JP7169646B2 - Rxrアゴニストおよび甲状腺ホルモンの組み合わせでの自己免疫疾患の治療 - Google Patents
Rxrアゴニストおよび甲状腺ホルモンの組み合わせでの自己免疫疾患の治療 Download PDFInfo
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Description
本願は、2016年3月10日に出願された米国仮特許出願第62/306,479号明細書の優先権を主張する。この出願の全内容は、本願明細書に参照により組み込まれる。
本開示は、レチノイドX受容体(RXR)アゴニストを甲状腺ホルモンと組み合わせて使用して、自己免疫疾患を治療する方法に関する。
以下の非限定的な実施例は、ここで企図されている代表的な実施形態のより完全な理解を容易にするためにのみ例示的目的で提供される。これらの実施例は、甲状腺ホルモンと組み合わせて、本明細書に開示されるRXRアゴニストを用いた自己免疫疾患の治療方法、自己免疫疾患を治療するための医薬品を製造するための本明細書に開示されるRXRアゴニストおよび甲状腺ホルモンの使用に関連するものを含む、本明細書に記載される実施形態のいずれかを限定するものと解釈されるべきではない。
選択的RXRアゴニスト、IRX4204、RXRシグナル伝達によるその生物学的効果を発揮する
RXRアゴニストがRXRα受容体ホモ二量体、RXRβ受容体ホモ二量体、RXRγ受容体ホモ二量体、またはそれらの任意の組み合わせ、あるいは対応するRAR/RXRヘテロ二量体を介してその効果を媒介することができるかどうかを決定するために、受容体媒介トランス活性化アッセイを行った。RXRホモ二量体シグナル伝達を評価するトランス活性化アッセイのために、CV-1細胞を、1)全長RXRα、RXRβ、またはRXRγを含む発現構築物;および2)ルシフェラーゼ遺伝子に連結されたRXRホモ二量体特異的RXRE/DR1応答要素を含むrCRBPII/RXRE-tk-Lucレポーター構築物でトランスフェクトした。RAR/RXRヘテロ二量体シグナル伝達を評価するトランス活性化アッセイのために、CV-1細胞を、1)RARα、RARβまたはRARγのリガンド結合ドメインに連結されたエストロゲン受容体(ER)DNA結合ドメインを含む融合タンパク質を含む発現構築物、および2)ルシフェラーゼ遺伝子に連結されたエストロゲン受容体応答要素を含むERE-tk-Lucレポーター構築物でトランスフェクトした。ER-RAR融合タンパク質は、トランスフェクトされたER-RARのみの正確な読み取りを提供した。トランスフェクト後、ルシフェラーゼ活性を測定する前に、CV-1細胞をRXRアゴニストIRX4204で20時間漸増濃度で処置した。ルシフェラーゼ活性は、RXRについて1μMのRXRアゴニストIRX4204およびRARについて1μMの全トランス-レチノイン酸(ATRA)を用いて得られた最大活性のパーセントとして表される(表1)。データは、5回の独立した実験からの平均値±SEである。
RXRアゴニストの結合親和性
RXRアゴニストに対する結合親和性を決定するために、競合的置換アッセイを行った。RXRα、RXRβ、RXRγ、RARα、RARβ、またはRARγは、バキュロウイルス発現系を用いてSF21細胞で発現させ、得られたタンパク質を精製した。RXRに対するRXRアゴニストの結合親和性を決定するために、精製したRXRα、RXRβおよびRXRγを別々に10nMの[3H]-9CRAと共にインキュベートし、RXRアゴニストIRX4204の結合親和性を受容体からの[3H]-9CRAの競合置換によって決定した。RARに対するRXRアゴニストの結合親和性を決定するために、精製したRARα、RARβおよびRARγを別々に5nMの[3H]-ATRAと共にインキュベートし、RXRアゴニストIRX4204の結合親和性を受容体からの[3H]-ATRAの競合置換によって決定した。Ki値は、少なくとも2つの独立した実験の平均値である(表2)。独立した実験の間の標準誤差(±)が示される。
RXRアゴニストは、B6マウスにおけるEAEを減弱させる
RXRアゴニストが多発性硬化症を減弱させることができるかどうかを決定するために、125μgのミエリンオリゴデンドロサイト糖タンパク質ペプチド(35~55)(MOGペプチド;Peptides International, Louisville, KY)および不完全フロイントアジュバントとリン酸緩衝生理食塩水(PBS)との混合物中に乳化した400μgの生存していないM.結核菌H37乾燥物を含有する200μLのアジュバントを脊椎の基部に皮下(s.c.)注射することによりC57BL/6(B6)マウスを免疫化して(0日目)実験的自己免疫性脳脊髄炎(EAE)を誘発した。マウスには、MOGエマルジョン注射(0日目)と同日および2日後(2日目)に腹腔内(i.p.)注射によって投与されたPBS中の200ngの百日咳毒素も与えられた。免疫化後7日目から、実験の期間中、マウスに、RXRアゴニストIRX4204(50μg i.p.)、ビヒクル対照(ip)、チロキシン(T4)、またはIRX4204+チロキシンを隔日投与した(n=6~7マウス/群)。統計は、マンホイットニー検定(処置開始から実験終了までの分析)の結果を示す。マウスを以下のスケールを用いて採点した:0-マウスには疾患はない、1-マウスは、末端が弱弱しい尾または片後脚の衰弱(麻痺)を有する、1.5-マウスは末端が弱弱しい尾および片後脚の衰弱を有する、2-マウスは全体が弱弱しい尾および片後脚の衰弱を有する、2.5-マウスは全体が弱弱しい尾および両後脚に衰弱を有する、3-マウスは全体が弱弱しい尾および両後脚に麻痺を有する、3.5-マウスは全体が弱弱しい尾、両後脚に麻痺および前肢に衰弱を有する。3.5のスコアを受けたマウスを直ちに安楽死させた。
RXRアゴニスト処置マウスは、中枢神経系浸潤細胞を減少させた。
RXRアゴニストが中枢神経系(CNS)浸潤細胞を減少させることができるかどうかを決定するために、C57BL/6(B6)マウスを実施例6に記載のように処置した。免疫後20日目に、マウスを屠殺し、リン酸緩衝生理食塩水(PBS)で灌流した。脳および脊髄組織を単離し、DNaseおよびLiberase DL(Roche Diagnostics, Indianapolis, IN)で30分間消化し、70ミクロンのナイロンメッシュフィルターでホモジナイズした。得られた細胞をPercoll勾配上に置き、ミエリンを除去した。残りの細胞(ミクログリアおよびCNS浸潤細胞)を計数し、対象の分子について染色し、フローサイトメーターで分析した。これらの細胞集団のFACSにより得られた頻度に基づいて、CD4+T細胞およびCD11c+CD11b+骨髄樹状細胞(DC)を含むCD45を発現するCNS浸潤白血球の総細胞数を計算した。
RXRアゴニストは、SJLマウスにおけるEAEを減弱させる
RXRアゴニストが多発性硬化症を減弱させることができるかどうかを決定するために、200μgのプロテオリピドタンパク質(139-151))(PLPペプド;Peptides International,Louisville,KY)ならびに不完全フロイントアジュバントおよびPBSの混合物中で乳化した400μgの生存していないM.結核菌H37乾燥物を含有する200μLのアジュバントを脊柱の基部にs.c.注射することにより、SJLマウスを免疫化してEAEを誘発した。マウスには、PLPエマルジョン注射と同じ日および2日後にPBSi.p.中で150ngの百日咳毒素も投与した。免疫化後7日目から、実験の期間中、マウスにRXRアゴニストIRX4204(50μg)またはビヒクル対照にipで隔日投与した(n=6マウス/群)。実施例3に記載のスケールを用いてマウスを採点した。
Nurr1/RXR許容性ヘテロ二量体の選択的活性化剤としてのRXRアゴニストIRX4204
RXRアゴニストIRX4204によってどの許容性RXRヘテロ二量体が活性化されているかを決定するために、PPARγ/RXR、FXR/RXR、LXRα/RXR、LXRβ/RXR、およびNurr1/RXRについて以下のように受容体トランス活性化アッセイを行った。PPARγについて:CV-1細胞を、3x(rAOX/DR1)-tk-Lucレポーター遺伝子およびPPARγの発現ベクターでトランスフェクトした。FXRについて:CV-1細胞を、3x(IBABP/IRI)-tk-Lucレポーター遺伝子ならびにFXRおよびRXRαのベクターでトランスフェクトした。LXRについて:CV-1細胞を、LXRαまたはLXRβのベクターと共に3x(PLTP/LXRE)-tk-Lucレポーター遺伝子でトランスフェクトした。Nurr1について:COS7細胞を、3xNBRE-tk-lucレポーター遺伝子および完全長RXRαプラスミドの有無にかかわらない完全長Nurr-1でトランスフェクトした。次いで、細胞をビヒクルまたはIRX4204で20時間処置した。ルシフェラーゼデータを、同時トランスフェクトされたβ-gal活性に対して正規化した。ルシフェラーゼ活性は、特異的アゴニストを用いて得られた最大活性のパーセントとして表した。ロシグリタゾン(PPARγ)、GW4064(FXR)、T0901317(LXR)。データは、IRX4204がFXR/RXR(図2A)、LXRα/RXRもしくはLXRβ/RXR(図2B)、またはPPARγ/RXR(図2C)を活性化しないことを示す。対照的に、IRX4204は強力に(EC50<1nm)、Nurr1/RXRヘテロ二量体を活性化する(図2D)。これらのデータは、Nurr1/RXRヘテロ二量体を選択的に活性化するが、PPARγ/RXR、FXR/RXRまたはLXR/RXRヘテロ二量体を選択的に活性化しないという点で、IRX4204が特有なRXRアゴニストであることをまとめて示している。
