JP2003300902A - Angiogenesis inhibitor - Google Patents
Angiogenesis inhibitorInfo
- Publication number
- JP2003300902A JP2003300902A JP2003084597A JP2003084597A JP2003300902A JP 2003300902 A JP2003300902 A JP 2003300902A JP 2003084597 A JP2003084597 A JP 2003084597A JP 2003084597 A JP2003084597 A JP 2003084597A JP 2003300902 A JP2003300902 A JP 2003300902A
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- Prior art keywords
- angiogenesis
- neovascularization
- diseases
- intraocular
- compound
- Prior art date
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- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
Description
【0001】[0001]
【発明の属する技術分野】本発明はキマーゼ阻害作用を
有するSuc-Val-Pro-HNCH(CH2Ph)P(O)(OPh)2を有効成分
とする血管新生阻害剤に関するものである。TECHNICAL FIELD The present invention relates to an angiogenesis inhibitor containing Suc-Val-Pro-HNCH (CH 2 Ph) P (O) (OPh) 2 having a chymase inhibitory activity as an active ingredient.
【0002】[0002]
【従来の技術】血管新生(angiogenesis)とは、既存の
血管から新しい血管ネットワーク、すなわち新生血管が
形成される現象である。血管新生は生体における種々の
生理的および病的状態でみられる。生理的な血管新生
は、黄体形成や胎盤形成の際に、また病的状態における
血管新生は、炎症、創傷治癒、腫瘍の増殖などで認めら
れている。2. Description of the Related Art Angiogenesis is a phenomenon in which a new blood vessel network, that is, a new blood vessel is formed from existing blood vessels. Angiogenesis is found in various physiological and pathological conditions in the body. Physiological angiogenesis is recognized during luteinization and placenta formation, and angiogenesis in a pathological state is recognized by inflammation, wound healing, tumor growth and the like.
【0003】眼球の組織構築上最も重要な特徴は、組織
の透明性であり、血管新生が一度惹起されれば、その透
明性が障害され、著しい視機能障害が起こる。眼科領域
において、糖尿病網膜症、加齢黄斑変性症、未熟児網膜
症などのさまざまな疾患が、血管新生病の範疇に入ると
考えられ、眼内血管新生性疾患と呼ばれている(眼科,
40, 1677-1683 (1998))。[0003] The most important characteristic of the tissue construction of the eyeball is the transparency of the tissue, and once angiogenesis is induced, the transparency is impaired and a remarkable visual dysfunction occurs. In the field of ophthalmology, various diseases such as diabetic retinopathy, age-related macular degeneration, and retinopathy of prematurity are considered to fall into the category of angiogenic diseases and are called intraocular angiogenic diseases (ophthalmology,
40 , 1677-1683 (1998)).
【0004】血管新生病(angiogenic diseases )とし
ては、眼内血管新生性疾患の他、固形がん、慢性関節リ
ウマチ、乾せん(psoriasis )、粥状動脈化巣における
血管新生、虚血性心疾患や動脈硬化症に伴う側副血行路
形成、血管腫、カポジ肉腫などが挙げられるが、固形が
んを対象とする研究が最も進んでいる(最新医学,53,
2671-2678 (1998))。また、血管新生は創傷の治癒過程
において起こることもよく知られている。Examples of angiogenic diseases include intraocular angiogenic diseases, solid tumors, rheumatoid arthritis, psoriasis, angiogenesis in atheromatous lesions, ischemic heart disease and arteries. Examples include collateral circulation associated with sclerosis, hemangiomas, and Kaposi's sarcoma, but research on solid tumors is the most advanced (Latest Medicine, 53 ,
2671-2678 (1998)). It is also well known that angiogenesis occurs during the healing process of wounds.
