JP5522030B2 - 線維化抑制剤 - Google Patents
線維化抑制剤 Download PDFInfo
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- JP5522030B2 JP5522030B2 JP2010500744A JP2010500744A JP5522030B2 JP 5522030 B2 JP5522030 B2 JP 5522030B2 JP 2010500744 A JP2010500744 A JP 2010500744A JP 2010500744 A JP2010500744 A JP 2010500744A JP 5522030 B2 JP5522030 B2 JP 5522030B2
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- 229940113147 shellac Drugs 0.000 description 1
- 235000013874 shellac Nutrition 0.000 description 1
- 208000017520 skin disease Diseases 0.000 description 1
- 239000002893 slag Substances 0.000 description 1
- 238000009491 slugging Methods 0.000 description 1
- 210000002460 smooth muscle Anatomy 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 238000009495 sugar coating Methods 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 208000014001 urinary system disease Diseases 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D241/20—Nitrogen atoms
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4965—Non-condensed pyrazines
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/08—Drugs for disorders of the urinary system of the prostate
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Description
式(1)中、R1、R2は、同一又は異なって、ハロゲン原子、アルキル、ハロアルキル、アリールアルキル、アルコキシ、アルキルチオ、アルコキシアルキル、アルキルスルホニル、ヒドロキシ、アミノ、モノアルキルアミノ、ジアルキルアミノ、カルボキシ、シアノ及びニトロからなる群から選ばれる1〜3個の置換基で置換されていてもよいアリールを表し;
R3、R4は、同一又は異なって、水素原子又はアルキルを表し;
R5は水素原子、アルキル又はハロゲン原子を表し;
YはN又はN→Oを表し;
AはNR6を表し、R6は水素原子、アルキル、アルケニル又はシクロアルキルを表し;
Dはヒドロキシで置換されていてもよいアルキレン又はアルケニレンを表すか、又はAとDとが一緒になって、次の式(2)で表される二価の基を表し;
[式(2)中、rは0〜2の整数を表し、qは2又は3を表し、tは0〜4の整数をそれぞれ表す。]
Eは、フェニレン又は単結合を表すか、又はDとEとが一緒になって、次の式(3)で表される二価の基を表し;
[式(3)中、uは0〜2の整数を表し、vは0又は1を表す。]
Gは、O、S、SO又はSO2を表し;
Qは、カルボキシ、アルコキシカルボニル、テトラゾリル、カルバモイル、モノアルキルカルバモイル、ジアルキルカルバモイル又は次の式(4)で表される基を表す。
[式(4)中、R7は、アミノ、モノアルキルアミノ、ジアルキルアミノ、若しくはヒドロキシ、又はハロゲン原子、アルキル、ハロアルキル、アリールアルキル、アルコキシ、アルキルチオ、アルコキシアルキル、アルキルスルホニル、ヒドロキシ、アミノ、モノアルキルアミノ、ジアルキルアミノ、カルボキシ、シアノ及びニトロからなる群から選ばれる1〜3個の置換基で置換されていてもよい下記1)〜4)のいずれかの基を表す;