稀突起膠細胞前駆細胞分化に対するRXRアゴニストの効果
この研究の目的は、稀突起膠細胞前駆細胞(OPC)の稀突起膠細胞への分化に対するIRX4204の効果を評価することであった。OPCは、E14.5 PLP-EGFP(C57BL/6Jバックグラウンドで)マウスの脳のニューロスフェア培養物から生成された。OPCの稀突起膠細胞への分化と相関する緑色蛍光タンパク質(EGFP)の発現を評価するために、単離されたOPCをIRX4204および/またはT3で処置した。EGFP発現細胞を、Cellomicsニューロンプロファイリングアルゴリズムで定量化した。陽性(T3)対照は、期待されるOPCの分化を示した。結果は、IRX4204が、陰性対照(DMSO)と比較してEGFP陽性細胞の数の増加によって示されるように、稀突起神経膠細胞へのOPC分化を促進することを示す。試験した全ての濃度は、稀突起神経膠細胞へのOPC分化の有意な増加を示した(図6)。しかしながら、IRX4204で処置した培養物にT3を添加すると、さらにより高い濃度のEGFP+稀突起神経膠細胞が誘発され、IRX4204および甲状腺ホルモンの組み合わせの有意な利益が示された。
IRX4204は、再髄鞘形成プロセスに直接作用することにより、in vivoモデルにおける中枢神経系(CNS)の再髄鞘形成を増強する
IRX4204の免疫調節効果とは無関係に、急性脱髄に対するIRX4204の直接作用を確認するために、脱髄の焦点毒素(臭化エチジウム)誘発ラットモデルを使用する。そのようなラットが効率よくは再髄鞘形成を受けないのでこの実験では比較的高年齢(1歳)のラットを使用し、それにより、多発性硬化症または他の脱髄疾患を有するヒト患者の臨床的処置にさらに関連するデータを提供する。
甲状腺ホルモンと組み合わせたIRX4204は、毒性脱髄のクプリゾン/ラパマイシンマウスモデルにおける再髄鞘形成を促進する
クプリゾン(ビス-シクロヘキサノンオキサルジヒドラゾン)モデルは、白質および灰白質の両方におけるミエリンパラメータの信頼性のある、再現性のある、および明白な分析を容易にする。クプリゾンモデルは、有毒な脱髄のモデルである。このモデルでは、若いマウスに銅キレート剤クプリゾンを与え、稀突起神経膠細胞死およびその後の可逆的な脱髄をもたらす。mTORおよび自発的再髄鞘形成を遮断する薬物であるラパマイシンと共にクプリゾンを摂取したマウスは、稀突起膠細胞の代謝回転のより良い定量化を可能にする。急性のクプリゾンパラダイムでは、6~9週齢の雄のC57BL/6マウスに、6週間にわたって0.2%クプリゾンを混合した食餌を与える。クプリゾン摂食の3週目までに、マウスの脳における最大の白質路である脳梁で一貫した脱髄が観察され得る。脱髄は、5または6週で最大に達する。C57BL/6マウスに12週間クプリゾン摂取を維持した場合、慢性脱髄が誘発され得る。
非免疫媒介性脱髄のマウスモデルにおけるIRX4204およびIRX4204+チロキシンの神経保護能の評価
改変されたクプリゾンモデル(クプリゾン+ラパマイシン)は、脱髄によって引き起こされる神経変性の信頼性、再現性、および明確な分析を容易にする。SMI-32免疫染色により、脳梁中の腫脹および切断された軸索(卵形)の視覚化および定量化が可能になり、軸索変性の程度の評価が可能になる。この研究では、マウスの4つの群:クプリゾン+ラパマイシン(CR)のみ(n=6)、CR+ビヒクル(n=12)、CR+IRX4204(n=12)、およびCR+IRX4204+チロキシン(n=12)があった。試験物質をCRと同時に6週間投与した。IRX4204を10mg/kg体重で1日1回経口投与した。チロキシン(T4)処置は、IRX4204処置の開始1日後に開始された。T4を毎日20ng/g体重で皮下(SC)投与した。CR+ビヒクル群は、IRX4204ビヒクル(経口)およびT4ビヒクル(SC)を受けた。全ての動物に血漿T4濃度を測定するための終末血液採取を施した。屠殺後、単位面積当たりのSMI-32陽性卵形の密度を各群について測定した。SMI-32陽性卵形密度が高いほど、軸索変性の程度が大きい。IRX4204単独によるいくらかの神経保護が示されるビヒクル群と比べて、IRX4204群ではSMI-32+卵巣が13.3%減少した。しかし、IRX4204+チロキシン群は、IRX4204+チロキシンの組み合わせが、脳梁における軸索切断の阻害によるCR誘発性神経毒性からかなりの程度の神経保護を提供することを示すビヒクル群と比較して37.5%の減少を与えた(図19)。
RXRアゴニストはT細胞分化を調節する
RXRアゴニストがT細胞分化を調節できるかどうかを決定するために、Th17細胞分化条件下でTreg細胞分化を促進しTh17細胞分化を阻害するRXRアゴニストの能力を、Foxp3およびIL-17A発現をモニターすることによって評価した。ナイーブCD4+CD25-FoxP3-細胞を、Foxp3-GFPマウスから、フローサイトメトリーを用いて、GFP-表現型に基づいた選別および単離により精製した。次いで、これらの細胞を、0nM、1nM、10nMおよび100nMのRXRアゴニストIRX4204(194204)を含む培地中のTh17細胞分化条件下で培養し、Foxp3およびIL-17Aの発現を分析した。結果は、RXRアゴニストの濃度が増加するにつれて、Foxp3発現が増加し、Treg細胞の存在が増加したことを示した(図21A)。さらに、データは、RXRアゴニストの濃度が増加するにつれて、IL-17A発現が減少し、Th17細胞の存在が減少したことを示している(図21B)。これらの結果は、RXRアゴニストが免疫抑制性Treg細胞の分化を促進し、in vitroでナイーブT細胞からの炎症性Th17細胞の分化を同時に阻害することによってT細胞分化を調節することを示す。
RXRアゴニストは、RARシグナル伝達とは独立したT細胞分化を調節する
RXRアゴニストがRAR/RXR受容体ヘテロ二量体、RXR受容体ホモ二量体、または他のいくつかのRXR含有複合体を介してその作用を媒介することができるかどうかを決定するために、T細胞をpan-RARアンタゴニストの存在下でRXRアゴニストとインキュベートし、Foxp3の発現を評価した。ナイーブCD4+CD25-FoxP3-細胞を、Foxp3-GFPマウスから、フローサイトメトリーを用いて、GFP-表現型に基づいた選別および単離により精製した。次に、IL-2およびTGF-βの存在下でαCD3およびαCD28ポリクローナル抗体で細胞を処置することにより、Treg細胞分化条件下でこれらの細胞を培養した。培養した細胞を、0nM、1nM、または10nMのpan-RARアンタゴニスト194310と一緒に1.0nMでRXRアゴニストIRX4204(194204)と共にインキュベートした。次いで、培養細胞をFoxp3の発現についてアッセイした。結果は、pan-RARアンタゴニストのインキュベーションは、RXRアゴニスト単独で観察されたFoxp3発現の誘発を部分的に遮断することを示した(図22)。しかし、このFox3p発現の部分的阻害は、実際には、培地中の内在性RAの効果の阻止に起因し得る。したがって、これらの結果は、T細胞のTreg細胞への観察された変換は、RXR受容体ホモ二量体および/または他のRXR含有複合体の使用によって生じ、RAR介在機構を介するものではないようであることを示す。
IRX4204がコラーゲン誘発性関節炎に及ぼす影響
完全フロインドアジュバント(CFA)に乳化したII型コラーゲン(CII)による免疫化により、遺伝的に感受性のマウス系統において、コラーゲン誘発性関節炎(CIA)が誘発される。その後の病因は、滑膜肥厚、単核細胞浸潤、軟骨分解を含む慢性関節リウマチ(RA)といくつかの病理学的特徴を共有し、RAのように、感受性は特異的MHCクラスII遺伝子の発現に関連する。
パーキンソン病におけるIRX4204の効果を実証するためのヒト臨床試験
IRX4204で処置した早期パーキンソン病患者のオープンラベル、シングルサイト臨床試験は、PDの疾患改変薬としてのIRX4204の前臨床的な裏付けが、Unified Parkinson’s Disease Rating Scale(UPDRS)測定および安全性評価によって決定されたIRX4204による初期PD患者の処置時の臨床的設定に変換されるどうかを決定するために行われた。UPDRSスコアの変化は、血中チロキシン濃度と相関していた。
・スクリーニング(訪問1)-適格性を決定するためのスクリーニング(ベースライン訪問の前の30日まで)
・ベースライン期間(訪問2)-IRX4204による処置は、1日目に開始された。
・2週目(訪問3)-対象は安全性と有効性評価のためにIRX4204の開始から約17日後に診療所に戻った。
パーキンソン病モデルにおけるIRX4204の効果
この研究の目的は、ラット6-OHDA誘発性パーキンソン病(PD)モデルにおける行動障害の改善のためのIRX4204処置を評価することであった。PDのラットモデルは、神経毒6-ヒドロキシドパミン(6-OHDA)の片側線条体注射により生成された。この注射は、対側のDAニューロンを使わずに、注入側でドーパミン作動性(DA)ニューロン喪失を生じる。試験設計を表7に示す。
ビタミンDの存在下でのマウス分化稀突起膠細胞前駆細胞の分化
この試験の目的は、マウス稀突起膠細胞前駆細胞(OPC)の稀突起膠細胞への分化に対する、ビタミンD、またはビタミンDおよびトリヨードチロニン(T3)と組み合わせたIRX4204の潜在的な効果を評価することであった。OPCは、plp-EGFP発現マウス由来であった。