【0005】一方、キマーゼは、心血管系の組織をはじ
め、消化管、皮膚、肺、関節(滑膜)などの全身の組織
に存在し、心血管病変、炎症、免疫機能、組織構築改変
などの生理機能の発揮に関与していることが報告されて
いる(医学のあゆみ,174, 743-747 (1995) )。また、
キマーゼは、動脈硬化、心筋梗塞、心不全、経皮的冠動
脈形成術(PTCA)後の血管再狭窄などの発生(血管
と内皮, 5,461-468(1995) )、糖尿病合併症(Biol. Ch
em. Hoppe-Seyler , 369, Suppl. 299-305(1988) )、
アレルギー性疾患(J. Biochem.,103, 820-822(1988)
)、喘息(J. Pharmacol. Exp. Ther., 244, 133-137
(1988) )、慢性関節リウマチ(Ann. Rheum. Dis., 56,
151-161 (1997))などに関与していることが報告され
ている。On the other hand, chymase is present in tissues of the whole body such as the digestive tract, skin, lungs, joints (synovium) as well as tissues of the cardiovascular system, and is affected by cardiovascular lesions, inflammation, immune function, tissue structure modification, etc. It has been reported that it is involved in the exertion of physiological functions of A. (medical history, 174 , 743-747 (1995)). Also,
Chymase causes arteriosclerosis, myocardial infarction, heart failure, vascular restenosis after percutaneous coronary angioplasty (PTCA) (vascular and endothelium, 5 , 461-468 (1995)), diabetic complications (Biol. Ch.
em. Hoppe-Seyler, 369 , Suppl. 299-305 (1988)),
Allergic diseases (J. Biochem., 103 , 820-822 (1988)
), Asthma (J. Pharmacol. Exp. Ther., 244 , 133-137
(1988)), Rheumatoid arthritis (Ann. Rheum. Dis., 56 ,
151-161 (1997)).
【0006】しかしながら、キマーゼと血管新生、特
に、眼内血管新生との関係についての報告は未だなされ
ていない。However, no report has yet been made on the relationship between chymase and angiogenesis, particularly intraocular neovascularization.
【0007】[0007]
【発明が解決しようとする課題】上記のように、キマー
ゼと血管新生との関係は、未だ詳細には解明されておら
ず、キマーゼ阻害作用を有する化合物の血管新生に及ぼ
す影響についての研究は非常に興味ある課題である。ま
た、血管新生が関与する疾患の治療剤の研究としては、
がん等の治療を目的とした薬物に関する研究が数多く行
われているが、眼内血管新生性疾患の治療を目的とした
薬物の研究は少なく、この分野における薬物の研究開発
が望まれている。As described above, the relationship between chymase and angiogenesis has not yet been elucidated in detail, and research on the effect of compounds having a chymase inhibitory effect on angiogenesis is extremely difficult. This is an interesting subject. Further, as research on therapeutic agents for diseases associated with angiogenesis,
There have been many studies on drugs for the treatment of cancer, etc., but there are few studies on the drugs for the treatment of intraocular angiogenic diseases, and research and development of drugs in this field are desired. .
【0008】[0008]
【課題を解決するための手段】そこで、本発明者等は種
々の化学構造を有するキマーゼ阻害作用を有する化合物
と血管新生との関係について鋭意研究を行ったところ、
Suc-Val-Pro-HNCH(CH2Ph)P(O)(OPh)2が血管新生を阻害
することを見出した。すなわち、キマーゼ阻害作用を有
するSuc-Val-Pro-HNCH(CH2Ph)P(O)(OPh)2が、血管新生
阻害作用を示し、血管新生が関与する疾患、特に糖尿病
網膜症、黄斑変性症、網膜静脈閉塞症、未熟児網膜症、
血管新生緑内障などの眼内血管新生性疾患の予防または
治療剤として期待されることを見出した。The inventors of the present invention have conducted extensive studies on the relationship between angiogenesis and compounds having various chemical structures having a chymase inhibitory action.
It was found that Suc-Val-Pro-HNCH (CH 2 Ph) P (O) (OPh) 2 inhibits angiogenesis. That is, Suc-Val-Pro-HNCH (CH 2 Ph) P (O) (OPh) 2 having a chymase inhibitory action shows an angiogenesis inhibitory action, and diseases associated with angiogenesis, particularly diabetic retinopathy, macular degeneration , Retinal vein occlusion, retinopathy of prematurity,
It has been found that it is expected as a prophylactic or therapeutic agent for intraocular angiogenic diseases such as neovascular glaucoma.
【0009】[0009]
【発明の実施の形態】本発明は、キマーゼ阻害作用を有
するSuc-Val-Pro-HNCH(CH2Ph)P(O)(OPh)2を(以下、特
記なき限り本化合物という)を有効成分とする血管新生
阻害剤に関するものである。BEST MODE FOR CARRYING OUT THE INVENTION The present invention uses Suc-Val-Pro-HNCH (CH 2 Ph) P (O) (OPh) 2 (hereinafter referred to as the present compound unless otherwise specified) having an inhibitory effect on chymase as an active ingredient. The present invention relates to an angiogenesis inhibitor.