1)アルキル、
2)アリール、
3)アリールオキシ、
4)複素環基。]
R1、R2が、同一又は異なって、ハロゲン原子、アルキル及びアルコキシからなる群から選ばれる1〜3個の置換基で置換されていてもよいフェニルであり、
R3、R4が、同一又は異なって、水素原子又はアルキルであり、
R5が水素原子であり、
YがNであり、
AがNR6であり、R6がアルキルであり、
Dがアルキレンであり、
Eが単結合であり、
GがOであり、
Qが、カルボキシ又は式(4)で表される基であり、R7が、アミノ、モノアルキルアミノ、ジアルキルアミノ、若しくはヒドロキシ、又はハロゲン原子、アルキル、ハロアルキル、アリールアルキル、アルコキシ、アルキルチオ、アルコキシアルキル、アルキルスルホニル、ヒドロキシ、アミノ、モノアルキルアミノ、ジアルキルアミノ、カルボキシ、シアノ及びニトロからなる群から選ばれる1〜3個の置換基で置換されていてもよい下記1)〜4)のいずれかの基である化合物が好ましい。
1)アルキル、
2)アリール、
3)アリールオキシ、
4)複素環基
2−{4−[N−(5,6−ジフェニルピラジン−2−イル)−N−イソプロピルアミノ]ブチルオキシ}酢酸(以下、「化合物A」という。)、及び
2−{4−[N−(5,6−ジフェニルピラジン−2−イル)−N−イソプロピルアミノ]ブチルオキシ}−N−(メチルスルホニル)アセトアミド(以下、「化合物B」という)
が好ましい。
(1)窒素原子、酸素原子及び硫黄原子から選択される1〜4個までのヘテロ原子を有する5又は6員の芳香環基、又はそれらのベンゼン縮合環であって、かかる環構成原子が窒素原子又は硫黄原子の場合、かかる窒素原子、硫黄原子はオキシドを形成していてもよい。例えば、1−ピロリル、2−ピロリル、3−ピロリル、3−インドリル、2−フラニル、3−フラニル、3−ベンゾフラニル、2−チエニル、3−チエニル、3−ベンゾチエニル、1,3−オキサゾール−2−イル、4−イソオキサゾリル、2−チアゾリル、5−チアゾリル、2−ベンゾチアゾリル、1−イミダゾリル、2−イミダゾリル、4−イミダゾリル、2−ベンズイミダゾリル、1H−1,2,4−トリアゾール−1−イル、1H−テトラゾール−5−イル、2H−テトラゾール−5−イル、2−ピリジル、3−ピリジル、4−ピリジル、3−ピラゾリル、2−ピリミジニル、4−ピリミジニル、2−ピラジニル、1,3,5−トリアジン−2−イルを挙げることができる。
(2)環構成原子として、窒素原子、酸素原子又は硫黄原子を、同一又は異なって、1〜4個含んでいてもよい、4〜8員環の飽和環基、又はそれらのベンゼン縮合環基であって、環構成原子が窒素原子又は硫黄原子の場合、かかる窒素原子、硫黄原子はオキシドを形成していてもよい。例えば、ピペリジノ、ピペラジニル、3−メチルピペラジン−1−イル、ホモピペラジニル、モノホリノ、チオモノホリノ、1−ピロリジニル、2−ピロリジニル、2−テトラヒドロフラニルを挙げることができる。
本複素環誘導体(1)が塩基性を示す場合の「塩」としては、例えば、塩酸、硫酸、硝酸、リン酸、フッ化水素酸、若しくは臭化水素酸の無機酸の塩、又は酢酸、酒石酸、乳酸、クエン酸、フマール酸、マレイン酸、コハク酸、メタンスルホン酸、エタンスルホン酸、ベンゼンスルホン酸、p−トルエンスルホン酸、ナフタレンスルホン酸、若しくはカンファースルホン酸の有機酸の塩を挙げることができる。
本複素環誘導体(1)が酸性を示す場合の「塩」としては、例えば、ナトリウム塩、カリウム塩等のアルカリ金属塩、又はカルシウム塩等のアルカリ土類金属塩を挙げることができる。
(1)腎臓疾患
尿細管間質性腎炎
(2)呼吸器疾患
間質性肺炎(肺線維症)
(3)消化器疾患
肝硬変、慢性膵炎、スキルス胃癌
(4)心血管疾患
心筋線維症
(5)骨・関節疾患
骨髄線維症、関節リウマチ
(6)皮膚疾患
手術後の瘢痕、熱傷性瘢痕、ケロイド、肥厚性瘢痕、強皮症
(7)産科疾患
子宮筋腫
(8)泌尿器疾患
前立腺肥大症
(9)その他の疾患
アルツハイマー病、硬化性腹膜炎、I型糖尿病、手術後臓器癒着
粉末混合物は、適当に粉末化された物質を上述の希釈剤やベースと混合することにより製造することができる。必要に応じて、結合剤(例えば、カルボキシメチルセルロースナトリウム、メチルセルロース、ヒドロキシプロピルメチルセルロース、ゼラチン、ポリビニルピロリドン、ポリビニルアルコール)、溶解遅延化剤(例えば、パラフィン)、再吸収剤(例えば、四級塩)、吸着剤(例えばベントナイト、カオリン)等を添加することができる。
