TW200946113A - PAI-1 expression and activity inhibitors for the treatment of ocular disorders - Google Patents
PAI-1 expression and activity inhibitors for the treatment of ocular disorders Download PDFInfo
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- TW200946113A TW200946113A TW098113153A TW98113153A TW200946113A TW 200946113 A TW200946113 A TW 200946113A TW 098113153 A TW098113153 A TW 098113153A TW 98113153 A TW98113153 A TW 98113153A TW 200946113 A TW200946113 A TW 200946113A
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Description
200946113 六、發明說明： 【發明所屬之技術領域】 相關申請案之交互引述 本申請案係於2〇07年10月31曰提出申請之共審查中的 申請案美國申請案序號11/931，393之部份延續申請案，依據 35 U.S.C. §12G主張其優先權，其内容在此併人本案以為參 考資料。本申請案依據35 U.S.C. §119亦主張於2008年4月26 參日提出申睛之美國暫准專利申請案序號61/〇48 176之優先 權，其完整内容在此併入本案以為參考資料。 發明之技術領域 . 本發明整體而言係有關於眼睛疾病之治療，及更詳細 _ 地係有關於使用經由向下調控PAI -1表現或活性而降低眼 内壓及/或治療或預防青光眼之藥劑，藉此改善由PAPi調節 之對於組織纖維蛋白溶酶原活化劑(t_pA)及/或尿激酶纖維 蛋白溶酶原活化劑（U-PA)的活性之抑制作用。
❹ 【先前冬好;J 發明背景 原發性開角型青光眼(P〇AG)係一種常見的破壞性眼 科疾病，右未加以治療將造成漸進性的視界喪失。大部分 的青光眼病患出現眼内壓(IOP)升高，及目前的許多療法係 朝向降低眼内壓之升高或維持正常的眼内壓。 纖維蛋白溶酶原活化劑抑制劑-1(PAI_1)水平之增加， 似乎在多種疾病狀態中扮演一角色，包括癌症、肥胖及糖 尿病。已在青光眼病患的眼房液中檢測到PAU水平之升高 3 200946113 (Dan等人於2005年期刊“Archives of Ophthalmology”第 123 期第220-224頁乙文）。除了其他内源性刺激之外，pAI_j水 平亦因細胞激素TGFP而增加（Binder等人於2002年期刊 “News Physiol Science”第 17期第56-61 頁乙文）。ΡΑϊ]抑制 組織纖維蛋白溶酶原活化劑(t-PA)與尿激酶纖維蛋白溶酶 原活化劑(u-PA)二者之活性。t-PA與u-PA二者催化纖維蛋白 溶酶原轉化為纖維蛋白溶酶之作用’纖維蛋白溶酶係纖維 蛋白溶解級聯中之一關鍵媒介物（Wu等人於2002年期刊 “Current Drug Targets”第2期第27-42頁乙文）。已知纖維蛋白 溶酶促進特定的前基質金屬蛋白酶(MMP)轉化為其等的活 性細胞外基質（ECM)降解形式（He等人於1989年期刊 PNAS第86期第2632-2636頁乙文）。PAI-1亦調控一種ECM 組份玻璃黏連蛋白（Vitronectin)與作用為黏附受體的細胞表 面組合蛋白之結合作用（Zhou等人於2003年期刊“Nature Structura Biology”第1〇⑺期第⑷巧料頁乙文）。因此，pAli 係與非眼睛組織中的黏附作用之降低及細胞剝離之增加相 關連。人類眼睛組織亦表現不同程度的t_pA及/或u_pA ;然 而已有報導指出小樑網（TM)主要表現丨^八（Shuman等人於 柳8年期刊“IOVS”第π期第4〇M〇5頁乙文；丁_似等人於 1990 年期刊“Exp Eye Research’’f51 期第 545 5S2 頁乙文）。 t-PA亦似乎是人類眼房液(AH)中所存在的主要形式。 在降低眼内壓及/或治療原發性開角型青光眼(p〇AG) 方面已證明有效的藥物療法，同時包括減少眼房液產生之 藥劑及增加流出順暢性之藥劑。該等療法一般藉由二種可 200946113 能的途徑投藥：局部（直接施用i眼睛）或口服。然而，藥學 上的抗尚眼壓方法已顯現各種的不良副作用。例如，縮瞳 藥諸如毛果芸香鹼可造成視力模糊、頭痛及其他對於視力 的負面副作用。碳酸酐酶抑制劑之全身性投藥亦可造成噁 %、消化不良、疲勞及代謝性酸中毒。一些前列腺素造成 充血症、眼睛發癢及睫毛與眼周圍皮膚發黑。該等負面的 副作用可能導致病患遵囑性之降低或終止治療，視力因而 q 持續惡化。此外，有一些個體對於現行的特定青光眼療法 之反應就是不佳。因此，需要用於治療眼睛疾病諸如青光 眼與眼壓過高之其他治療藥劑。 於2006年12月15日提出申請及公開為第2008/0107644 號美國專利公開案之第11/931,393號美國專利申請案，揭露 調節PAI-1與玻璃黏連蛋白（vitronectin)的結合作用之藥劑 作為一種預防小樑網細胞喪失及最終降低眼内壓之方式之 可忐用途。本發明係有關於抑制PAI-1對於組織纖維蛋白溶 鲁 畴原活化劑(t-PA)及/或尿激酶纖維蛋白溶酶原活化劑(u_pA) 之作用。
ί ^^明内J 發明概要 本發明的實施例係有關於抑制ΡΑΙ-1的表現或活性，以 冶療眼睛疾病及/或降低眼内壓。一實施例提供用於治療一 病患的青光眼或眼内壓（Ι〇ρ)升高之一種方法，其包括對於 病患技予一有效量之一組成物，該組成物包含抑制PAI_l表 現或阻止ΡΑΙ-1抑制組織纖維蛋白溶酶原活化劑(t_pA)或尿 200946113 激酶纖維蛋白溶酶原活化劑(u-PA)的活性之一藥劑。 本發明的另一實施例係與PAI-1相關聯的眼睛疾病之 一種治療方法，其包括投予一有效量之一組成物，該組成 物包含抑制PAI-1表現及/或PAI-1對於t_pA或u-PA活性的作 用之一藥劑。 在特定的該等實施例中，該藥劑為堤普拉堤寧 (tiplaxtinin)(PAI-039)、迪普拉希寧(diaplasinin)(PAI-749)、 ZK-4044、WAY-140312、HP-129、T-686、XR5967、XR334、 又11330、乂尺5118、愛迪普拉希寧(^1)1狀丨11丨11)(?八2_417)、 T-2639、S35225、SK216、SK116、2-[2-甲氧基-6-[[[3_(三 氟甲基)_4-[4-[3_(三氟曱基)苯基]-1-旅嗪基]苯基]胺基]曱基] 苯氧基]-5-硝基笨曱酸(在此亦稱作“化合物39” ； Ye等人於 2004年期刊 “Bioorganic & Medicinal Chemistry Letters” 第 14(3)期第761-765頁乙文）及其組合物。其他實施例可使用 藥劑諸如SB202190、U0126、SP600125、雙"弓卜朵基馬來醯 亞胺I、粗糠柴苦素、SB431542及SIS3。可使用抑素藥劑諸 如洛伐他汀(lovastatin)、辛伐他汀(simvastatin)、普伐他汀 (pravastatin)、氟伐他；丁（fluvastatin)、阿托伐他〉、丁 (atorvastatin)作為其他實施例中之藥劑。在特定實施例中亦 可使用PAI-1抗體與擬肽類。亦預期該等藥劑的組合物。 又另一實施例係用於治療青光眼或眼内壓（IOP)升高 的一化合物之一種製造方法，其包括提供一種疑似抑制 PAI-1表現或活性之候選物質’藉由評估候選物質在患有青 光眼或PAI-1升高之一個體的小樑網中降低活性形態的 200946113 :二=擇化:物’及製造所選擇的化合物。 列群t=中眼::r組成物進，含選自下 割、増_劑— 緩衝劑、氣化鈉、水及其組合物。 純、載劑、 劑二=施例中，選自下列群中的-化合物1阻斷 】腺素類似物、碳酸酐酶抑制劑、同效劑
