(4-(1-hydroxy-3Z-nonenyl)phenyl)-5S-hydroxy-6Z-heptenoic acid lithium salt (SL 45694), [0045] (5 S)-6-[6-[(1E,3,R5Z)-3-hydroxyundeca-1,5-dienyl]pyridin-2-yl]hexane-1,5-diol (U 75302), [0046] 5-[2-(2-carboxyethyl)-3-[(E)-6-(4-methoxyphenyl)hex-5-enoxy]phenoxy]pentanoic acid (ONO-4057), [0047] (E)-7-carboxy-3-((6-(4-methoxyphenyl)-5-hexenyl)oxy)-9-oxo-9H-xanthene-4-propanoic acid (LY 210073), [0048] 2-[3-[3-[2-ethyl-4-(fluorophenyl)-5-hydroxyphenoxy]propoxy]-2-propylphenoxy]benzoic acid (etalocib), [0049] 1-(5-ethyl-2-hydroxy-4-[[6-methyl-6-(1H-tetrazol-5-yl)-heptyl]oxy]-phenyl]ethanone (LY 255283), [0050] 3-[[3-(2-carboxyethyl)-4-[[(5E)-6-(4-methoxyphenyl)hex-5-en-1-yl]oxy]phenyl]carbonyl]benzoic acid (LY 223982), 4,6-diphenyl-2-(3-(1H)tetrazolyl)pentyloxy-pyridine (CHEMBL 95799), and 2,2-dimethyl-7-[3-(3-phenylpropyl)thiophen-2-yl]heptanoic acid (RP 66153).

[0051] These compounds exemplified as BLT1 antagonists are all known compounds and can be produced, for example, by the method disclosed in JP-A-H7-502536, EP 0743064 A1, WO 95/33742, JP-A-H11-503737, JP-A-H5-25159, and the like. More specifically, the compounds of formula (1) are disclosed in JP-A-H7-502536, U.S. Pat. No. 5,552,435, and the like, the compounds of formulas (2) and (3) are disclosed in EP 0743064 A1, and the like, the compounds of (6) are disclosed in JP-A-H11-503737, and the like, and the compounds of the other formulas are disclosed in JP-A-H5-25159, WO 95/33742, and the like. In addition, these compounds are found in IUPHAR DATABASE and Pubchem OPEN CHEMISTRY DATABASE.

[0052] These BLT1 antagonists and LTB.sub.4 biosynthesis inhibitors significantly suppress angiogenesis of the choroid of the AMD model, and are useful as preventive or therapeutic agents for AMD.

[0053] Any of the LTB.sub.4 biosynthesis inhibitors may be used, so long as it inhibits the biosynthesis of LTB.sub.4, and for example, inhibitors for a LTB.sub.4 producing enzyme may be mentioned. Examples of the LTB.sub.4 biosynthesis inhibitor include zileuton (N-[1-(1-benzothien-2-yl)ethyl]-N-hydroxyurea), bestatin (N-[(2S,3R)-3-amino-2-hydroxy-4-phenylbutyryl]-L-leucine), MK-886 (1-[(4-chlorobenzyl)methyl]-3-[(1,1-dimethylethypthio]-α,α-dimethyl-5-(1-methylethyl)-1H-indole-2-propanoic acid), caffeic acid, licofelone, 3,4-dihydroxyphenyl ethanol, CAY10649 ((Z)-2-(4-chlorophenyl)-5-(4-methoxybenzylidene)thiazol-4(5H)-one), and captopril.

[0054] Examples of the administration form of the preventive or therapeutic agent for AMD of the present invention include eye drops, injections, oral agent (tablets, granules, dispersions, capsules), ointments, and creams. Of these, eye drops are particularly preferable. The form of these pharmaceutical compositions can be formulated by combining with a pharmaceutically acceptable carrier. Examples of the carrier include lactose, glucose, D-mannitol, starch, crystalline cellulose, calcium carbonate, kaolin, starch, gelatin, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinylpyrrolidone, ethanol, carboxymethyl cellulose, calcium carboxymethyl cellulose, magnesium stearate, talc, acetyl cellulose, sucrose, titanium oxide, benzoic acid, p-hydroxybenzoic acid esters, sodium dehydroacetate, gum arabic, tragacanth, methylcellulose, egg yolk, surfactants, sucrose, simple syrups, citric acid, distilled water, ethanol, glycerin, propylene glycol, macrogol, disodium hydrogen phosphate, sodium dihydrogen phosphate, sodium phosphate, glucose, sodium chloride, phenol, thimerosal, p-hydroxybenzoic acid esters, and sodium bisulfite, and these can be used by blending with the BLT1 antagonists depending on the form of the preparation.