マウス稀突起膠細胞前駆細胞の分化
この試験の目的は、マウス稀突起膠細胞前駆細胞(OPC)の稀突起膠細胞への分化に対する、トリヨードチロニン(T3)と組み合わせたIRX4204の潜在的な効果を評価することであった。OPCは、plp-EGFP発現マウス由来であった。
脱髄のマウスモデルにおけるIRX4204の神経保護効果
この研究の目的は、非免疫媒介性脱髄のマウスモデルにおけるIRX4204の神経保護効果を評価することであった。
関節リウマチに対するIRX4204およびチロキシンの組み合わせ効果を確認するためのヒト臨床試験
慢性関節リウマチ(RA)患者において、このような患者群における組み合わせの直接的効果を確認するために、IRX4204およびチロキシンの組み合わせの概念実証臨床試験が実施される。RAを有する患者は、臨床試験に参加するよう募集され、参加のリスクおよび潜在的利益を説明するインフォームドコンセントが提供される。RS患者は、1日1回カプセル剤として経口投与される、1mg/日~40mg/日の範囲のいくつかの用量濃度のうちの1つの用量濃度のIRX4204、および12.5μg/日~250μg/日で経口投与される、チロキシンで治療される。一部の患者は、IRX4204もしくはチロキシンを含有しないマッチングカプセル、またはIRX4204単独を使用してプラセボ投与を受けるように無作為化されている。患者には、最低30日間、そして2年まで投与される。患者の血清甲状腺ホルモンレベルを定期的に試験し、必要に応じてチロキシンの用量を調整する。患者は、DAS臨床指標を介してRA疾患活性について評価される。RAX診断基準およびDASスコアに対するIRX4204/チロキシン組み合わせの用量反応関係は、患者反応およびRA疾患活性に対する任意の影響について、IRX4204およびチロキシンの様々な用量レベルで治療された患者のコホートにわたって分析される。
乾癬の進行に対するIRX4204とチロキシンの組み合わせ療法の効果を評価するためのヒト臨床試験
乾癬患者において、このような患者群における組み合わせの直接的効果を確認するために、IRX4204およびチロキシンの組み合わせの概念実証臨床試験が実施される。乾癬を有する患者は、臨床試験に参加するよう募集され、参加のリスクおよび潜在的利益を説明するインフォームドコンセントが提供される。乾癬患者は、1日1回カプセル剤として経口投与される、1mg/日~40mg/日の範囲のいくつかの用量濃度のうちの1つの用量濃度のIRX4204、および12.5μg/日~250μg/日で経口投与される、チロキシンで治療される。一部の患者は、IRX4204もしくはチロキシンを含有しないマッチングカプセル、またはIRX4204単独を含有するカプセルを使用してプラセボ投与を受けるように無作為化されている。患者には、最低30日間、そして2年まで投与される。患者の血清甲状腺ホルモンレベルを定期的に試験し、必要に応じてチロキシンの用量を調整する。臨床経過を通して、皮膚科医または同様の医療従事者による身体検査および乾癬発症のモニタリングを通じて、乾癬活性について患者を評価する。IRX4204/チロキシン組み合わせの用量反応関係は、患者反応および乾癬活性に対する任意の影響について、IRX4204およびチロキシンの様々な用量レベルで治療された患者のコホートにわたって分析される。
IBDの進行に対するIRX4204とチロキシンの組み合わせ療法の効果を評価するためのヒト臨床試験
クローン病患者において、このような患者群における組み合わせの直接的効果を確認するために、IRX4204およびチロキシンの組み合わせの概念実証臨床試験が実施される。クローン病患者は、臨床試験に参加するよう募集され、参加のリスクおよび潜在的利益を説明するインフォームドコンセントが提供される。クローン病患者は、1日1回カプセル剤として経口投与される、1mg/日~40mg/日の範囲のいくつかの用量濃度のうちの1つの用量濃度のIRX4204、および12.5μg/日~250μg/日で経口投与される、チロキシンで治療される。一部の患者は、IRX4204またはチロキシンを含まないマッチングカプセルを使用してプラセボ投与を受けるように無作為化されている。患者には、最低30日間、そして2年まで投与される。患者の血清甲状腺ホルモンレベルを定期的に試験し、必要に応じてチロキシンの用量を調整する。臨床経過全体を通して、患者は、限定されないが、完全血液細胞検査、電解質パネル、肝機能検査、および便潜血検査などの実験検査を通じて、クローン病活性について評価される。IRX4204/チロキシン組み合わせの用量反応関係は、患者反応およびクローン病活性に対する任意の影響について、IRX4204およびチロキシンの様々な用量レベルで治療された患者のコホートにわたって分析される。
(付記1)
自己免疫疾患を治療する方法であって、当該治療を必要とする個体に治療的有効量のRXRアゴニストおよび甲状腺ホルモンを投与することを含み、前記RXRアゴニストは、式IIの構造
前記RXRアゴニストおよび甲状腺ホルモンの投与は、前記RXRアゴニストまたは前記甲状腺ホルモン単独よりも効果的に前記個体の前記自己免疫疾患を治療する、方法。
前記RXRアゴニストは、3,7-ジメチル-6(S),7(S)-メタノ,7-[1,1,4,4-テトラメチル-1,2,3,4-テトラヒドロナフト-7-イル]2(E),4(E)ヘプタジエン酸を含む選択的RXRアゴニストである、付記1に記載の方法。
前記RXRアゴニストは、3,7-ジメチル-6(S),7(S)-メタノ,7-[1,1,4,4-テトラメチル-1,2,3,4-テトラヒドロナフト-7-イル]2(E),4(E)ヘプタジエン酸エチルエステルである、付記1に記載の方法。
前記RXRアゴニストは、ベキサロテンである、付記1に記載の方法。
前記RXRアゴニストは、LG268である、付記1に記載の方法。
前記甲状腺ホルモンは、チロキシンである、付記1に記載の方法。
前記RXRアゴニストのエステルの前記治療的有効量は、約0.001mg/日~約1000mg/日である、付記1に記載の方法。
前記RXRアゴニストの前記治療的有効量は、約0.001mg/日~約1000mg/日である、付記1に記載の方法。
前記RXRアゴニストの前記治療的有効量は、約1mg/日~約100mg/日である、付記1に記載の方法。
チロキシンの前記治療的有効量は、約12.5μg/日~約250μg/日である、付記1に記載の方法。
前記RXRアゴニストは、経鼻投与によって投与される、付記1に記載の方法。
前記RXRアゴニストおよび前記チロキシンの両方は、経鼻投与により投与される、付記6に記載の方法。
前記RXRアゴニストは、経口投与される、付記1に記載の方法。
前記RXRアゴニストおよび前記チロキシンの両方は、実質的に同時に投与される、付記6に記載の方法。
前記RXRアゴニストおよび前記チロキシンは、異なるスケジュールで投与される、付記6に記載の方法。
前記チロキシンは、経口投与される、付記6に記載の方法。
前記チロキシンは、皮下投与される、付記6に記載の方法。
前記方法は、急性散在性脳脊髄炎(ADEM)、アジソン病、アレルギー、アレルギー性鼻炎、抗リン脂質抗体症候群(APS)、関節炎、喘息、後天性免疫不全症候群(AIDS)、自己免疫性溶血性貧血、自己免疫性肝炎、自己免疫内耳疾患、水疱性類天疱瘡、セリアック病、シャーガス病、慢性閉塞性肺疾患(COPD)、糖尿病1型(IDDM)、子宮内膜症、胃腸障害、糸球体腎炎、グッドパスチャー症候群、グレーブス病、ギラン・バレー症候群(GBS)、橋本甲状腺炎、汗腺膿瘍(hidradenitis suppurativa)、特発性血小板減少性紫斑病、間質性腎炎、間質性膀胱炎、狼瘡、斑状強皮症、多発性硬化症(MS)、重症筋無力症、ミオパチー、筋炎、ナルコレプシー、神経線維腫、尋常性天疱瘡、悪性貧血、原発性胆汁性肝硬変、乾癬、乾癬性関節炎、肺線維症、再発性播種性脳脊髄炎、リウマチ熱、統合失調症、強皮症、シェーグレン症候群、皮膚障害、腱鞘炎、ブドウ膜炎、血管炎、または白斑からなる群から選択される自己免疫疾患を治療する、付記1に記載の方法。
前記関節炎は、単関節炎、少関節炎、多発性関節炎、変形性関節症、リウマチ性関節炎、若年性特発性関節炎、敗血症性関節炎、脊椎関節症、痛風、擬似流出、またはスティル病である、付記18に記載の方法。
前記胃腸障害は、過敏性腸疾患または炎症性腸疾患である、付記18に記載の方法。
前記炎症性腸疾患は、クローン病または潰瘍性大腸炎である、付記20に記載の方法。
前記狼瘡は、円板状エリテマトーデス、薬物誘発性エリテマトーデス、狼瘡腎炎、新生児狼瘡、亜急性皮膚エリテマトーデス、または全身性エリテマトーデスである、付記18に記載の方法。
前記ミオパチーは、皮膚筋炎、封入体筋炎、または多発性筋炎である、付記18に記載の方法。
前記皮膚障害は、皮膚炎、湿疹、ステイシス皮膚炎、汗腺炎、乾癬、酒さ、または強皮症である、付記18に記載の方法。
前記血管炎は、バージャー病、脳血管炎、チャーグ・シュトラウス動脈炎、クリオグロブリン血症、本態性クリオグロブリン血症、巨細胞性動脈炎、ゴルファーの血管炎、ヘノッホ-シェーンライン紫斑病、過敏性脈管炎、川崎病、顕微鏡的多発動脈炎/多脈管炎、結節性多発動脈炎、多発性筋痛症(PMR)、リウマチ性血管炎、高安動脈炎、またはウェゲナー肉芽腫症である、付記18に記載の方法。
前記自己免疫疾患は、乾癬、関節リウマチ、糸球体腎炎、肺線維症、または炎症性腸疾患である、付記1に記載の方法。