:神經保護劑、rh〇激酶抑制劑及其級合物，可 成物的—部份投予或單獨投予。 為、、且 2述_找明歧地収本翻㈣施狀特性與 說點。其他的特性與技術優點將在本發明的後續詳細 纽。當連同任起考量時，將自本發明的 七田說明中更加瞭解據信為本發明特徵之新難性。然 而’在此提供關式係意欲協助說明本發明，或協助建立 對本發明的瞭解，而非意欲界定本發明的範圍。 圖式簡單說明 藉由參照下列說明及連同所附圖示，可更完整地瞭解 本發明及其優點。 第1圖係實驗結果之一圖，其顯示TGFp2(24小時)對於 人類小樑網（GTM-3)細胞上清液中的PAI-1水平之濃度依賴 型效應。數據以平均與SEM呈現，n=3。*係指依序藉由單 因子變異數分析(ANOVA)與唐奈特氏(Dunnett)檢定進行之 相對於對應載劑組的p<〇.〇5。 第2圖係實驗結果之一圖，其顯示經TGFp2 (5毫微克/毫 200946113 升）處理不同的時間週期或未經處理之GTM-3細胞上清液中 的PAI-1水平。數據係以平均與SEm呈現，n=3。*係指藉由 學生（Student)t-檢定進行之相對於對應載劑時間點組的 ρ<0·05。 第3圖係顯示TGFP2對於經處理的GTM-3細胞培養上 清液中之ΡΑΙ-1總含量與活性ΡΑΙ-1含量的效應之一圖。納入 TNFa與地塞米松(Dexamethasone)之效應以供比較。數據係 暴露於試驗藥劑24小時之後的平均與SEm ; “0”的數值係指 表現水平低於該分析的檢測極限。 第4圖所顯示的二個柱狀圖係概要說明pAI_i抑制作用 對於GTM-3細胞培養中的活性PAI-1之效應。 第5圖係顯示一種PAI-1合成抑制劑（T-2639)對於經處 理的GTM-3細胞培養上清液中之ΡΑΙ· 1總蛋白質水平經 TGFp2調節而增加之效應之一圖。 第6圖係顯示在第I型TGFP受體抑制劑SB431542存在或 不存在下之TGFp2 (5毫微克/毫升）的效應之圖。上圖： SB431542 (ΙΟμΜ)在不同的HTM細胞株中之效應。下圖： SB431542對於GTM-3細胞之劑量依賴型效應。數據係暴露於 試驗藥劑24小時之後的平均與SEM。（*表示依序藉由單因子 變異數分析(ANOVA)與邦弗洛尼氏(Bonferroni)檢定進行之相 對於經TGFP2處理的個別對照組之p<〇 ·〇〇 1或* *表示p<〇 〇5)。 第7圖係顯示在Smad3抑制劑SIS3(Jinnin等人於2006年 期刊 “MolecularPharmacology” 第 69期第 597-607 頁乙文）存 在或不存在下之TGF02(5毫微克/毫升）的效應之圖。上圖： 200946113 SIS3(10pM)在不同的HTM細胞株中之效應。下圖：SIS3對 於GTM-3細胞之劑量依賴型效應。數據係暴露於試驗藥劑 24小時之後的平均與SEM ^ 表示依序藉由單因子變異數 分析(ANOVA)與邦弗洛尼氏(B〇nferroni)檢定進行之相對於 經TGF β2處理的個別對照組之p<〇 〇〇 j)。 第8圖係顯示不同的細胞内訊息傳遞路徑酵素抑制劑 對於經TGF02刺激的GTM_3細胞（上圖）與SGTM2697細胞 (下圖）的效應之圖。所用的抑制劑：SB202190(P38 MAPK 抑制劑）、U0126(MEK 1/2抑制劑）、SP600125(JNK抑制劑）、 雙吲哚基馬來醯亞胺I(“BisI” ； PKCct、β、δ、ζ抑制劑）及粗 糠柴苦素(PKC5抑制劑）。數據係暴露於試驗藥劑24小時之 後的平均與SEM。（*表示依序藉由單因子變異數分析 (ANOVA)與邦弗洛尼氏(B〇nferr〇ni)檢定進行之相對於經 TGFp2處理的對照組之？<〇 〇〇1);及 第9圖係顯示抑素對於經TGFp2刺激的GT]vi_3細胞之 效應之圖。上圖：各種抑素（1〇μΜ)之效應。下圖：阿托伐 他’/丁 (atorvastatin)之劑量依賴型效應。數據係暴露於試驗藥 劑24小時之後的平均與SEM。（*表示依序藉由單因子變異 數刀析(ANOVA)與邦弗洛尼氏(B〇nferroni)檢定進行之相對 於經TGFβ2處理的對照組之p<〇 〇〇丨或㈣表示p<〇 〇5)。 第ίο圖係描述化合物(堤普拉堤寧(tiplaxtinin)、迪普拉 希寧(diaplasinin)及“化合物39，，)在細胞外基質清除作用的 一替代分析中之效應之一系列圖。試驗化合物在6種不同的 HTM細胞株中之各者的上清液測試用量中，引發高於基礎 200946113 (無治療）之可證明性的活性增加。 第11圖係呈現實驗結果的二個圖，其顯示二種化合物(堤 普拉堤寧(tiplaxtinin)與迪普拉希寧(diaplasinin))之效應，其阻 止PAI-1抑制t-PA與u-PA活性之能力及在Balb/cJ小鼠中由 Ad.TGFp2引發之眼内壓增加。藉由在注射Adv. TGFP2之前與 之後的PAI-1抑制劑給藥作用，均達成眼内壓之降低。
第12圖係呈現實驗結果的二個圖，其顯示同樣的二種 PAI-1抑制劑（堤普拉堤寧（tiplaxtinin)與迪普拉希寧 (diaplasinin))對於在Balb/cJ小鼠中由Adv.PAI-Ι引發的眼内 壓增加之效應。 【實施方式3 較佳實施例之詳細說明 本發明的特定實施例係以PAI-1在眼睛疾病諸如青光 眼中的作用為標把之方法，其藉由干擾與t-PA及u-PA相關 的PAI-1活性及/或PAI-1表現，如下列流程圖中所示：
TGF jS_2/其他刺激 4 PAI-1基團 轉錄作用 ♦ t PAI-1 活性—| *麵m