粉末混合物は、まず結合剤、例えば、シロップ、澱粉糊、アラビアゴム、セルロース溶液又は高分子物質溶液で湿らせ、攪拌混合し、これを乾燥、粉砕して顆粒とすることができる。このように粉末を顆粒化する代わりに、まず打錠機にかけた後、得られる不完全な形態のスラグを破砕して顆粒にすることも可能である。このようにして作られる顆粒に、滑沢剤としてステアリン酸、ステアリン酸塩、タルク、ミネラルオイル等を添加することにより、互いに付着することを防ぐことができる。
また、錠剤は、上述のように顆粒化やスラグ化の工程を経ることなく、本複素環誘導体(1)を流動性の不活性担体と混合した後に直接打錠することによっても製造することができる。
こうして製造された錠剤にフィルムコーティングや糖衣を施すことができる。シェラックの密閉被膜からなる透明又は半透明の保護被覆、糖や高分子材料の被覆及びワックスよりなる磨上被覆をも用いることができる。
(1)試験方法
ヒト肺線維芽細胞(Lonza Walkersville社製。以下同じ。)は、ヒト肺線維芽細胞用基礎培地(Lonza Walkersville社製。以下同じ。)(以下、「基礎培地」という。)にFGM−2添加因子セット(Lonza Walkersville社製。以下同じ。)を加えた増殖用培地を用いて、37℃、5%CO2条件下で培養した。ヒト肺線維芽細胞を96wellプレートに1×103cells/wellで播種し、増殖用培地で一晩培養した。
当該細胞を100μLのリン酸緩衝生理食塩水(日水製薬社製。以下同じ。)で1回洗浄し、基礎培地を加え24時間培養した。更に、100μLのリン酸緩衝生理食塩水にて1回洗浄し、80μL/wellの基礎培地を加えた。ここに100μMの化合物A又は化合物Bの薬液を各wellに10μLずつ添加し、2時間培養した。なお、加えた薬液は、化合物A又は化合物Bを予めジメチルスルホキシド(DMSO)に溶解して、10mMの薬液を調製し、これを基礎培地で100倍に希釈したものを用いた。無刺激対照群及び対照群に対しては、DMSOを基礎培地で100倍希釈したものを用いた。
ここに100ng/mLの上皮成長因子(Epidermal Growth Factor:EGF)(PeproTech社製)溶液を各wellに10μLずつ添加し、48時間培養した。なお、無刺激対照群に対しては、基礎培地を用いた。
48時間培養後、細胞増殖活性を調べるために、CellTiter 96、AQueousアッセイ(Promega社製)を用いて、490nmにおける吸光度を測定した。吸光度の測定にはマイクロプレートリーダー(Benchmark、Bio−Rad社製。以下同じ。)を用いた。
(2)結果
図1に示すように、ヒト肺線維芽細胞は、EGF刺激により細胞増殖活性が有意に増加した。一方、化合物A及び化合物Bを処理した細胞は、対照群と比べて、細胞増殖活性が有意に減少した。
(1)試験方法
ヒト肺線維芽細胞は、増殖用培地を用いて、37℃、5%CO2条件下で培養した。ヒト肺線維芽細胞を96wellプレートに3×103cells/wellで播種し、増殖用培地で一晩培養した。
当該細胞を100μLのリン酸緩衝生理食塩水で1回洗浄し、基礎培地を加え24時間培養した。更に、100μLのリン酸緩衝生理食塩水にて1回洗浄し、80μL/wellの基礎培地を加えた。ここに1μMの化合物Aの薬液を各wellに10μLずつ添加し、2時間培養した。なお、加えた薬液は、化合物Aを予めDMSOに溶解して、1mMの薬液を調製し、これを基礎培地で100倍に希釈したものを用いた。無刺激対照群及び対照群に対しては、DMSOを基礎培地で100倍希釈したものを用いた。
ここに100ng/mLのトランスフォーミング増殖因子−α(Transforming Growth Factor−α:TGFα)(CHEMICON社製)溶液を各wellに10μLずつ添加し、48時間培養した。なお、無刺激対照群に対しては、基礎培地を用いた。
48時間培養後、細胞増殖活性を調べるために、試験例1と同様に細胞増殖活性測定試薬を用いて、490nmにおける吸光度を測定した。吸光度の測定にはマイクロプレートリーダーを用いた。
(2)結果
図2に示すように、ヒト肺線維芽細胞は、TGFα刺激により細胞増殖活性が有意に増加した。一方、化合物Aを処理した細胞は、対照群と比べて、細胞増殖活性が有意に減少した。