自己免疫疾患を治療する方法であって、当該治療を必要とする個体に治療的許容量の3,7-ジメチル-6(S),7(S)-メタノ,7-[1,1,4,4-テトラメチル-1,2,3,4-テトラヒドロナフト-7-イル]2(E),4(E)ヘプタジエン酸(IRX4204)および治療的有効量のチロキシンを投与することを含み、その組み合わせの投与は、前記IRX4204または前記チロキシン単独よりもより効果的に前記個体の前記自己免疫疾患の重症度を低減する、方法。
Claims (24)
- 前記RXRアゴニストは、3,7-ジメチル-6(S),7(S)-メタノ,7-[1,1,4,4-テトラメチル-1,2,3,4-テトラヒドロナフト-7-イル]2(E),4(E)ヘプタジエン酸を含む選択的RXRアゴニストである、請求項1に記載の医薬組成物。
- 前記RXRアゴニストは、3,7-ジメチル-6(S),7(S)-メタノ,7-[1,1,4,4-テトラメチル-1,2,3,4-テトラヒドロナフト-7-イル]2(E),4(E)ヘプタジエン酸エチルエステルである、請求項1に記載の医薬組成物。
- 前記甲状腺ホルモンは、チロキシンである、請求項1に記載の医薬組成物。
- 前記RXRアゴニストのエステルの前記治療的有効量は、約0.001mg/日~約10mg/日である、請求項3に記載の医薬組成物。
- 前記RXRアゴニストの前記治療的有効量は、約0.001mg/日~約10mg/日である、請求項1に記載の医薬組成物。
- 前記RXRアゴニストの前記治療的有効量は、約1mg/日~約10mg/日である、請求項1に記載の医薬組成物。
- チロキシンの前記治療的有効量は、約12.5μg/日~約250μg/日である、請求項1に記載の医薬組成物。
- 前記RXRアゴニストは、経鼻投与によって投与される、請求項1に記載の医薬組成物。
- 前記RXRアゴニストおよび前記チロキシンの両方は、経鼻投与により投与される、請求項4に記載の医薬組成物。
- 前記RXRアゴニストは、経口投与される、請求項1に記載の医薬組成物。
- 前記RXRアゴニストおよび前記チロキシンの両方は、実質的に同時に投与される、請求項4に記載の医薬組成物。
- 前記RXRアゴニストおよび前記チロキシンは、異なるスケジュールで投与される、請求項4に記載の医薬組成物。
- 前記チロキシンは、経口投与される、請求項4に記載の医薬組成物。
- 前記チロキシンは、皮下投与される、請求項4に記載の医薬組成物。
- 前記自己免疫疾患は、急性散在性脳脊髄炎(ADEM)、アジソン病、アレルギー、アレルギー性鼻炎、抗リン脂質抗体症候群(APS)、関節炎、喘息、後天性免疫不全症候群(AIDS)、自己免疫性溶血性貧血、自己免疫性肝炎、自己免疫内耳疾患、水疱性類天疱瘡、セリアック病、シャーガス病、慢性閉塞性肺疾患(COPD)、糖尿病1型(IDDM)、子宮内膜症、胃腸障害、糸球体腎炎、グッドパスチャー症候群、グレーブス病、ギラン・バレー症候群(GBS)、橋本甲状腺炎、汗腺膿瘍(hidradenitis suppurativa)、特発性血小板減少性紫斑病、間質性腎炎、間質性膀胱炎、狼瘡、斑状強皮症、多発性硬化症(MS)、重症筋無力症、ミオパチー、筋炎、ナルコレプシー、神経線維腫、尋常性天疱瘡、悪性貧血、原発性胆汁性肝硬変、乾癬、乾癬性関節炎、肺線維症、再発性播種性脳脊髄炎、リウマチ熱、統合失調症、強皮症、シェーグレン症候群、皮膚障害、腱鞘炎、ブドウ膜炎、血管炎、または白斑からなる群から選択される、請求項1に記載の医薬組成物。
- 前記関節炎は、単関節炎、少関節炎、多発性関節炎、変形性関節症、リウマチ性関節炎、若年性特発性関節炎、敗血症性関節炎、脊椎関節症、痛風、擬似流出、またはスティル病である、請求項16に記載の医薬組成物。
- 前記胃腸障害は、過敏性腸疾患または炎症性腸疾患である、請求項16に記載の医薬組成物。
- 前記炎症性腸疾患は、クローン病または潰瘍性大腸炎である、請求項18に記載の医薬組成物。
- 前記狼瘡は、円板状エリテマトーデス、薬物誘発性エリテマトーデス、狼瘡腎炎、新生児狼瘡、亜急性皮膚エリテマトーデス、または全身性エリテマトーデスである、請求項16に記載の医薬組成物。
- 前記ミオパチーは、皮膚筋炎、封入体筋炎、または多発性筋炎である、請求項16に記載の医薬組成物。
- 前記皮膚障害は、皮膚炎、湿疹、ステイシス皮膚炎、汗腺炎、乾癬、酒さ、または強皮症である、請求項16に記載の医薬組成物。
- 前記血管炎は、バージャー病、脳血管炎、チャーグ・シュトラウス動脈炎、クリオグロブリン血症、本態性クリオグロブリン血症、巨細胞性動脈炎、ゴルファーの血管炎、ヘノッホ-シェーンライン紫斑病、過敏性脈管炎、川崎病、顕微鏡的多発動脈炎/多脈管炎、結節性多発動脈炎、多発性筋痛症(PMR)、リウマチ性血管炎、高安動脈炎、またはウェゲナー肉芽腫症である、請求項16に記載の医薬組成物。
- 前記自己免疫疾患は、乾癬、関節リウマチ、糸球体腎炎、肺線維症、または炎症性腸疾患である、請求項1に記載の医薬組成物。
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Families Citing this family (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
BRPI0616454A2 (pt) | 2005-09-30 | 2011-06-21 | Vitae Pharmaceuticals Inc | métodos de tratamento de cáncer |
CN110151745A (zh) | 2011-12-13 | 2019-08-23 | Io治疗公司 | 使用rxr激动剂的自身免疫紊乱的治疗 |
KR102489706B1 (ko) | 2015-10-31 | 2023-01-17 | 아이오 테라퓨틱스, 인크. | Rxr 아고니스트와 갑상선 호르몬의 조합을 사용한 신경계 질환의 치료 |
CN114904000A (zh) | 2016-03-10 | 2022-08-16 | Io治疗公司 | Rxr激动剂和甲状腺激素在制备用于治疗自身免疫疾病的药物中的用途 |
US10835507B2 (en) | 2016-03-10 | 2020-11-17 | Io Therapeutics, Inc. | Treatment of muscular disorders with combinations of RXR agonists and thyroid hormones |
MX2020003223A (es) * | 2017-09-20 | 2020-09-21 | Io Therapeutics Inc | Tratamiento de enfermedades con ésteres de agonistas de rxr selectivos. |
CN111465402B (zh) | 2017-11-17 | 2022-05-24 | Io治疗公司 | 用于制备类视黄醇x受体-特异性类视黄醇的化合物和合成方法 |
US10966950B2 (en) | 2019-06-11 | 2021-04-06 | Io Therapeutics, Inc. | Use of an RXR agonist in treating HER2+ cancers |
WO2023108012A1 (en) | 2021-12-07 | 2023-06-15 | Io Therapeutics, Inc. | Use of an rxr agonist and taxanes in treating her2+ cancers |
US11998521B2 (en) | 2021-12-07 | 2024-06-04 | Io Therapeutics, Inc. | Use of an RXR agonist in treating drug resistant HER2+ cancers |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2007501800A (ja) | 2003-08-07 | 2007-02-01 | アラーガン インコーポレイテッド | レチノイドリガンドを用いて悪液質を処置するための方法 |
JP2009504774A (ja) | 2005-08-18 | 2009-02-05 | メルク エンド カムパニー インコーポレーテッド | 癌を治療するためにsaha及びターグレチンの併用方法 |
US20130190395A1 (en) | 2011-12-13 | 2013-07-25 | Dartmouth College | Autoimmune disorder treatment using rxr agonists |
US20150038585A1 (en) | 2011-12-13 | 2015-02-05 | Io Therapeutics, Inc. | Treatment of Diseases by Concurrently Eliciting Remyelination Effects and Immunomodulatory Effects Using Selective RXR Agonists |
Family Cites Families (101)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4756911A (en) | 1986-04-16 | 1988-07-12 | E. R. Squibb & Sons, Inc. | Controlled release formulation |
US5378475A (en) | 1991-02-21 | 1995-01-03 | University Of Kentucky Research Foundation | Sustained release drug delivery devices |