I 令流出 个眼内壓 10 200946113 其中TGFP2(或其他刺激)促進Μ]基因轉錄作用，接著增 加PAI-1蛋自質表現及増加活性ρΑιι的水平活性Μ]抑 制纖維蛋白溶酶原藉由t_pA及/或u_pA轉化為纖維蛋白溶酶 之作用。結果造成纖維蛋白溶酶水平之降低，纖維蛋白溶 解能力減少及細料基質(ECM)蓄積作用增加。ECM蓄積 作用增加流出阻力，及最終增加眼内壓。本發明的實施例 看出抑制ΡΑΙ· 1表現及/或干擾與t_pA及/或u_pA相關的pAi_ i 活性，係一種有用的青光眼療法。 技藝中已知抑制PAM表現或活性之各種化合物。第 11/611，312號美國專利申請案（Fleenor等人於2006年12月15 曰提出申請及公開為第2008/0107644號美國專利公開案）及 第7,351，407號美國專利（於2〇〇8年4月1日授與Fieen〇r等 人）’揭露可適於作為抑制ΡΑμ!表現或活性的化合物之該等 化合物，其等在此完整地併入本案以為參考資料。 本發明的PAI-1抑制劑包括但不限於PAI-039(堤普拉堤 寧（tiplaxtinin))(Crandall 等人於 2006 年期刊 “Arterioscler Thrombosis Vascular Biology Journal” 第 26(10)期第 2209-2215頁乙文）；pai_749(迪普拉希寧（diaplasinin))(Gardell等 人於2007 年期刊 “MolecularPharmacology” 第 72(4)期第 897-906頁乙文）；ZK4044(Liang等人於2005年期刊“Thrombosis Research” 第 115(4)期第 341-350 頁乙文）；WAY-140312 (Crandall 等人於 2004 年期刊 “Journal Thrombosis Haemostasis” 第 2(8)期第 1422-1428 頁乙文）；HP-129 (芬多沙 (fendosal)) (Gils 等人於 2002 年期刊 “Thrombosis 200946113
Haemostasis” 第 88(1)期第 137-143 頁乙文）；T-686(Murakami 等人於 1997年期刊 “Japanese Journal of Pharmacology”第 75 (3)期第291-294頁乙文）；PAZ-417(愛迪普拉希寧 (aleplasinin))(Zhao 等人於 2008 年期刊 “Cell Research” 第 18 期第803-804頁乙文）；T-2639(Miyazaki等人於2008年期刊 “Biorganic & Medicinal Chemistry Letters” 第 18期第 6419-6422頁乙文）；S-35225(Rupin等人於2008年期刊 “Thrombosis Research”第 122 期第 265-270 頁乙文；SK-216 與 SK-116(Mutoh 等人於2008 年期刊 “Carcinogenesis” 第 29(4) 期第824-829頁乙文）；及2-[2-曱氧基-6-[[[3-(三氟甲基)-4-[4-[3-(二氣甲基）本基]_ι_旅唤基]苯基]胺基]曱基]苯氧 基]-5-硝基苯曱酸（“化合物39” ；（Ye等人於2004年期刊 “Bioorganic & Medicinal Chemistry Letters” 第 14(3)期第 761- 765頁乙文）。 亦可使用其他小型分子諸如旅唤與薄荷醇衍生物（Ye 等人於 2004 年期刊 “Bioorganic & Medicinal Chemistry Letters”第14(3)期第761-765頁乙文；Ye等人於2003年期刊 “Biorganic & Medicinal Chemistry Letters” 第 13(19)期第 3361-3365頁乙文）、ΡΑΙ-l抗體（Verbeke等人於2004年期刊 “Journal of Thrombosis and Haemostasis” 第 2(2)期第 289-297頁乙文；van Giezen等人於 1997年期刊“Thrombosis and Haemostasis”第 77(5)期第 964-969頁乙文；及Abrahamsson 等人於 1996年期刊 “Thrombosis and Haemostasis”第 75(1)期 第118-126頁乙文）及蛋白質藥劑諸如派歐寧（pai〇nin)_4 12 200946113 (Mathiasen 等人於 2008 年期刊 “Molecular Pharmacology” 第 74(3)期第64l-653頁乙文）’作為本發明的特定實施例中之 抑制PAI-1表現或活性的化合物。 其他實施例可使用藥劑諸如SB202190、HP-129、 U0126、SP600125、雙吲哚基馬來醯亞胺〗、粗糠柴苦素、 SB431542及SIS3。可使用抑素藥劑諸如洛伐他汀 (lovastatin)、辛伐他汀(Simvastatin)、普伐他汀(pravastatin)、 乱伐他>丁(fluvastatin)、阿托伐他汀（at〇rvastatin)作為其他實 施例中之藥劑。抑制PAI-1表現或活性的較佳化合物係堤普 拉堤寧（tiplaxtinin)、迪普拉希寧（diaplasinin)、化合物外及 T-2639。 可將本發明之抑制PAM表現或活性的化合物納入供 輸送用之各種類型的眼用配方。使用具有一般技藝者所熟 知的技術，可將該化合物可直接輸送至眼睛（例如局部眼用 滴劑或軟膏；緩慢釋出裝置諸如植入眼陷凹或植入鄰近輩 膜處或眼睛内之藥學用藥物輸送海錦；眼睛周圍、結膜、 眼球筋膜囊下、前房内、玻璃體内或視神經管内注射作 用），或輸送至全身（例如口服、靜脈内、皮下或肌内注射作 用；非經腸、皮或鼻輸送作用）。進一步預期本發明的PAW 表現或活性抑制劑可配製成眼内植入劑或可植入式裝置。 在此揭露之PAI-1表現或活性抑制劑較佳納入局部眼 用配方中，以輸送至眼睛。該化合物可與眼科學上可接受 的保存劑、表面活性劑、增黏劑、滲透促進劑、緩衝劑、 氣化鈉及水組合形成一種含水的無菌眼用懸浮液或溶液。 13 200946113 可藉由將一化合物溶解於一種生理上可接受之等張的含水 緩衝劑中，而製備眼用溶液配方。更進一步，眼用溶液可 包括一種眼科學上可接受的表面活性劑，以協助溶解該化 合物。而且，眼用溶液可含有用於增加黏度之一藥劑，諸 如羥基曱基纖維素、羥基乙基纖維素、羥基丙基甲基纖維 素、甲基纖維素、聚乙烯基吡咯烷酮等，以增進該配方在 結膜囊中之滯留作用。亦可使用膠凝劑，其包括但不限於 結蘭膠(Gellan)與黃原膠。為製備無菌的眼用軟膏配方，可 在適宜的載劑諸如礦物油、液態羊毛脂或白礦脂中，將活 性成份與一保存劑混合。依據類似的眼用製劑之公開配 方，可藉由將化合物懸浮於自例如聚羧乙烯-974等的組合 物所製得的一種親水性基料中，而製備無菌的眼用凝膠配 方；及可納入保存劑與張力劑。 PAI-1表現或活性抑制劑較佳配製為局部眼用懸浮液 或溶液，其pH值約為4至8。局部用懸浮液或溶液中所含有 的化合物量，係足以在經歷眼内壓（IOP)升高的病患中降低 其眼内壓，及/或足以在青光眼病患中維持正常的眼内壓水 平。該量在此稱作“有效控制眼内壓之一量”或更簡要地稱 作“一有效量”。該等配方所含有的化合物量，一般為0.01 至5重量/體積百分比(“w/v%”），但該量較佳為0.25至2重量/ 體積％。因此，就供局部用的形式而言，依據有經驗醫師 的判斷，每天對於眼睛表面投予1至2滴的該等配方1至4次。 PAI-1表現或活性抑制劑亦可與用於治療眼内壓（IOP) 升高或青光眼的其他藥劑組合使用，諸如但不限於rho激酶 14 200946113
