JP2011513203A - Mmp−2及び/又はmmp−9阻害剤 - Google Patents
Mmp−2及び/又はmmp−9阻害剤 Download PDFInfo
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Abstract
Description
で表されるチアゾール誘導体又はその塩は、活性酸素(O2 −)産生抑制作用、サイトカイン産生抑制作用、接着抑制作用及び慢性閉塞性肺疾患治療作用を有していることが知られている(例えば、特許文献1、特許文献2、特許文献3等)。
項1. 一般式(1)
で表されるチアゾール誘導体及びその塩からなる群より選ばれた少なくとも1種を有効成分として含有することを特徴とするMMP−2及び/又はMMP−9阻害剤。
項2. チアゾール誘導体が、6−[2−(3,4−ジエトキシフェニル)チアゾール−4−イル]ピリジン−2−カルボン酸又はその塩である項1に記載のMMP−2及び/又はMMP−9阻害剤。
項3. 線維症の治療に用いられる項1又は2に記載のMMP−2及び/又はMMP−9阻害剤。
項4. 肺気腫の治療に用いられる項1又は2に記載のMMP−2及び/又はMMP−9阻害剤。
化合物A 150g
アビセル(商標名、旭化成社製) 40g
コーンスターチ 30g
ステアリン酸マグネシウム 2g
ヒドロキシプロピルメチルセルロース 10g
ポリエチレングリコール−6000 3g
ヒマシ油 40g
エタノール 40g
化合物A、アビセル、コーンスターチ及びステアリン酸マグネシウムを混合研磨後、糖衣R10mmのキネで打錠した。得られた錠剤をヒドロキシプロピルメチルセルロース、ポリエチレングリコール−6000、ヒマシ油及びエタノールを含むフィルムコーティング剤で被覆を行い、フィルムコーティング錠を製造した。
化合物A 150 g
クエン酸 1.0g
ラクトース 33.5g
リン酸二カルシウム 70.0g
プルロニックF−68 30.0g
ラウリル硫酸ナトリウム 15.0g
ポリビニルピロリドン 15.0g
ポリエチレングリコール(カルボワックス1500) 4.5g
ポリエチレングリコール(カルボワックス6000) 45.0g
コーンスターチ 30.0g
乾燥ステアリン酸ナトリウム 3.0g
乾燥ステアリン酸マグネシウム 3.0g
エタノール 適量
化合物A、クエン酸、ラクトース、リン酸二カルシウム、プルロニックF−68及びラウリル硫酸ナトリウムを混合した。
化合物A 5 g
ポリエチレングリコール(分子量:4000) 0.3g
塩化ナトリウム 0.9g
ポリオキシエチレン−ソルビタンモノオレエート 0.4g
メタ重亜硫酸ナトリウム 0.1g
メチル−パラベン 0.18g
プロピル−パラベン 0.02g
注射用蒸留水 10.0ml
上記パラベン類、メタ重亜硫酸ナトリウム及び塩化ナトリウムを撹拌しながら80℃で上記の約半量の蒸留水に溶解させた。得られた溶液を40℃まで冷却し、化合物A、次いでポリエチレングリコール及びポリオキシエチレンソルビタンモノオレエートを、上記溶液中に溶解させた。次にその溶液に注射用蒸留水を加えて最終の容量に調製し、適当なフィルターペーパーを用いて滅菌濾過することにより滅菌して、注射剤を調製した。
試験方法:
ウサギを3群に分け(n=10匹/群)、Vehicle群及び化合物A群には200U/kgのブタ膵臓由来エラスターゼ(porcine pancreatic elastase:PPE)を経気管的に動物の肺内に投与した。Sham群の動物には、PPEの代りに同じ容量の生理食塩水を経気管的に動物の肺内に投与した。PPE投与28日後にウサギを解剖した。各ウサギの肺組織をホルマリンで固定した後に病理組織標本を作製した。Vehicle(0.5% Tragacanth)或いは化合物A(10mg/kg)はPPEの投与2時間前にVehicle群及び化合物A群のウサギに強制経口投与を行い、翌日より1日1回、週5日間、実験終了までVehicle又は化合物Aの経口投与を続けた。
各群の動物の肺のMMPの発現を表1に示す。Vehicle群のMMP−2及びMMP−9の発現スコアはSham群のそれぞれの発現スコアに比較して有意に高値(いずれもp<0.01)を示し、またVehicle群の肺で気道上皮下に肥厚が観察され線維化像が存在することを確認した。一方、化合物A群におけるMMP−2およびMMP−9の発現スコアはVehicle群と比較して有意に低値(MMP−2:p<0.05、MMP−9:p<0.01)を示し、また気道上皮下の線維化による肥厚も軽減されていた。又、肺胞の破壊も有意に抑制されていた。肺胞腔拡張の抑制をまとめた結果を表2に示す。以上の結果より、化合物AはMMP−2およびMMP−9の発現を有意に抑制することが判明した。