US5466861A (en) | 1992-11-25 | 1995-11-14 | Sri International | Bridged bicyclic aromatic compounds and their use in modulating gene expression of retinoid receptors |
BR9307528A (pt) | 1992-11-25 | 1999-08-31 | Jolla Cancer Research Foudatio | Processo para inspecionar subst‰ncia quanto à capacidade de afetar a formação de homodìmero em receptor de retinóide x, processo para inspecionar subst‰ncia quanto à capacidade de induzir seletivamente a formação de heterodìmero em receptor de retinóide x, processo para inspecionar subst‰ncia quanto à capacidade de afetar a capacidade de um homodìmero, em um receptor de retinóide x, se ligar ao dna, processo para inspecionar um elemento de resposta quanto à capacidade de se ligar a um homodìmero em receptor de retinóide x, homodìmero em receptor de retinóide x, composto aromático bicìclico, processo para inibir atividade de heterodìmero em receptor de retinóide x, processo para promover transcrição de um gene ativado por homodìmero em receptor de retinóide em uma célula, processo para inibir atividade de homodìmero em receptor de retinóide x, processo para determinar maior probabilidade de patologia, processo para tratar patologia, processo para ativar seletivamente formação de homodìmero em receptor de retinóide x em uma célula, processo para promover a formação de homodìmero em receptor de retinóide x em uma célula, composição farmacêutica, processo para modular expressão de gene, e processo para tratar paciente |
DK0638071T3 (da) | 1992-12-28 | 1997-10-27 | Eisai Co Ltd | Heterocykliske carboxylsyrederivater, der bindes til retenoidreceptorer (RAR) |
US5455265A (en) | 1993-02-11 | 1995-10-03 | Allergan, Inc. | Method of treatment with compounds having selective agonist-like activity on RXR retinoid receptors |
US5869079A (en) | 1995-06-02 | 1999-02-09 | Oculex Pharmaceuticals, Inc. | Formulation for controlled release of drugs by combining hydrophilic and hydrophobic agents |
US5917082A (en) | 1995-06-06 | 1999-06-29 | Allergan Sales, Inc. | 2,4-pentadienoic acid derivatives having retinoid-like biological activity |
US5675033A (en) | 1995-06-06 | 1997-10-07 | Allergan | 2,4-pentadienoic acid derivatives having retinoid-like biological activity |
JP3964478B2 (ja) | 1995-06-30 | 2007-08-22 | エーザイ・アール・アンド・ディー・マネジメント株式会社 | ヘテロ環含有カルボン酸誘導体及びそれを含有する医薬 |
US5958954A (en) | 1995-09-01 | 1999-09-28 | Allergan Sales, Inc. | Synthesis and use of retinoid compounds having negative hormone and/or antagonist activities |
US6008204A (en) | 1995-09-01 | 1999-12-28 | Allergan Sales, Inc. | Synthesis and use of retinoid compounds having negative hormone and/or antagonist activities |
US6218128B1 (en) | 1997-09-12 | 2001-04-17 | Allergan Sales, Inc. | Methods of identifying compounds having nuclear receptor negative hormone and/or antagonist activities |
US5776699A (en) | 1995-09-01 | 1998-07-07 | Allergan, Inc. | Method of identifying negative hormone and/or antagonist activities |
US5952345A (en) | 1995-09-01 | 1999-09-14 | Allergan Sales, Inc. | Synthesis and use of retinoid compounds having negative hormone and/or antagonist activities |
US6942980B1 (en) | 1995-09-01 | 2005-09-13 | Allergan, Inc. | Methods of identifying compounds having nuclear receptor negative hormone and/or antagonist activities |
US5675024A (en) | 1995-11-22 | 1997-10-07 | Allergan | Aryl or heteroaryl amides of tetrahydronaphthalene, chroman, thiochroman and 1,2,3,4,-tetrahydroquinoline carboxylic acids, having an electron withdrawing substituent in the aromatic or heteroaromatic moiety, having retinoid-like biological activity |
US5965606A (en) | 1995-12-29 | 1999-10-12 | Allergan Sales, Inc. | Methods of treatment with compounds having RAR.sub.α receptor specific or selective activity |
US5877207A (en) | 1996-03-11 | 1999-03-02 | Allergan Sales, Inc. | Synthesis and use of retinoid compounds having negative hormone and/or antagonist activities |
US20030219832A1 (en) | 1996-03-11 | 2003-11-27 | Klein Elliott S. | Synthesis and use of retinoid compounds having negative hormone and/or antagonist activities |
US6441025B2 (en) | 1996-03-12 | 2002-08-27 | Pg-Txl Company, L.P. | Water soluble paclitaxel derivatives |