【0010】本化合物は、Biochemistry, 30, 485-493
(1991)に記載されている公知のペプチド誘導体である。This compound is a compound of Biochemistry, 30 , 485-493.
It is a known peptide derivative described in (1991).
【0011】後述の薬理試験の項で詳細に説明するが、
in vivoの血管新生評価モデルとして、汎用されている
アッセイ系の1つであるニワトリ漿尿膜(chorioallant
oic membrane:CAM)法を用いて検討した結果、本化
合物が血管新生に対して阻害効果を有することを見いだ
した。As will be described in detail in the section of the pharmacological test described below,
Chicken chorioallantoic membrane (chorioallant), which is one of the widely used assay systems for evaluating angiogenesis in vivo
As a result of examination using the oic membrane (CAM) method, it was found that this compound has an inhibitory effect on angiogenesis.
【0012】本発明は、血管新生が関与する疾患の予防
または治療剤を提供するものであり、その疾患の例とし
ては、眼内血管新生性疾患、固形がん、慢性関節リウマ
チ、乾せん(psoriasis )、粥状動脈化巣における血管
新生、虚血性心疾患や動脈硬化症に伴う側副血行路形
成、血管腫、カポジ肉腫などが挙げられる。ところで、
これらの血管新生が関与する疾患の治療剤の研究として
は、がん等の治療を目的とした薬物の研究は数多く行わ
れているが、眼内血管新生性疾患を対象とした薬物の研
究は少なく、本発明の主なる目的は、この眼内血管新生
性疾患に有用な薬物を提供することにある。無論、本発
明は血管新生が関与する疾患に広く適用できるものであ
り、眼内血管新生性疾患に対象が限定されるものではな
い。The present invention provides a preventive or therapeutic agent for diseases associated with angiogenesis, and examples of the diseases include intraocular angiogenic diseases, solid cancer, rheumatoid arthritis and psoriasis. ), Angiogenesis in atheromatous lesions, collateral blood vessel formation associated with ischemic heart disease and arteriosclerosis, hemangiomas, Kaposi's sarcoma and the like. by the way,
As research on therapeutic agents for diseases associated with angiogenesis, many researches on drugs for treating cancer etc. have been conducted, but research on drugs for intraocular angiogenic diseases has been conducted. At the very least, the main object of the present invention is to provide a drug useful for this intraocular angiogenic disease. Of course, the present invention is widely applicable to diseases associated with angiogenesis, and the subject is not limited to intraocular angiogenic diseases.
【0013】眼内血管新生性疾患では、血管新生そのも
のが病勢を左右する決定因子となりうるため、血管新生
を抑制することによってこれら疾患の予防および治療が
可能となる(炎症と免疫, 4, 343-349 (1996) )ことか
ら、本試験結果は、キマーゼ阻害作用を有する本化合物
が、血管新生が関与する疾患、特に糖尿病網膜症、黄斑
変性症、網膜静脈閉塞症、未熟児網膜症、血管新生緑内
障などの眼内血管新生性疾患の予防剤または治療剤とし
て有用であることを示すものである。[0013] In intraocular angiogenic diseases, angiogenesis itself can be a determinant that influences the disease state, and therefore inhibition of angiogenesis enables prevention and treatment of these diseases (inflammation and immunity, 4 , 343). -349 (1996)), the results of this test show that this compound, which has a chymase inhibitory effect, is associated with angiogenesis-related diseases, in particular diabetic retinopathy, macular degeneration, retinal vein occlusion, retinopathy of prematurity, and blood vessels. It is shown to be useful as a prophylactic or therapeutic agent for intraocular angiogenic diseases such as neonatal glaucoma.
【0014】眼内血管新生は、部位別に、網膜血管新生
および硝子体内血管新生、虹彩血管新生、脈絡膜血管新
生に分類される。Intraocular neovascularization is classified by site into retinal neovascularization, intravitreal neovascularization, iris neovascularization, and choroidal neovascularization.
【0015】網膜血管新生および硝子体内血管新生を伴
う眼内血管新生性疾患として、糖尿病網膜症、網膜中心
静脈閉塞症、未熟児網膜症等の眼内血管新生性疾患が挙
げられる。Examples of intraocular neovascular diseases associated with retinal neovascularization and intravitreal neovascularization include intraocular neovascular diseases such as diabetic retinopathy, central retinal vein occlusion and retinopathy of prematurity.