[0055] Furthermore, the amount of BLT1 antagonist or LTB.sub.4 biosynthesis inhibitor included in the pharmaceutical composition preparation of the present invention varies dramatically depending on the form of the preparation, and although not restricted in particular, the amount is normally 0.01 to 100 weight %, preferably 1 to 100 weight %, based on the total amount of the composition.

[0056] The dosage of the preventive or therapeutic agent for AMD of the present invention varies depending on the symptoms and age of the patient receiving the administration, and the administration method, but the dosage is preferably 0.01 to 100 mg/kg/day as a BLT1 antagonist or LTB.sub.4 biosynthesis inhibitor.

EXAMPLES

[0057] The present invention is described below in further detail by presenting examples.

Test Example 1

[0058] Angiogenesis that occurred from the choroid plexus after laser injury was analyzed using C57BL/6 background BLT1 wild type (BLT1.sup.+/+) mice and BLT1 deficient (BLT1.sup.−/−) mice.

[0059] Laser light (power: 200 mW, exposure time: 0.10 seconds, wavelength: 532 nm) was irradiated in 4 to 5 spots onto male young (8 to 12 weeks) and old (44 to 48 weeks) BLT1.sup.+/+ mice and BLT1.sup.−/− mice, and after 7 days, the eyes were isolated and fixed using a phosphate buffered saline (PBS) containing 4% paraformaldehyde (PFA), the cornea, lens, and retina were removed, and then fixed again using 4% PFA/PBS. The ocular tissue containing the retinal pigment epithelia and choroid plexus were immersed in PBS containing methanol in order of 50%, 75%, 100%, 75%, 50%, and 25% to remove water, and then incubated at 4° C. for 1 hour in a blocking solution (1% bovine blood serum albumin, phosphate buffered saline containing 0.1% Triton X-100), and then stained overnight at 4° C. using isolectin B4 (IB4, 7 mg/mL) labeled with FITC. Incisions were made in the samples and the samples were molded on a slide glass, sealed with a mounting agent containing an antifading reagent, and then a cover glass was placed thereon to produce a flat mount. A three-dimensional IB4 positive blood vessels image was captured using a confocal microscope, and the volume of angiogenesis that occurred in each mouse was measured.

[0060] As shown in FIG. 1, the results indicate that there was no observable difference in the angiogenesis between BLT1.sup.−/− mice and BLT1.sup.−/− mice in the young mice group. However, angiogenesis was significantly lower in the BLT1.sup.−/− mice as compared to the BLT.sup.+/+ mice in the old mice group.

[0061] From these results, it can be seen that age-related progressive angiogenesis of the retina was milder in the BLT1.sup.−/− mice.

Test Example 2

[0062] Immediately after laser light irradiation of C57BL/6 background old mice purchased (Japan SLC, wild mice, 40 weeks or older, male), DMSO (final: 0.1%, diluted with PBS), CP105696 (where in the formula (1), R.sup.1=phenyl and R.sup.2=1-carboxycyclopentyl group) which is a BLT1 antagonist, or zileuton, bestatin, or MK886 each of which is an inhibitor for LTB.sub.4 production-related enzyme was administered into a vitreous body of each mouse. Similar to Test Example 1, angiogenesis from the choroid plexus was evaluated 7 days after laser irradiation.

[0063] The results showed that, in the mice administered with CP 105696, the angiogenesis volume was significantly reduced in a concentration-dependent manner. Similarly, it was observed that the inhibitors for LTB.sub.4 production-related enzyme showed an effect of suppressing angiogenesis. These suggest that a BLT1 antagonist and a LTB.sub.4 biosynthesis inhibitor are new therapeutic agents that suppress the onset of AMD.