US6555690B2 (en) | 1996-06-21 | 2003-04-29 | Allergan, Inc. | Alkyl or aryl substituted dihydronaphthalene derivatives having retinoid and/or retinoid antagonist-like biological activity |
US5773594A (en) | 1996-06-21 | 1998-06-30 | Allergan | Alkyl or aryl substituted dihydronaphthalene derivatives having retinoid and/or retinoid antagonist-like biological activity |
US5763635A (en) | 1996-06-21 | 1998-06-09 | Allergan | Tetrahydronaphthalene derivatives substituted in the 8 position with alkyhidene groups having retinoid and/or retinoid antagonist-like biological activity |
US5739338A (en) | 1996-11-05 | 1998-04-14 | Allergan | N-aryl substituted tetrahydroquinolines having retinoid agonist, retinoid antagonist or retinoid inverse agonist type biological activity |
EP1410799B1 (en) | 1996-12-11 | 2010-03-31 | Dana-Farber Cancer Institute, Inc. | Methods and pharmaceutical compositions for inhibiting tumour cell growth |
US5728846A (en) | 1996-12-12 | 1998-03-17 | Allergan | Benzo 1,2-g!-chrom-3-ene and benzo 1,2-g!-thiochrom-3-ene derivatives |
US6037488A (en) | 1997-04-19 | 2000-03-14 | Allergan Sales, Inc. | Trisubstituted phenyl derivatives having retinoid agonist, antagonist or inverse agonist type biological activity |
US5919970A (en) | 1997-04-24 | 1999-07-06 | Allergan Sales, Inc. | Substituted diaryl or diheteroaryl methanes, ethers and amines having retinoid agonist, antagonist or inverse agonist type biological activity |
US6670398B2 (en) | 1997-05-14 | 2003-12-30 | Atherogenics, Inc. | Compounds and methods for treating transplant rejection |
US6063768A (en) | 1997-09-04 | 2000-05-16 | First; Eric R. | Application of botulinum toxin to the management of neurogenic inflammatory disorders |
WO1999058486A1 (en) | 1998-05-11 | 1999-11-18 | Novo Nordisk A/S | New compounds, their preparation and use |
EP1093362A1 (en) | 1998-06-12 | 2001-04-25 | Ligand Pharmaceuticals Incorporated | Treatment of anti-estrogen resistant breast cancer using rxr modulators |
US6048873A (en) | 1998-10-01 | 2000-04-11 | Allergan Sales, Inc. | Tetrahdroquinolin-2-one 6 or 7-yl, tetrahdroquinilin-2-thione 6 or 7-yl pentadienoic acid and related derivatives having retinoid-like biological activity |
US6147224A (en) | 1998-10-01 | 2000-11-14 | Allergan Sales, Inc. | 2,4-pentadienoic acid derivatives having selective activity for retinoid X (RXR) receptors |
US6403638B1 (en) | 1998-10-01 | 2002-06-11 | Allergan Sales, Inc. | 2,4-pentadienoic acid derivatives having selective activity for retinoid X (RXR) receptors |
US6521641B1 (en) | 1998-10-08 | 2003-02-18 | Allergan, Inc. | Male anti-fertility agents |
US6776984B1 (en) | 1999-08-20 | 2004-08-17 | George R. Schwartz | Induced regeneration and repair of damaged neurons and nerve axon myelin |
US6043381A (en) | 1999-05-07 | 2000-03-28 | Allergan Sales, Inc. | Process for preparing substituted benzo[1,2-g]-chrom-3-ene, benzo[1,2-g]-thiochrom-3-ene and benzo[1,2-g]-1,2-dihydroquinoline derivatives |
AU6228000A (en) | 1999-07-23 | 2001-02-13 | Allergan Sales, Inc. | The use of retinoid receptor antagonists in the treatment of prostate carcinoma |
US6187750B1 (en) | 1999-08-25 | 2001-02-13 | Everyoung Technologies, Inc. | Method of hormone treatment for patients with symptoms consistent with multiple sclerosis |
AU7586600A (en) | 1999-09-14 | 2001-04-17 | Ligand Pharmaceuticals Incorporated | Rxr modulators with improved pharmacologic profile |
US6313168B1 (en) | 1999-12-15 | 2001-11-06 | Allergan Sales, Inc. | Use of retinoid receptor antagonists in the treatment of cartilage and bone pathologies |
TWI281911B (en) | 2000-04-04 | 2007-06-01 | Allergan Inc | Treatment of tumors with RARalpha selective retinoid compounds in combination with other anti-tumor agents |
US20030077664A1 (en) | 2001-04-18 | 2003-04-24 | Yi Zhao | Methods of screening for compounds that modulate hormone receptor activity |
US20020193403A1 (en) | 2001-05-03 | 2002-12-19 | Allergan Sales, Inc. | Methods of treating hyperlipidemia |
JP2004528368A (ja) | 2001-05-08 | 2004-09-16 | メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフトング | 抗egfr抗体と抗ホルモン剤を用いた組合せ療法 |
GB0111314D0 (en) * | 2001-05-09 | 2001-07-04 | Karobio Ab | Dermatological formulations |