【0016】虹彩血管新生を伴う眼内血管新生性疾患と
して、網膜中心静脈閉塞症、糖尿病網膜症、網膜中心動
脈閉塞症、頸動脈疾患、ぶどう膜炎、眼内腫瘍等の眼内
血管新生性疾患が挙げられる。As an intraocular neovascularization disease accompanied by iris neovascularization, intraocular neovascularization such as central retinal vein occlusion, diabetic retinopathy, central retinal artery occlusion, carotid artery disease, uveitis, intraocular tumor, etc. Diseases are mentioned.
【0017】脈絡膜血管新生を伴う眼内血管新生性疾患
として、加齢黄班変性症(老人性円板状黄班変性症)、
網膜色素線条症、高度近視、眼ヒストプラズマ症(pres
umedocular histoplasmosis;POHS)、脈絡膜破裂、突
発性脈絡膜新生血管等の眼内血管新生性疾患が挙げられ
る。As an intraocular neovascular disease accompanied by choroidal neovascularization, age-related macular degeneration (senile discoid macular degeneration),
Retinitis pigmentosa, severe myopia, ocular histoplasmosis (pres
umedocular histoplasmosis (POHS), choroidal rupture, sudden choroidal neovascularization and other intraocular neovascular diseases.
【0018】本化合物は、経口でも、非経口でも投与す
ることができる。投与剤型としては、錠剤、カプセル
剤、顆粒剤、散剤、注射剤、点眼剤等が挙げられる。こ
れらは汎用されている技術を用いて調製することができ
る。例えば、錠剤、カプセル剤、顆粒剤、散剤等の経口
剤であれば、乳糖、結晶セルロース、デンプン、植物油
等の増量剤;ステアリン酸マグネシウム、タルク等の滑
沢剤;ヒドロキシプロピルセルロース、ポリビニルピロ
リドン等の結合剤;カルボキシメチルセルロースカルシ
ウム、低置換ヒドロキシプロピルメチルセルロース等の
崩壊剤;ヒドロキシプロピルメチルセルロース、マクロ
ゴール、シリコン樹脂等のコーティング剤;ゼラチン皮
膜等の皮膜剤などを必要に応じて加えて、上記化合物を
製剤化すればよい。点眼剤であれば、塩化ナトリウム、
濃グリセリン等の等張化剤;リン酸ナトリウム、酢酸ナ
トリウム等の緩衝化剤;ポリオキシエチレンソルビタン
モノオレート、ステアリン酸ポリオキシル40、ポリオ
キシエチレン硬化ヒマシ油等の界面活性剤;クエン酸ナ
トリウム、エデト酸ナトリウム等の安定化剤;塩化ベン
ザルコニウム、パラベン等の防腐剤等を必要に応じて用
いて、上記化合物を製剤化することができる。pHは眼
科製剤に許容される範囲内にあればよいが、4〜8の範
囲が好ましい。また、眼軟膏であれば、白色ワセリン、
流動パラフィン等の汎用される基剤を用いて調製するこ
とができる。The compound can be administered orally or parenterally. Examples of dosage forms include tablets, capsules, granules, powders, injections and eye drops. These can be prepared using a commonly used technique. For example, in the case of oral preparations such as tablets, capsules, granules and powders, bulking agents such as lactose, crystalline cellulose, starch and vegetable oils; lubricants such as magnesium stearate and talc; hydroxypropyl cellulose, polyvinylpyrrolidone etc. A binder such as carboxymethylcellulose calcium, a low-substituted hydroxypropylmethylcellulose or the like, a disintegrator such as hydroxypropylmethylcellulose, macrogol, a silicone resin or the like, a film forming agent such as a gelatin film, etc. It may be formulated. For eye drops, sodium chloride,
Isotonic agents such as concentrated glycerin; buffering agents such as sodium phosphate and sodium acetate; surfactants such as polyoxyethylene sorbitan monooleate, polyoxyl 40 stearate, polyoxyethylene hydrogenated castor oil; sodium citrate, edet The above compound can be formulated by using a stabilizer such as sodium acid salt; a preservative such as benzalkonium chloride and paraben, if necessary. The pH may be in the range acceptable for ophthalmic preparations, but is preferably in the range of 4-8. If it is an eye ointment, white petrolatum,
It can be prepared using a commonly used base such as liquid paraffin.