種々の組織における線維化は重篤で予後不良の疾患である。その主な病理像は、内皮細胞と上皮細胞の損傷、好中球、マクロファージ及びリンパ球の浸潤からなる炎症、線維芽細胞の増殖、そしてコラーゲンなどの細胞外マトリックス(ECM:extracellular matrix)成分の過剰な合成と沈積からなる。特にECMの過剰な合成と沈積には、これを選択的に分解する酵素であるMMPと、その活性を制御する生体内物質であるTIMP(tissue inhibitor of metalloproteiase)のバランスの乱れが関与していると考えられているが、その機序の詳細は不明である。その一方で、肺線維症の患者の肺組織や肺胞洗浄液においてMMP(特にMMP−2やMMP−9)の発現レベルが上昇していること、また肺線維症を惹起した病態モデルでも患者における知見と同様の結果が得られており、肺組織又は肺胞洗浄液中でMMP活性が上昇していることが報告されている。更にbleomycinやasbestosで惹起した肺線維症の病態モデルにbatimastatやGM6001などのMMP阻害剤を投与することで肺胞洗浄液中のMMP活性と共に浸潤白血球数の上昇を抑制し、病理組織学的にも生化学的にも肺線維症が抑制されることが示されている。これらの結果から、組織におけるMMP発現量の上昇又は活性化が当該組織における線維症を惹起し、そのMMP活性を抑制することで線維化が抑制されたと考えられる。
Claims (4)
- チアゾール誘導体が、6−[2−(3,4−ジエトキシフェニル)チアゾール−4−イル]ピリジン−2−カルボン酸又はその塩である請求項1に記載のMMP−2及び/又はMMP−9阻害剤。
- 線維症の治療に用いられる請求項1又は請求項2に記載のMMP−2及び/又はMMP−9阻害剤。
- 肺気腫の治療に用いられる請求項1又は請求項2に記載のMMP−2及び/又はMMP−9阻害剤。
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EP3837256B1 (en) | 2018-08-17 | 2023-03-08 | Novartis AG | Urea compounds and compositions as smarca2/brm-atpase inhibitors |
WO2023192880A2 (en) * | 2022-03-29 | 2023-10-05 | The Trustees Of The University Of Pennsylvania | Methods of treating, ameliorating and/or preventing fibrodysplasia ossificans progressiva and heterotopic ossification, and kits for the same |
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BRPI0909288A2 (pt) | 2015-08-18 |
IL228484A0 (en) | 2013-12-31 |
NZ587591A (en) | 2012-10-26 |
CN101969949A (zh) | 2011-02-09 |
UA108979C2 (uk) | 2015-07-10 |
KR20100135255A (ko) | 2010-12-24 |
CN101969949B (zh) | 2013-12-25 |
WO2009113736A1 (en) | 2009-09-17 |
RU2010141996A (ru) | 2012-04-20 |
CN103622962A (zh) | 2014-03-12 |
AU2009224209B2 (en) | 2015-01-22 |
EP2280708A1 (en) | 2011-02-09 |
TW200942237A (en) | 2009-10-16 |
RU2487131C2 (ru) | 2013-07-10 |
MX2010010073A (es) | 2010-10-04 |
TWI436767B (zh) | 2014-05-11 |
ZA201005991B (en) | 2011-10-26 |
IL207816A0 (en) | 2010-12-30 |
AU2009224209A1 (en) | 2009-09-17 |
CA2718005A1 (en) | 2009-09-17 |
JP2014221839A (ja) | 2014-11-27 |
CN103463084A (zh) | 2013-12-25 |
AR070882A1 (es) | 2010-05-12 |
US20110054179A1 (en) | 2011-03-03 |
SG188852A1 (en) | 2013-04-30 |
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