AU2002333655A1 (en) | 2001-09-25 | 2003-04-07 | Smithkline Beecham Corporation | Bicyclic heterocycles as rxr ligands |
US6645526B2 (en) | 2001-11-13 | 2003-11-11 | Mylan Pharmaceuticals, Inc. | Storage stable thyroxine active drug formulations and methods for their production |
IL152904A0 (en) | 2002-01-24 | 2003-06-24 | Gamida Cell Ltd | Utilization of retinoid and vitamin d receptor antagonists for expansion of renewable stem cell populations |
CA2479679A1 (en) | 2002-03-18 | 2003-09-25 | Gamida-Cell Ltd. | Methods of inducing differentiation in ex vivo expanded stem cells |
US6720423B2 (en) | 2002-04-30 | 2004-04-13 | Allergan, Inc. | Dihydrobenzofuran and dihydrobenzothiophene 2,4-pentadienoic acid derivatives having selective activity for retinoid X (RXR) receptors |
CA2483817C (en) | 2002-06-04 | 2013-01-15 | Thibaud Biadatti | Novel ligands that are inhibitors of the rar receptors, process for preparing them and use thereof in human medicine and in cosmetics |
US20040005304A1 (en) | 2002-07-08 | 2004-01-08 | Mak Wood, Inc. | Novel compositions and methods for treating neurological disorders and associated gastrointestinal conditions |
JP4275365B2 (ja) | 2002-08-06 | 2009-06-10 | 三菱電機株式会社 | 複合形ガス絶縁開閉装置 |
US7105566B2 (en) | 2002-10-22 | 2006-09-12 | Allergan, Inc. | Methods of treatment during vascular procedures |
DE60312548T2 (de) | 2002-11-18 | 2007-12-13 | Galderma Research & Development, S.N.C. | Neue liganden, die antagonisten der rar-rezeptoren sind, herstellungsverfahren für diese liganden und verwendung dieser liganden in der humanmedizin und in der kosmetik |
US7019034B2 (en) | 2003-01-28 | 2006-03-28 | Allergan, Inc. | Compositions and methods for reducing serum glucose and triglyceride levels in diabetic mammals |
US6936636B2 (en) | 2003-06-26 | 2005-08-30 | Allergan, Inc. | 5-[phenyl-tetrahydronaphthalene-2-yl dihydronaphthalen-2-yl and heteroaryl-cyclopropyl]-pentadienoic acid derivatives having serum glucose reducing activity |
WO2005027895A2 (en) | 2003-09-15 | 2005-03-31 | Ordway Research Institute | Thyroid hormone analogs and methods of use in angiogenesis |
WO2005046726A2 (en) | 2003-11-12 | 2005-05-26 | Allergan, Inc. | Combinations for inhibiting cell growth which contains an inhibitor of human ck1 alpha activity and a rxr agonist |
AU2005209201B2 (en) | 2004-01-20 | 2010-06-03 | Allergan, Inc. | Compositions for localized therapy of the eye, comprising preferably triamcinolone acetonide and hyaluronic acid |
US7799336B2 (en) | 2004-04-30 | 2010-09-21 | Allergan, Inc. | Hypotensive lipid-containing biodegradable intraocular implants and related methods |
EP1799812A4 (en) | 2004-09-16 | 2009-09-09 | Gamida Cell Ltd | EX VIVO CULTIVATION METHODS OF STEM CELLS AND PRECURSOR BY CO-CULTURE WITH MESENCHYMAL CELLS |
US8105611B2 (en) | 2005-06-17 | 2012-01-31 | Allergan, Inc. | Treatment of autoimmune disorder with a neurotoxin |
WO2007041076A2 (en) | 2005-09-30 | 2007-04-12 | Janssen Pharmaceutica N.V. | 1,2,3,5-tetrahydro-cyclopental[c]quinolin-4-one derivatives as rxr agonists for the treatment of dyslipidemia, hypercholesterolemia and diabetes |
BRPI0616454A2 (pt) | 2005-09-30 | 2011-06-21 | Vitae Pharmaceuticals Inc | métodos de tratamento de cáncer |
EP1948623A2 (en) | 2005-09-30 | 2008-07-30 | Janssen Pharmaceutica, N.V. | Heterocyclic amide derivatives as rxr agonists for the treatment of dyslipidemia, hypercholesterolemia and diabetes |
US7638533B2 (en) * | 2005-09-30 | 2009-12-29 | Janssen Pharmaceutica N.V. | Dihydro-1[1H]-quinolin-2-one derivatives as RXR agonists for the treatment of dyslipidemia, hypercholesterolemia and diabetes |
US20070185055A1 (en) | 2006-02-06 | 2007-08-09 | Guang Liang Jiang | Method for treating cachexia with retinoid ligands |
CN1806798A (zh) * | 2006-02-23 | 2006-07-26 | 北京阜康仁生物制药科技有限公司 | 一种以贝沙罗汀为活性成分的药用组合物及其制备方法、用途 |
KR101530050B1 (ko) | 2007-03-02 | 2015-06-22 | 주식회사 노브메타파마 | 알츠하이머 질환 및 치매를 치료하기 위한 조성물 및 방법 |
EP2167647A2 (en) | 2007-06-13 | 2010-03-31 | La Jolla Institute For Allergy And Immunology | Regulatory t cells and methods of making and using same |
US20090209601A1 (en) | 2008-02-15 | 2009-08-20 | Wyeth | Use of rxr agonists for the treatment of osteoarthritis |