【0019】投与量は症状、年令、剤型等によって適宜
選択できるが、点眼剤であれば0.0001〜5%(w
/v)、好ましくは0.001〜3%(w/v)、特に
好ましくは0.001〜1%(w/v)のものを1日1
〜数回点眼すればよい。また、経口剤であれば通常1日
当り0.1〜5000mg、好ましくは1〜1000m
gを1回または数回に分けて投与すればよい。The dose can be appropriately selected according to the symptoms, age, dosage form, etc., but in the case of eye drops, 0.0001 to 5% (w
/ V), preferably 0.001 to 3% (w / v), and particularly preferably 0.001 to 1% (w / v) per day.
~ It may be applied several times. If it is an oral preparation, it is usually 0.1 to 5000 mg, preferably 1 to 1000 m per day.
g may be administered once or in several divided doses.
【0020】以下に、製剤例および薬理試験の結果を示
すが、これらの実施例は本発明をよりよく理解するため
のものであり、本発明の範囲を限定するものではない。Formulation examples and results of pharmacological tests are shown below, but these examples are for the purpose of better understanding of the present invention, and do not limit the scope of the present invention.
【0021】[0021]
【実施例】[製剤例]本発明の経口剤、点眼剤および注
射剤の一般的な製剤例を以下に示す。EXAMPLES [Formulation Example] The following are general formulation examples of the oral preparation, eye drop preparation and injection preparation of the present invention.
【0022】 1)カプセル剤 処方(150mg中) 本化合物 5.0mg 乳糖 145.0mg[0022] 1) Capsules Prescription (in 150 mg) This compound 5.0 mg Lactose 145.0 mg
【0023】本化合物と乳糖の混合比を変えることによ
り、本化合物の成分量が10.0mg/カプセル、3
0.0mg/カプセル、50.0mg/カプセル、10
0.0mg/カプセルのカプセル剤も調製できる。By changing the mixing ratio of the present compound and lactose, the amount of the present compound was 10.0 mg / capsule, 3
0.0 mg / capsule, 50.0 mg / capsule, 10
Capsules of 0.0 mg / capsule can also be prepared.
【0024】 2)点眼剤(10ml中) 本化合物 1mg 濃グリセリン 250mg ポリソルベート80 200mg リン酸二水素ナトリウム二水和物 適量 1N水酸化ナトリウム 適量 1N塩酸 適量 滅菌精製水[0024] 2) Eye drops (in 10 ml) This compound 1 mg Concentrated glycerin 250mg Polysorbate 80 200 mg Sodium dihydrogen phosphate dihydrate Suitable amount 1N sodium hydroxide suitable amount 1N hydrochloric acid suitable amount Sterile purified water
【0025】本化合物と添加物量を適宜変更することに
より、本化合物の濃度が、0.0001%、0.001
%、0.005%、0.05%、0.1%、0.5%、
1.0%、3.0%、5.0%(w/v)である点眼剤
も調製できる。By appropriately changing the amounts of the present compound and additives, the concentration of the present compound is 0.0001%, 0.001%.
%, 0.005%, 0.05%, 0.1%, 0.5%,
Eye drops of 1.0%, 3.0%, 5.0% (w / v) can also be prepared.
【0026】 3)注射剤(100ml中) 本化合物 10.0〜100.0mg 1N水酸化ナトリウム 適量 1N塩酸 適量 生理食塩水 適量[0026] 3) Injection (in 100 ml) The present compound 10.0 to 100.0 mg 1N sodium hydroxide suitable amount 1N hydrochloric acid suitable amount Saline solution
【0027】[薬理試験]
1.漿尿膜法による血管新生阻害効果
血管新生に及ぼす薬物の阻害効果を測定するため汎用さ
れるin vivo 血管新生評価モデルの1つとして、受精卵
胚を用いたニワトリ漿尿膜(CAM)法(Biochem. Bio
phys. Res. Commun., 174 , 1070-1076 (1991))が報告
されている。そこで、上記文献に記載された方法を参考
にして、本化合物の血管新生に対する阻害効果について
検討した。[Pharmacological test] 1. Angiogenesis inhibitory effect by chorioallantoic membrane method As one of the in vivo angiogenesis evaluation models that are widely used to measure the inhibitory effect of drugs on angiogenesis, the chicken chorioallantoic membrane (CAM) method using a fertilized egg embryo ( Biochem. Bio
phys. Res. Commun., 174 , 1070-1076 (1991)). Therefore, the inhibitory effect of the present compound on angiogenesis was examined with reference to the method described in the above literature.