J制劑、β_阻斷劑、前列腺素類似物、碳酸酐酶抑制射、α2 5效劑、縮瞳樂、類血清素功能型同效鼓神經保護射。 如用於此之ΡΑΜ表現或活性抑制劑，，涵蓋該等抑制 劑以及其等藥學上可接受的鹽類。ρ組表現或活性抑制劑 2種藥學上可接受的鹽類，係保有對於表現或活性 Ρ制性活性及為人體可接受的一鹽類。鹽類可為酸式或 鹼式鹽’因在此所述的藥劑可具有胺基或絲取代基。可 與-酸形成-鹽類，諸如乙酸、苯甲酸、桂皮酸、檸檬酸、 乙基績酸、反式丁婦二酸、録乙酸、氫驗、氯氯酸、 順式丁稀二酸、丙二酸、苯乙醇酸、甲基續酸、石肖酸、草 酸、磷酸、丙酸、丙酮酸、水揚酸、 酸、對-甲苯顧、三氣乙酸等。可與一鹽形成一鹽類= 如-種-級、二級或三級胺、銘、錢、約、銅、鐵、鐘、 鎂、猛、钟、鈉、辞等。
、.’内入下列實例，以顯不本發明的較佳實施例。該等綱 熟技藝者應瞭解在後述實财所揭露的技術，係代表本案 發明者在本發明的實施中所發現之作用良好的技術，及因 此二視為構成實施本發明陳佳模式。然而，鑑於本揭露 内令X等嫻热技藝者應瞭解可在所揭露的特定實施例中 進行眾多改變，而仍獲致相等或類似的結果，及不偏離本 發明的精神與範圍。 第1例 八可使用結合分析或亦可用於測定其等生物活性之功能 刀析、進行ΡΑΙ_1表現或活性抑制劑之選擇。該等嫻熟 15 200946113 技藝者可使用先前所述的方法，發展出該等分析。用於選 擇PAI-1表現或活性抑制劑之其他適用的分析，係示於第2 至5例。 可藉由活體内分析方式，評估特定的PAI-1表現或活性 抑制劑安全降低眼内壓之能力。在使用食蟹猴之一種該分 析中，在以0.1%丙對卡因（proparacaine)進行輕度角膜麻醉 之後，以愛爾康(Alcon)氣壓式眼壓計測定眼内壓。（Sharif 等人於 2006 年期刊 “Journal Ocular Pharmacology & Therapeutics”第 17(4)期第 305-317 頁乙文；May 等人於 2〇03 年期刊 “Journal of Pharmacology & Experimental Therapeutics”第306(1)期第301-309頁乙文）。在各次測量之 後，以1或2滴的食鹽水沖洗眼睛。在測量基線眼内壓之後， 在所選擇的眼中滴入1或2份的30微升測試用量之試驗化合 物。後續在1、3及6小時進行眼内壓測量。在所有動物的右 眼進行雷射小梁成型術，以引發眼壓過高。所有的左眼皆 正常’因而具有正常的眼内壓。 在使用紐西蘭白兔的另一種分析中，在以0.1%丙對卡因 (proparacaine)進行輕度角膜麻醉之後，以曼特經典(Mentor Classic) 30型氣壓式眼壓計測定眼内壓。在各次測量之後， 以1或2滴的食鹽水沖洗眼睛。在測量基線眼内壓之後，在各 動物的一或二隻眼睛中滴入一份的30微升測試用量之試驗 化合物，或在一眼中滴入化合物及在對側眼中滴入載劑。後 續在0·5、1、2、3、4及5小時進行眼内壓測量。 第2例 16 200946113 自死後的人類捐贈者之組織中分離人類TM細胞，及如 刖述進行特性分析與培養。轉型（GTM_3)細胞株之世代與特 ϋ刀析係如Pang等人所述（於丨994年期刊“Current Eye ReSearch”第13(1)期第51-63頁乙文）。TM細胞培養的24槽式 平皿·缺乏血清24小時，接著在無血清培養基中與1(}1^2培 養另外2 4小時（或如所示）。在經處理的培養上清液之測試用 量中，藉由人類PAM ELISA套組（美國康乃迪克州格林威 治（Greenwich)的美國診斷(American
Diagnostica Inc.)有限 公司的伊苗百德(imubind))之方式，定量所釋出的PAI1含 置。ELISA同時檢測潛伏性與活性PAI-1以及PAI-1複合物， 其最低可檢測極限為5〇微微克/毫升。 第1圖係顯示TGFp2增加小樑網細胞培養(GTM-3)中的 PAI-1含量之一圖。由PAM調節的效應，可能對於先前觀察 到之由TGFP2調節的細胞外基質物質在包括TM&織的不 同組織中之蓄積作用有所貢獻。第2圖顯示，由TGFp2調節的 PAI-1增加作用，係持續存在於經TGFp2處理的細胞培養中。 因此’TGFP2之處理似乎在TM細胞上清液中同時產生濃度依 賴型與時間依賴型的PAI-1蓄積作用。因應TGFp2，ΡΑΙ-1水 平逐漸地增加’而在處理約24小時後達到一穩定水平。 第3例 變型生長因子-P(TGFP)調節廣泛種類的基因與蛋白質 產物之生產作用，及因此調節多種的細胞作用。研究已顯 示在活體外以TGFP2異構形式處理人類小樑網（HTM)細 胞，導致纖維蛋白溶酶原活化劑抑制表現之改 17 200946113 變，而PAI-l係對眼睛細胞外基質(ECM)的蓄積作用可能有 所貢獻之一種重要的調節劑。在TM區域中之不按比例的 ECM增積作用，可能對於眼房液(AH)之流出造成更大的阻 力，及因而增加眼内壓，諸如在原發性開角型青光眼中所 見者。此外，自人類原發性開角型青光眼的眼房液中所收 集之TGFP2與PAI-1的水平，均高於非青光眼的眼睛。而且， 當灌注TGFp2時，活體外人類前眼部所產生的反應係降低 流出順暢性。 在該等研究中，如前述進行人類TM細胞之分離、特性 分析及培養(Pang等人於1994年期刊“Current Eye Research” 第13(1)期第51-63頁乙文）。為進行該等分析，平皿培養的細 胞缺乏血清24小時’接著在無血清培養基中與試驗藥劑培養 另外24小時。然後自經處理的培養中，取出測試用量的上清 液，藉由人類PAI-1 ELISA套組（美國康乃迪克州格林威治 (Greenwich)的美國診斷(American Diagnostica Inc_)有限公司 的伊苗百德(Imubind))之方式，定量PAI-1總含量。ELISA同 時檢測潛伏性與活性PAI-1以及PAI-1複合物，其最低可檢測 極限為50微微克/毫升。以用於定量活性與尿激酶的結 合作用之一種ELISA套組（美國密西根州南園市（s〇uthfleld) 的分子創新(Molecular Innovations)公司），評估細胞上清液中 的活性PAI-1含量。因潛伏性與複合型pAl-1不與尿激酶結 合，因而未被該分析檢測出。該分析之預期檢測極限約為 0.〇45單位/毫升（其中1單位等於約134毫微克的活性paw)。 第3至9圖係呈現使用上述方法進行的試管中實驗之結 200946113 果。在研究中，GTM-3細胞的PAI-l平均基礎釋出作用為 33·9±1·5毫微克/毫升/24小時(n=233)。TGFp2係以時間與劑 量依賴型方式，增加GTM-3細胞上清液中的PAI-1含量。以 5毫微克/毫升的TGFP2處理24小時，PAI-1水平升高達12.02 土 0.03 倍。 在試管中藉由與眼内壓增加相關連的因子（TGFP2、 TNFa、地塞米松(Dexamethasone))，將HTM細胞的PAI-1 總 蛋白質水平向上調節。藉由TGFP2，亦增加活性PAI-1的水 平（第3圖）。第4圖顯示，堤普拉堤寧(tiplaxtinin)降低在經 TGF02處理的GTM-3培養中之活性PAI-1水平。