(1)試験方法
ヒト肺線維芽細胞は96wellプレートに5×103cells/wellで播種し、試験例1と同様に増殖用培地で一晩培養した。当該細胞を100μLの基礎培地で1回洗浄し、100μLの基礎培地を加え24時間培養した。更に、100μLの基礎培地にて1回洗浄し、80μL/wellの基礎培地を加えた。ここに0.1、1、10又は100μMの化合物Aの薬液を各wellに10μLずつ添加した。なお薬液は、化合物Aを予めDMSOに溶解して、10μM、100μM、1mM及び10mM濃度に調製し、これらを基礎培地で100倍に希釈したものを用いた。また無刺激対照群及び対照群として、DMSOを基礎培地で100倍希釈したものを10μLずつ添加した。2時間培養後に、100ng/mLのトランスフォーミング増殖因子β1(Transforming Growth Factor β1:TGFβ1)(PeproTech社製。以下同じ。)溶液を10μLずつ、また無刺激対照群に対しては基礎培地を10μLずつ添加した。48時間培養後に培地中のプロコラーゲンI型C末端ペプチド(PIP)濃度を測定するために培地を回収し、新たに100μLの基礎培地を加え、3−(4,5−dimethyl−2−thiazolyl) −2,5−diphenyl−2H tetrazolium bromide (MTT)(ナカライテスク社製)を用いて、細胞増殖活性を測定した。細胞増殖活性の測定は、5mg/mLのMTTストック溶液を各wellに10μLずつ添加し、4時間培養した後、各wellに0.04M塩酸イソプロパノール溶液を100μLずつ加え、マイクロプレートリーダーで595nmにおける吸光度(参照波長655nm)を測定した。48時間培養後の培地中PIP濃度は、Procollagen Type I C−peptide(PIP) EIA Kit(Takara社製。以下同じ。)を用いて、添付の手順書に従い測定した。本試験の考察は、PIP濃度測定値を細胞増殖活性値(吸光度)で補正し、無刺激対照群の平均値を1とした相対値として算出した値(コラーゲン産生の指標)を用いて行った。
(2)結果
図3に示すように、ヒト肺線維芽細胞は、TGFβ1刺激によりコラーゲン産生が有意に増加した。一方、化合物Aを処理した細胞は、対照群と比べてコラーゲン産生が有意に減少した。
(1)試験方法
ヒト肺線維芽細胞は24wellプレートに1×105cells/wellで播種し、試験例1と同様に増殖用培地で一晩培養した。当該細胞を500μLの基礎培地で1回洗浄し、500μLの基礎培地を加え24時間培養した。更に、500μLの基礎培地にて1回洗浄し、400μL/wellの基礎培地を加えた。ここに試験例3と同様の方法で調製した1、10又は100μMの化合物Aの薬液を各wellに50μLずつ添加した。また無刺激対照群及び対照群として、DMSOを基礎培地で100倍希釈したものを50μLずつ添加した。2時間培養後に100ng/mLのTGFβ1溶液を各wellに50μLずつ添加し、また無刺激対照群に対しては基礎培地を50μLずつ添加した。24時間培養後、SV Total RNA Isolation System(Invitrogen社製)を用いてRNAを抽出し、SuperScriptIII(Invitrogen社製)を用いてRNAから1st strand cDNAを合成した。こうして作製したcDNAを鋳型として、リアルタイム定量PCR法により、I型コラーゲンα1鎖(COL1α1)、I型コラーゲンα2鎖(COL1α2)、α平滑筋アクチン(ACTA)、TGFβ1及びグリセルアルデヒド3−リン酸デヒドロゲナーゼ(GAPDH)のmRNA発現量を測定した。リアルタイム定量PCRはPlatinum SYBR Green qPCR Super−Mix−UDG with ROX(Invitrogen社製)及び各遺伝子に特異的なプライマーを使用し、Platinum SYBR Green qPCR Super−Mix−UDG with ROX添付の手順書に従い、ABI PRISM 7000(Applied Biosystems社)を用いて行った。本試験の考察は、各遺伝子のmRNAの発現量をGAPDHのmRNA発現量で補正し、無刺激対照群の平均値を1とする相対値として算出した値(mRNA発現レベル)を用いて行った。
(2)結果
図4〜7に示すように、ヒト肺線維芽細胞はTGFβ1刺激により各mRNA発現レベルが増加した。一方、化合物Aを処理した細胞は、対照群と比べて、各mRNAレベルが減少した。