【0028】(投与用ペレットの調製)
1. メチルセルロース4000cP (0.1g)を滅
菌精製水(10ml)に溶解し、1%メチルセルロース
溶液とする。(Preparation of pellets for administration) 1. Methylcellulose 4000 cP (0.1 g) is dissolved in sterile purified water (10 ml) to give a 1% methylcellulose solution.
【0029】2. 本化合物をエタノール/滅菌精製水
(1/1)で溶解し、24μmol/mlの本化合物溶
液を調製する。2. This compound is dissolved in ethanol / sterilized purified water (1/1) to prepare a 24 μmol / ml compound solution.
【0030】3. 24μmol/mlの本化合物溶液
(0.20ml)と1%メチルセルロース溶液(0.2
0ml)を混合し、本化合物混合液(12μmol/m
l)とする。3. 24 μmol / ml of this compound solution (0.20 ml) and 1% methylcellulose solution (0.2
0 ml) and mixed with the present compound mixture (12 μmol / m
l).
【0031】4. 本化合物混合液(10μl)を直径
3mmのパラフィンフィルム上で風乾し、本化合物ペレ
ットを得る(0.12μmol/ペレット)。4. The compound mixture (10 μl) is air-dried on a paraffin film having a diameter of 3 mm to obtain the compound pellet (0.12 μmol / pellet).
【0032】(実験方法)
1. 受精後3日齢の孵化卵(ホワイトレグホン)入荷
後、直ちに卵殻表面を70%エタノールで洗浄・消毒し
た。これら孵化卵を空気相を上にして6穴の培養プレー
トに3個づつ立てた後、CO2 インキュベーター(37
℃、湿度95%、CO2 濃度5%)内で20分間培養し
た。(Experimental Method) 1. Immediately after the arrival of hatched eggs (white leghorn) 3 days after fertilization, the surface of the eggshell was washed and disinfected with 70% ethanol. These hatched eggs were placed in a 6-well culture plate with the air phase facing upwards, and 3 eggs were placed in each, and then the CO 2 incubator (37
° C., 95% humidity and incubated for 20 minutes at 5% CO 2) in the.
【0033】2. CO2 インキュベーターから孵化卵
を取り出し、クリーンベンチ内で孵化卵の空気相上部の
卵殻に約1cm四方の穴をあけた。2. The hatched eggs were taken out from the CO 2 incubator, and about 1 cm square holes were opened in the eggshell above the air phase of the hatched eggs in a clean bench.
【0034】3. 引き続き殻膜を卵黄膜から注意深く
剥離した。卵殻上の穴を直径13mmの培養シャーレで
覆った後、孵化卵をCO2 インキュベーターに再搬入
し、1日間培養した。3. Subsequently, the shell membrane was carefully peeled from the yolk membrane. After covering the hole on the egg shell with a culture dish having a diameter of 13 mm, the hatched eggs were re-loaded into a CO 2 incubator and cultured for 1 day.
【0035】4. 4日齢孵化卵の胚漿尿膜上(既存血
管の少ないところ)にパラフィンフィルム上の本化合物
ペレットをその薬物面が胚漿尿膜に接着するように静置
した。本化合物の投与量は、0.12μmol/卵であ
る。4. The compound pellet on a paraffin film was placed on the embryo chorioallantoic membrane of a 4-day-old hatched egg (where there are few existing blood vessels) so that the drug surface adheres to the chorioallantoic membrane. The dose of this compound is 0.12 μmol / egg.
【0036】5. この孵化卵を再びCO2 インキュベ
ーターに搬入し2日間培養した。5. The hatched eggs were again loaded into the CO 2 incubator and cultured for 2 days.
【0037】6. 10%イントラリピッド(血管造影
剤)約1mlを6日齢孵化卵の胚漿尿膜内に注入し、実
体顕微鏡(×10)にてペレット周囲の血管形成を観察
した。血管新生が認められない場合を陽性とし、血管新
生阻害率(%)は以下の式により算出した。6. About 1 ml of 10% intralipid (angiographic agent) was injected into the chorioallantoic membrane of 6-day-old embryonated eggs, and blood vessel formation around the pellet was observed with a stereoscopic microscope (× 10). The case where no angiogenesis was observed was regarded as positive, and the angiogenesis inhibition rate (%) was calculated by the following formula.