藉由典型（經 Smad調節型）與非典型（與Smad無關型）訊息傳遞途徑的抑 制劑，顯著地(ρ<0·05)向下調節經TGFp2刺激的PAI-1水 平。第5圖係顯示一種PAI-1合成抑制劑(T-2639)對於經處理 的GTM-3細胞培養上清液中之經TGFP2調節的PAI-1總蛋白 質水平增加之效應之一圖。經TGFP2調節的典型（Smad)訊 息傳遞路徑之抑制劑（SB431542與SIS3) ’阻斷在人類小樑 網（HTM)細胞培養中之總PAI-1的試管中表現作用（第6與7 圖）。經TGF02調節的非典型（與Smad無關型）訊息傳遞路徑 之抑制劑（SB202190、U0126、SP600125、雙β引β朵基馬來醯 亞胺I及粗糖柴古素）’亦阻止在ΗΤΜ細胞培養中之總ρΑΐ_ 1 的試管中表現作用。目前鑑定出之訊息傳遞路徑包括ρ38 ΜΑΡΚ、ΜΕΚ 1/2、JNK及PKC?(第 8圖）。 抑素藥劑之處理，亦降低在ΗΤΜ細胞培養中之總ΡΑΜ 的試管中表現作用（第9圖）。整體反應自諸如SB431542 19 200946113 (TGFP第1型受體抑制劑；1μΜ)與粗糠柴苦素(pKc5抑制 劑；ΙΟμΜ)等藥劑的完全抑制作用，至SB2〇219〇(p38
MAPK 抑制劑，ΙΟΟηΜ)、8?600125((^11111^_端激酶抑制劑；ΐμΜ) 及各種的抑素藥劑的部份抑制作用不等。 第4例 進行一研究’以評估本發明的化合物對於細胞外基質 '/月除作用之效應。在丨疋普拉堤寧(tipiaxtinin)、迪普拉希寧 (diaplasinin)及化合物39存在或不存在下，處理人類tm細胞 24小時。然後將細胞上清液的測試用量與經紅外線染料 © (IRDye) 800RS標記的酪蛋白（李-寇爾生物科學（Li-Cor Biosciences)公司）培養2小時，接著以一種奥德赛(Odyssey) 紅外線成像系統（李-寇爾生物科學(Li-Cor Biosciences)公 司）檢測所累積的螢光性降解產物。第10圖顯示在6種不同 -- 的HTM細胞株中之各者的上清液測試用量中，堤普拉堤寧 (tiplaxtinin)、迪普拉希寧(diaplasinin)及化合物39引發高於 基礎（無治療）之可證明性的活性增加。因此，該等化合物之 處理，增進小樑網細胞的基質蛋白質降解作用。 第5例 使用一種小鼠模式，以評估本發明的化合物之活體内 效應。在各BALB/cJ小鼠之一眼的玻璃體内’注射AdiCMV. hPAI-1或Ad.CMV.hTGFp2226/228。未經注射的對側眼睛係作 為對照組。經由回彈式眼壓計(TonoLab®)，在所選擇的時 間點，測量清醒動物的眼内壓。在圖式中所示的時段，經 由每日局部給藥（每日二次）而投予試驗藥劑。 20 200946113 第11圖係呈現實驗結果的二個圖，其顯示抑制Pai 於t-PA與u-PA的抑制性活性之化合物（堤普技 疋寧 (tiplaxtinin)與迪普拉希寧（diaplasinin))之效應。該等化人 幾乎完全逆轉Ad.TGFp2在Balb/C小鼠中所引發的限内壓# 加。藉由在注射Adv.TGFp2之前與之後的PAI-1抑制舞丨故^ 作用，均達成眼内壓之降低。 '
第12圖係呈現實驗結果的二個圖，其顯示阻止pAl i_ 於t-PA與u-PA的抑制性活性之化合物（堤普抵 是寧 (tiplaxtinin)與迪普拉希寧（diaplasinin))之效應。該二藥制、、 少Ad.TGF02在Balb/C小鼠中所引發的眼内壓增加。 第6例 成份 濃度（重量/體' 堤普拉堤寧(tiplaxtinin) 0.01-2%°" 羥基丙基甲基纖維素 0^5% ~~ 磷酸二鈉（無水） 0.2% ~~---- 氣化納 0.5% ~--— EDTA二鈉（乙二胺四乙酸二鈉） 0.01% ~~~~~~— 縮聚山梨醇油酸醋（Polysorbate) 80 0.05% --— 氣化笨甲烴銨 0.01 % -- 氫氧化鈉/氫氣酸 用於將pH值調整一' 純水 至 100% 的 — -- ---- 第7例 咸份 濃度(重量/體^ 迪普拉希寧(diaplasinin) 0.01-2% - 甲基纖維素 4.0% 磷酸二鈉(無水） 0.2% ' - 氯化鈉 0.5% - EDTA二鈉（乙二胺四乙酸二納） 0.01% 縮聚山梨醇油酸醋(Polysorbate) 80 0.05% ' 氣化苯甲烴銨 0.01% 氫氡化鈉/氫氣酸 用於將pH值調整至7.3-7.4 純水 至100%的餘量 21 200946113
已詳細地說明本發明及其實施例。然而，本發明的範 圍並非意欲侷限於說明書所述之任一操作、製造、組成物、 化合物、方式、方法及/或步驟的特定實施例。可進行所揭 露物質的各種修飾、取代及變化，而不偏離本發明的精神 及/或本質特性。因此，具一般技藝者自揭露内容即可理解 可依據本發明的該等相關實施例，使用所表現的功能或所 達成的結果與在此所述的實施例實質相同之後續的修飾、 取代及/或變化。因此’下列申請專利範圍係意欲在其等的 範疇内涵蓋在此揭露之操作、製造、組成物、化合物、方 式、方法及/或步驟的修倚、取代及/或變化。 參考文獻 下列參考文獻在此完整地併入本案以為參考資料： ABRAHAMSSON et al.? Anti-thrombotic Effect of a PAI-1 Inhibitor in Rats Given Endotoxin5,? Thrombosis and Haemostasis, Vol. 75(1):118-26, 1996 BINDER et al·，“Plasminogen Activator Inhibitor 1: Physiological and Pathophysiological Roles”，News Physiol Science，Vol. 17:56-61，2002
CRANDALL et al·，“Characterization and Comparative Evaluation of a Structurally Unique PAI-1 Inhibitor Exhibiting Oral in-vivo Efficacy”，Journal Thrombosis Haemostasis, Vol. 2(8):1422-8, 2004 CRANDALL et al·，“Modulation of Adipose Tissue Development by Pharmacological Inhibition of PAI-1，，，Arterioscler Thrombosis Vascular Biology Journal，Vol· 26(10):2209-2215, 2006 DAN et al·，“Plasminogen Activator Inhibitor-1 in the Aqueous Humor of Patients With and Without Glaucoma”，Archives of Ophthalmology，Vol. 123:220-224, 2005 GARDELL et al.