(1)試験方法
ラット腎間質細胞(NRF49F細胞)は、96wellプレートに1×104cells/well播種し、10%牛胎児血清(JRH Bioscience社製。以下同じ)を含むMinimum Essential Medium(MEM培地:日本製薬社製。以下同じ。)を用いて、37℃、5%CO2条件下で一晩培養した。牛胎児血清を含まないMEM培地(以下、「無血清MEM培地」という。)で1回洗浄し、100μLの無血清MEM培地を加え24時間培養した。更に、無血清MEM培地にて1回洗浄した後、無血清MEM培地を80μL/well加えた。ここに試験例1と同様の方法で調製した、100μMの化合物Aの薬液を各wellに10μLずつ添加した。また無刺激対照群及び対照群に対しては、DMSOを無血清MEM培地で100倍希釈したものを10μLずつ添加した。2時間培養後に100ng/mLの血小板由来成長因子(Platelet−Derived Growth Factor−BB:PDGFBB)(Sigma社製)溶液を各wellに10μLずつ、また無刺激対照群は無血清MEM培地を10μLずつ添加し培養した。48時間培養後に、試験例3と同様にMTT法により細胞増殖活性(吸光度)を測定した。本試験の考察は、無刺激対照群の吸光度の平均値を1とする相対値で表した値(細胞増殖レベル)を用いて行った。
(2)結果
図8に示すように、ラット腎間質細胞は、PDGFBB刺激により細胞増殖レベルが有意に増加した。一方、化合物Aを処理した細胞は、対照群と比べて、細胞増殖レベルが有意に減少した。
(1)試験方法
ヒト皮膚線維芽細胞(クラボウ社製。以下同じ。)は、96wellプレートに5×103cells/wellで播種し、10%の牛胎児血清を含むDulbecco’s Modified Eagle’s Medium(DMEM培地)(日本製薬社製。以下同じ。)を用いて、37℃、5%CO2条件下で一晩培養した。ヒト皮膚線維芽細胞を牛胎児血清を含まないDMEM培地(以下、「無血清DMEM培地」という。)で1回洗浄し、100μLの無血清DMEM培地を加え24時間培養した。更に無血清DMEM培地にて1回洗浄し、80μL/wellの無血清DMEM培地を加えた。ここに試験例3と同様の方法で調製した0.1、1、10又は100μMの化合物Aの薬液を各wellに10μLずつ添加した。また無刺激対照群及び対照群に対しては、DMSOを無血清DMEM培地で100倍希釈したものを10μLずつ添加し培養した。2時間培養後に100ng/mLのTGFβ1溶液を各wellに10μLずつ添加し、無刺激対照群に対しては無血清MEM培地を10μLずつ添加した。48時間培養後に試験例3と同様にMTT法により細胞増殖活性(吸光度)と、培地中のPIP濃度を測定した。本試験の考察は、PIP濃度測定値を細胞増殖活性値(吸光度)で補正し、無刺激対照群の平均値を1とした相対値として算出した値(コラーゲン産生の指標)を用いて行った。
(2)結果
図9に示すように、ヒト皮膚線維芽細胞は、TGFβ1刺激によりコラーゲン産生が有意に増加した。一方、化合物Aを処理した細胞は、対照群と比べて、コラーゲン産生が有意に減少した。
Claims (3)
- 2−{4−[N−(5,6−ジフェニルピラジン−2−イル)−N−イソプロピルアミノ]ブチルオキシ}酢酸、2−{4−[N−(5,6−ジフェニルピラジン−2−イル)−N−イソプロピルアミノ]ブチルオキシ}−N−(メチルスルホニル)アセトアミド又はその医薬上許容される塩を有効成分として含有する線維化抑制剤。
- 尿細管間質性腎炎、間質性肺炎、肝硬変、慢性膵炎、スキルス胃癌、心筋線維症、骨髄線維症、関節リウマチ、手術後の瘢痕、熱傷性瘢痕、ケロイド、肥厚性瘢痕、強皮症、子宮筋腫、前立腺肥大症、アルツハイマー病、硬化性腹膜炎、I型糖尿病及び手術後臓器癒着からなる群より選択される疾患を治療するための請求項1に記載の線維化抑制剤。
- 間質性肺炎を治療するための請求項1に記載の線維化抑制剤。
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TW201922230A (zh) | 2017-11-16 | 2019-06-16 | 日商日本新藥股份有限公司 | 控釋製劑 |
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