【0038】血管新生阻害率(%)=[(陽性を示した孵
化卵数)/(試験に供した孵化卵数)]×100Angiogenesis inhibition rate (%) = [(number of hatched eggs showing positive) / (number of hatched eggs used in the test)] × 100
【0039】(結果)本化合物の血管新生阻害率は75
%であった。(Results) The angiogenesis inhibition rate of this compound was 75.
%Met.
【0040】上記のことから、本化合物が、血管新生阻
害作用を有していることが明らかとなった。From the above, it became clear that the present compound has an angiogenesis inhibitory action.
【0041】[0041]
【発明の効果】したがって、キマーゼ阻害作用を有する
Suc-Val-Pro-HNCH(CH2Ph)P(O)(OPh)2は血管新生阻害作
用を有しており、血管新生が関与する疾患、特に糖尿病
網膜症、黄斑変性症、網膜静脈閉塞症、未熟児網膜症、
血管新生緑内障などの眼内血管新生性疾患の予防または
治療剤として有用であることが期待される。Therefore, it has a chymase inhibitory action.
Suc-Val-Pro-HNCH (CH 2 Ph) P (O) (OPh) 2 has an angiogenesis-inhibiting effect, and is associated with angiogenesis, especially diabetic retinopathy, macular degeneration, retinal vein occlusion. , Retinopathy of prematurity,
It is expected to be useful as a prophylactic or therapeutic agent for intraocular angiogenic diseases such as neovascular glaucoma.
───────────────────────────────────────────────────── フロントページの続き (51)Int.Cl.7 識別記号 FI テーマコート゛(参考) A61P 43/00 111 C12N 9/99 // C12N 9/99 A61K 37/64 ─────────────────────────────────────────────────── ─── Continued Front Page (51) Int.Cl. 7 Identification Code FI Theme Coat (Reference) A61P 43/00 111 C12N 9/99 // C12N 9/99 A61K 37/64
Claims (5)
有効成分とする血管新生阻害剤。1. An angiogenesis inhibitor comprising Suc-Val-Pro-HNCH (CH 2 Ph) P (O) (OPh) 2 as an active ingredient.
記載の阻害剤。2. The neovascularization is intraocular neovascularization.
The described inhibitor.
1記載の阻害剤。3. The inhibitor according to claim 1, wherein the neovascularization is choroidal neovascularization.
有効成分とする眼内血管新生性疾患治療剤。4. An intraocular angiogenic disease therapeutic agent comprising Suc-Val-Pro-HNCH (CH 2 Ph) P (O) (OPh) 2 as an active ingredient.
は黄斑変性症である請求項4記載の治療剤。5. The therapeutic agent according to claim 4, wherein the intraocular angiogenic disease is diabetic retinopathy or macular degeneration.
Priority Applications (1)
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JP2003084597A JP2003300902A (en) | 1999-08-12 | 2003-03-26 | Angiogenesis inhibitor |
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
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JP22812099 | 1999-08-12 | ||
JP11-228120 | 1999-08-12 | ||
JP2003084597A JP2003300902A (en) | 1999-08-12 | 2003-03-26 | Angiogenesis inhibitor |
Related Parent Applications (1)
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JP2000243554A Division JP2001114699A (en) | 1999-08-12 | 2000-08-11 | Angiogenesis inhibitor comprising compound having chymase inhibitory effect as active ingredient |
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JP2003300902A true JP2003300902A (en) | 2003-10-21 |
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ID=29404576
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Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH1087567A (en) * | 1996-06-05 | 1998-04-07 | Takeda Chem Ind Ltd | Phenol ester derivative, its production and use |
JPH10273450A (en) * | 1997-03-27 | 1998-10-13 | Toagosei Co Ltd | Therapeutic agent for intraocular neovascular disease |
-
2003
- 2003-03-26 JP JP2003084597A patent/JP2003300902A/en active Pending
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH1087567A (en) * | 1996-06-05 | 1998-04-07 | Takeda Chem Ind Ltd | Phenol ester derivative, its production and use |
JPH10273450A (en) * | 1997-03-27 | 1998-10-13 | Toagosei Co Ltd | Therapeutic agent for intraocular neovascular disease |
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