，“Neutralization of Plasminogen Activator Inhibitor I (PAI-1) by the Synthetic Antagonist PAI-749 via a Dual Mechanism of Action，’’ Molecular Pharmacology, Vol. 72(4):897-906, 2007 22 200946113 GILS et al·，“Characterization and Comparative Evaluation of a Novel PAI-1 Inhibitor’’，Thrombosis Haemostasis，Vol· 88(1):137-143, 2002 HE et al·，“Tissue Cooperation in a Proteolytic Cascade Activating Human Interstitial Collagenase，’，PNAS，Vol· 86:2632-2636, 1989 JINNIN et al.，“Characterization of SIS3, a Novel Specific Inhibitor of Smad3, and its Effect on Transforming Growth Factor-B 1 -Induced Extracellular Matrix Expression”，Molecular Pharmacology，Vol· 69:597-607, 2006 LIANG et al，“Characterization of a Small Molecule PAI-1 Inhibitor，ZK4044”， Thrombosis Research，Vol. 115(4):341- 350, 2005
MATHIASEN et al., UA Peptide Accelerating the Conversion of Plasminogen Activator Inhibitor-1 to an Inactive Latent State”，Molecular Pharmacology, Vol. 74(3):641-653,2008 MAY et al·，“Evaluation of the Ocular Hypotensive Response of Serotonin 5-HT1A and 5-HT2 Receptor Ligands in Conscious Ocular Hypertensive Cynomolgus Monkeys’’， Journal of Pharmacology & Experimental Therapeutics, Vol. 306(1):301-309, 2003 MIYAZAKI et al.，“Design，Synthesis，and Evaluation of Orally Active Inhibitors of Plasminogen Activator Inhibitor-1 (PAI-1) Production”，
Bioorganic & Medicinal Chemistry Letters, Vol. 18:6419-6422, 2008 MURAKAMI et al., “Protective Effect of T-686, an Inhibitor of Plasminogen Activator Inhibitor-1 Production, Against the Lethal Effect of
Lipopolysaccharide in Mice，’’ Japanese Journal of Pharmacology, Vol. 75(3):291-294, 1997 MUTOH et al., ''Plasminogen Activator Inhibitor-1 (Pai-1) Blockers Suppress Intestinal Polyp Formation in Min Mice99, Carcinogenesis, Vol. 29(4):824-829, 2008 PANG et al·，“Preliminary Characterization of a Transformed Cell Strain Derived from Human Trabecular Meshwork^, Current Eye Research, Vol. 13(1):51-63, 1994 RUPIN et al.，“S35225 is a Direct Inhibitor of Plasminogen Activator Inhibitor Type-1 Activity in the Blood’’，Thrombosis Research，Vol· 122:265-270, 2008 SHARIF et al” “Levobetaxolol (Betaxon™) and Other B-Adrenergic Antagonists: Preclinical Pharmacology, IOP- Lowering Activity and Sites of 23 200946113
Action in Human Eyes’’，Journal of Ocular Pharmacology and Therapeutics， Vol. 17(4):305-317, 2001 SHUMAN et al./Tissue Plasminogen Activator in Cultured Human Trabecular Meshwork Cells”，IOVS，Vol. 29:401-405, 1988 TRIPATHI et al·，“Aqueous Humor in Glaucomatous Eyes Contains an Increased Level of TGF-beta 2”，Exp Eye Research，Vol· 59:723-727, 1994 TRIPATHI et al.，“Localization of Urokinase-type Plasminogen Activator in Human Eyes: An Immunocytochemical Study99, Exp Eye Research, Vol. 51:545-552, 1990 van GIEZEN et al·，“The Fab-fragment of a PAI-1 Inhibiting Antibody Reduces Thrombus Size and Restores Blood Flow in a Rat Model of Arterial Thrombosis”，Thrombosis and Haemostasis，Vol· 77(5):964-969, 1997 VERBEKE et al·，“Cloning and Paratope Analysis of an Antibody Fragment, a Rational Approach for the Design of a PAI-1 inhibitor’’，Journal of Thrombosis and Haemostasis, Vol. 2(2):289-297, 2004 WU et al.