ES2332169B1 (es) | 2008-07-24 | 2010-10-25 | Universidad Del Pais Vasco | Empleo de microparticulas que comprenden celulas modificadas geneticamente en el tratamiento de enfermedades neurodegenerativas. |
WO2010041149A2 (en) | 2008-10-08 | 2010-04-15 | Cambridge Enterprise | Methods and compositions for diagnosis and treatment |
WO2010041449A1 (ja) | 2008-10-09 | 2010-04-15 | 国立大学法人 岡山大学 | Rxr作動性物質を有効成分とする抗アレルギー剤 |
WO2010123946A2 (en) | 2009-04-20 | 2010-10-28 | Allergan, Inc. | Silk fibroin hydrogels and uses thereof |
AU2010249015A1 (en) | 2009-05-15 | 2011-11-24 | The University Of Kentucky Research Foundation | Treatment of MCI and Alzheimer's disease |
US20100298434A1 (en) | 2009-05-21 | 2010-11-25 | Claude Rouillard | Neuroprotection and prevention of dopaminergic cell death by targeting nur77 translocation |
JP2010280585A (ja) | 2009-06-02 | 2010-12-16 | Okayama Univ | Rxr作動性物質を有効成分とする鎮痛剤 |
EP2451455A4 (en) | 2009-07-10 | 2013-01-16 | Univ Case Western Reserve | RXR AGONIST COMPOUNDS AND METHODS |
EP2536276B1 (en) | 2010-02-19 | 2016-11-23 | The Arizona Board Of Regents, A Body Corporate Of The State Of Arizona Acting For And On Behalf Of Arizona State University | Novel bexarotene analogs |
US20120238623A1 (en) | 2011-03-14 | 2012-09-20 | Chandraratna Roshantha A | Inflammation and Autoimmune Disorder Treatment using RARa Selective Agonists |
EP2556827A1 (en) | 2011-08-11 | 2013-02-13 | Acadia Pharmaceuticals Inc. | Treatment of neurodegenerative diseases |
EP2766018A4 (en) | 2011-10-13 | 2015-02-25 | Univ Case Western Reserve | RXR AGONIST COMPOUNDS AND ASSOCIATED METHODS |
US9446105B2 (en) | 2013-03-15 | 2016-09-20 | The Trustees Of The University Of Pennsylvania | Chimeric antigen receptor specific for folate receptor β |
US20160263189A1 (en) | 2013-10-23 | 2016-09-15 | Acadia Pharmaceuticals Inc. | Treatment of a neurodegenerative disease or disorder |
JP2016537414A (ja) | 2013-10-29 | 2016-12-01 | ベスティオン、インク. | 心臓神経堤細胞、及びその使用方法 |
JP2018512396A (ja) | 2015-03-09 | 2018-05-17 | キングス・カレッジ・ロンドン | Th1応答を増強するためのrarアルファアゴニストを用いた併用療法 |
KR102489706B1 (ko) | 2015-10-31 | 2023-01-17 | 아이오 테라퓨틱스, 인크. | Rxr 아고니스트와 갑상선 호르몬의 조합을 사용한 신경계 질환의 치료 |
EP3368160B1 (en) | 2015-10-31 | 2023-05-17 | IO Therapeutics, Inc. | Treatment of nervous system disorders using thyroid hormone neutral doses of rxr agonists |
US20190365681A1 (en) | 2015-10-31 | 2019-12-05 | Io Therapeutics, Inc. | Treatment of cancer with combinations of rxr agonists and thyroid hormones |
US10835507B2 (en) | 2016-03-10 | 2020-11-17 | Io Therapeutics, Inc. | Treatment of muscular disorders with combinations of RXR agonists and thyroid hormones |
CN114904000A (zh) | 2016-03-10 | 2022-08-16 | Io治疗公司 | Rxr激动剂和甲状腺激素在制备用于治疗自身免疫疾病的药物中的用途 |
CN106983738B (zh) * | 2017-04-13 | 2020-03-10 | 深圳市润佳通科技有限公司 | 甲状腺激素及其药学上可接受的盐或前药在制备治疗和/或预防皮肤疾病的药物中的应用 |
WO2019046591A1 (en) | 2017-08-31 | 2019-03-07 | Io Therapeutics, Inc. | SELECTIVE RAR AGONISTS IN ASSOCIATION WITH IMMUNE MODULATORS IN ANTICANCER IMMUNOTHERAPY |
MX2020003223A (es) | 2017-09-20 | 2020-09-21 | Io Therapeutics Inc | Tratamiento de enfermedades con ésteres de agonistas de rxr selectivos. |
CN111465402B (zh) | 2017-11-17 | 2022-05-24 | Io治疗公司 | 用于制备类视黄醇x受体-特异性类视黄醇的化合物和合成方法 |
US10966950B2 (en) | 2019-06-11 | 2021-04-06 | Io Therapeutics, Inc. | Use of an RXR agonist in treating HER2+ cancers |
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Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2007501800A (ja) | 2003-08-07 | 2007-02-01 | アラーガン インコーポレイテッド | レチノイドリガンドを用いて悪液質を処置するための方法 |
JP2009504774A (ja) | 2005-08-18 | 2009-02-05 | メルク エンド カムパニー インコーポレーテッド | 癌を治療するためにsaha及びターグレチンの併用方法 |
US20130190395A1 (en) | 2011-12-13 | 2013-07-25 | Dartmouth College | Autoimmune disorder treatment using rxr agonists |
US20150038585A1 (en) | 2011-12-13 | 2015-02-05 | Io Therapeutics, Inc. | Treatment of Diseases by Concurrently Eliciting Remyelination Effects and Immunomodulatory Effects Using Selective RXR Agonists |
Non-Patent Citations (4)
Title |
---|
American Journal of Physiology, 2002, Vol.283 No.2,Pt.1 p.E326-E331 |
Endocrinology,2002年,143(8),2880-2885 |
European Journal of Endocrinology,2014年,170(6),R253-R262 |
J Med Chem,2001年,44,2298-2303 |
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