，“Inhibition of PAI-1: A New Anti-thrombotic Approach”，Current Drug Targets, Vol. 2:27-42, 2002 YE et al·，“Synthesis and Biological Evaluation of Menthol-based Derivatives as Inhibitors of Plasminogen Activator Inhibitor-1 (PAI-1 )”，Bioorganic Medicinal Chemistry Letters, Vol. 13(19):3361-3365, 2003 YE et al·，“Synthesis and Biological Evaluation of Piperazine-Based Derivatives as Inhibitors of Plasminogen Activator Inhibitor-1 (PAI-1)’’， Bioorganic & Medicinal Chemistry Letters?Vol. 14(3):761-765, 2004 ZHAO et al.，“Evoking Plasmin for β-amyloid Clearance’’，Cell Research，Vol. 18:803-804, 2008 ZHOU et al., uHow Vitronectin Binds PAI-1 to Modulate Fibrinolysis and Cell Migration59, Nature Structural Biology, Vol. 10(7):541-544, 2003 U.S. Patent No. 7,351,407 (Fleenor et al, issued April 1, 2008) U.S. Patent Publication No. 2008/0107644 Fleenor et al., Published May 8, 2008 24 200946113 I：圖式簡單說明□ 第1圖係實驗結果之一圖，其顯示TGFP2 (24小時)對於 人類小樑網（GTM-3)細胞上清液中的PAI-1水平之濃度依賴 型效應。數據以平均與SEM呈現，n=3。*係指依序藉由單 因子變異數分析(ANOVA)與唐奈特氏(Dunnett)檢定進行之 相對於對應載劑組的p<0.05。 第2圖係實驗結果之一圖，其顯示經TGFp2 (5毫微克/毫 升）處理不同的時間週期或未經處理之GTM-3細胞上清液中 的PAI-1水平。數據係以平均與SEM呈現，n=3。*係指藉由 學生（Student)t-檢定進行之相對於對應載劑時間點組的 p<0.05。 第3圖係顯示TGFp2對於經處理的GTM-3細胞培養上 清液中之PAI-1總含量與活性PAI-1含量的效應之一圖。納入 TNFa與地塞米松(Dexamethasone)之效應以供比較。數據係 暴露於試驗藥劑24小時之後的平均與SEM ; “0”的數值係指 表現水平低於該分析的檢測極限。 第4圖所顯示的二個柱狀圖係概要說明PAM抑制作用 對於GTM-3細胞培養中的活性PAI-1之效應。 第5圖係顯示一種PAI-1合成抑制劑（T-2639)對於經處 理的GTM-3細胞培養上清液中之PAI-1總蛋白質水平經 TGFP2調節而增加之效應之一圖。 第6圖係顯示在第I型TGFP受體抑制劑SB431542存在或 不存在下之TGFP2 (5毫微克/毫升）的效應之圖。上圖： SB431542 (ΙΟμΜ)在不同的HTM細胞株中之效應。下圖： 25 200946113 SB431542對於GTM-3細胞之劑量依賴型效應。數據係暴露於 試驗藥劑24小時之後的平均與SEM。（*表示依序藉由單因子 變異數分析(ANOVA)與邦弗洛尼氏(Bonferroni)檢定進行之相 對於經TGFP2處理的個別對照組之ρ<〇.〇〇1或**表示p<0.05)。 第7圖係顯示在Smad3抑制劑SIS3(Jinnin等人於2006年 期刊 “MolecularPharmacology” 第 69期第 597-607 頁乙文）存 在或不存在下之TGF02 (5毫微克/毫升）的效應之圖。上圖： SIS3(10pM)在不同的HTM細胞株中之效應。下圖：SIS3對 於GTM-3細胞之劑量依賴型效應。數據係暴露於試驗藥劑 © 24小時之後的平均與SEM。（*表示依序藉由單因子變異數 分析(ANOVA)與邦弗洛尼氏(Bonferroni)檢定進行之相對於 經TGF02處理的個別對照組之pco.ooi)。 ' 第8圖係顯示不同的細胞内訊息傳遞路徑酵素抑制劑 - 對於經TGFP2刺激的GTM-3細胞（上圖）與SGTM2697細胞 (下圖）的效應之圖。所用的抑制劑：SB202190(p38 MAPK 抑制劑）、U0126(MEK 1/2抑制劑）、SP600125(JNK抑制劑）、 雙吲哚基馬來醯亞胺I(“BisI” ； PKC(X、β、δ、ς抑制劑）及粗 〇 糠柴苦素(pkcs抑制劑）。數據係暴露於試驗藥劑24小時之 後的平均與SEM。（*表示依序藉由單因子變異數分析 (ANOVA)與邦弗’各尼氏（B〇nferroni)檢定進行之相對於經 TGFP2處理的對照組之p<〇 〇〇1);及 第9圖係顯示抑素對於經T GF β 2刺激的G TM - 3細胞之 政應之圖。上圖：各種抑素（1〇μΜ)之效應。下圖：阿托伐 他丁 (atorvastatin)之劑量依賴型效應。數據係暴露於試驗藥 26 200946113 劑24小時之後的平均與SEM。（*表示依序藉由單因子變異 數分析(ANOVA)與邦弗洛尼氏(B〇nferroni)檢定進行之相對 於經TGF02處理的對照組之p<0 001或**表示p<〇 〇5)。 第10圖係描述化合物（堤普拉堤寧(tiplaxtinin)、迪普拉 希寧（diaplasinin)及“化合物39”)在細胞外基質清除作用的 一替代分析中之效應之一系列圖。試驗化合物在6種不同的 HTM細胞株中之各者的上清液測試用量中，引發高於基礎 (無治療）之可證明性的活性增加。 第11圖係呈現實驗結果的二個圖，其顯示二種化合物(堤 普拉堤l(tiplaxtinin)與迪普拉希寧(diaplasinin))之效應，其阻 止PAI-1抑制t-PA與u-PA活性之能力及在Balb/cJ小鼠中由 Ad_TGFp2引發之眼内壓增加。藉由在注射Adv. TGF02之前與 之後的PAI-1抑制劑給藥作用，均達成眼内壓之降低。 第12圖係呈現實驗結果的二個圖，其顯示同樣的二種 PAI-1抑制劑（堤普拉堤寧（tiplaxtinin)與迪普拉希寧 (diaplasinin))對於在Balb/cJ小鼠中由Adv.PAI-1引發的眼内 壓增加之效應。 【主要元件符號說明】 (無） 27
Claims (1)
- 200946113 七、申請專利範圍： 1. 一種包含抑制PAI-1表現或活性的一藥劑之一組成物在 製造用於治療一病患的青光眼或眼内壓（IOP)升高的一 藥物之用途。 2. 如申請專利範圍第1項之用途，其中該藥劑係選自於由 下列所組成的群組： 堤普拉堤寧(tiplaxtinin)、迪普拉希寧（diaplasinin)、 愛迪普拉希寧(aleplasinin)、芬多沙(fendosal)、ZK4044、 WAY-140312、T-686、T-2639、S-35225、SK-216、SK-116、 SB202190、U0126、HP-129、SP600125、XR5967、 XR334、XR330、XR5118、化合物39、雙吲哚基馬來醯 亞胺I、粗糠柴苦素、SB431542、SIS3、抑素、洛伐他 汀（lovastatin)、辛伐他汀（simvastatin)、普伐他 丁 (pravastatin)、氟伐他汀（fluvastatin)、阿托伐他；丁 (atorvastatin)、PAI-1抗體、PAI-1蛋白質抑制劑、派歐寧 (paionin)-4及其組合物。 3. 如申請專利範圍第2項之用途，其中該藥劑選自於由下列 所組成的群組： 愛迪普拉希寧（aleplasinin)、Sf#(fendosal)、T-2639、S-35225、SK-216、SK-116、SB202190、U0126、 SP600125、化合物39、雙吲哚基馬來醯亞胺I、粗糠柴 苦素、SB431542、SIS3、抑素、洛伐他汀(lovastatin)、 辛伐他ί丁（simvastatin)、普伐他汀(pravastatin)、氟伐他 汀（fluvastatin)、阿托伐他汀（atorvastatin)、PAI-1抗體、 28 200946113 PAI-l蛋白質抑制劑、派歐寧(pai〇nin)_4及其組合物。 4. 如申請專利範圍第3項之用途，其中該藥劑選自於由下列 所組成的群組： 堤普拉堤寧(tiplaxtinin)、迪普拉希寧(diaplasinin)、 雙弓丨°木基馬來酿亞胺I、T-2639、化合物39及其組合物。 5. 如申請專利範圍第1項之用途，其中該抑制作用干擾 PAI-1對於組織纖維蛋白溶酶原活化劑（t_pA)或尿激酶 φ 纖維蛋白溶酶原活化劑(u-PA)活性的抑制作用。 6. 如申請專利範圍第1項之用途，其中該組成物進一步包 含選自於由下列所組成的群組之一化合物： 眼科予上可接受的保存劑、表面活性劑、增黏劑、 〜透促進劑、膠凝劑、疏水性基料、載劑、緩衝劑、氯 化納、水及其組合物。 7. 如申請專利範圍第1項之用途，其中該藥物包含或適於 與選自於由下列所組成的群組之-化合物分開投藥： ❿ 卜阻斷劑、前列腺素類似物、碳酸酐酶抑制劑、α2 '】縮曈藥、神經保護劑、rho激酶抑制劑及其組 合物。 ί' 8. 如申請，範圍扪項之用途，其中該組成物包含自約 .01重ΐ/體積百分比至約5重量/體積百分比的該藥劑。 9. 如申請專利範圍第1項之用途，其中該組成物包含自約 二25重量/體積百分比至約2重量/體積百分比的該藥劑。 活性或表現的-藥劑之-組成物在 '化療一需要個體中與ρΑΙ“相關聯的—眼睛疾 29 200946113 病的一藥物之用途。 π.如申請專利範圍第10項之用途，其中該疾病係眼壓過高 或青光眼。 12.如申請專利範圍第1〇項之用途，其中該藥劑係選自於由 下列所組成的群組： 堤普拉堤寧(tiplaxtinin)、迪普拉希寧（diaplasinin)、 愛迪普拉希寧（aleplasinin)、芬多沙(fendosal)、ZK4044、 WAY-140312、T-686、T-2639、S-35225、SK-216、SK-116、 SB202190、U0126、HP-129、SP600125、XR5967、 XR334、XR330、XR5118、化合物39、雙吲哚基馬來醯 亞胺I、粗糠柴苦素、SB431542、SIS3、抑素、洛伐他 、/丁（lovastatin)、辛伐他汀（simvastatin)、普伐他 ί丁 (pravastatin)、氟伐他汀（fluvastatin)、阿托伐他灯 (atorvastatin)、PAI-1抗體、PAI-1蛋白質抑制劑、派歐寧 (paionin)-4及其組合物。 13·如申請專利範圍第12項之用途，其中該藥劑係選自於由 下列所組成的群組： 愛迪普拉希寧（aleplasinin)、S##(fendosal)、T-2639、S-35225、SK-216、SK-116、SB202190、U0126、 SP600125、化合物39、雙吲哚基馬來醯亞胺I、粗糠柴 苦素、SB431542、SIS3、抑素、洛伐他汀（l〇Vastatin)、 辛伐他汀(simvastatin)、普伐他汀(pravastatin)、氟伐他 汀（fluvastatin)、阿托伐他汀（atorvastatin)、PAI-1 抗體、 PAI-1蛋白質抑制劑、派歐寧(pai〇nin)_4及其組合物。 30 Φ Φ ζυ〇946ΐΐ3 14·如申請專利範圍第13項之用途，其中該藥劑係選自於由 下珂所組成的群組： 堤普拉堤寧⑽laxtinin)、迪普拉#寧(di物“㈣、 雙啊為來醯娜、τ_2639、化合物39及其組合物。 •如申請專利範圍第1〇項之用途’其中該抑制作用阻止 _對於組織纖維蛋白溶酶原活化__ΡΑ)或尿激酶 准蛋白溶酶原活化劑(u，活性的抑制作用。 16•如申請專利範圍第1〇項之 含選自於由下列所組成的群組之成物進-步包 滲透的:存劑、表面_、増_、 膠销、疏水性基 化鈉、水及其組合物。 、每衝劑、氯 17. 如申請專利範圍第1〇項之 與選自於由下列所址成的Cm藥物包含或適於 β_阻斷劑、前列腺麵⑽ 物分開投藥： 同效劑、縮瞳藥、神物、碳酸肝酶抑制劑、〇c2 合物。 …'遵劍、rh0激酶抑制劑及其紅 18. 如申請專利範圍第1G項 0.01重量/體積百分比至約5、」其中該組成物包含自約 19. 如申請專利範圍第1G項< 重垔/體積百分比的該藥劑。 0.25重量/體積百分：途’其中該組成物包含自約 ’’、、重量/體積百分比的該藥劑。 31
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| WO2014126997A1 (en) | 2013-02-13 | 2014-08-21 | The Research Foundation For The State University Of New York | Glaucoma treatment |
| UA118267C2 (uk) | 2013-08-13 | 2018-12-26 | Санофі | Антитіло до інгібітора активатора плазміногену 1 (раі-1) та його застосування |
| US10813920B2 (en) | 2013-11-14 | 2020-10-27 | The Doshisha | Drug for treating corneal endothelium by promoting cell proliferation or inhibiting cell damage |
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