JP2019533019A - Thr−ベータアゴニストで肝臓障害又は脂質障害を治療する方法 - Google Patents
Thr−ベータアゴニストで肝臓障害又は脂質障害を治療する方法 Download PDFInfo
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Abstract
Description
本開示は、肝臓障害又は脂質障害の治療を必要とする対象における肝臓障害又は脂質障害を治療する方法であって、(a)第1の期間、毎日対象に2−(3,5−ジクロロ−4−((5−イソプロピル−6−オキソ−1,6−ジヒドロピリダジン−3−イル)オキシ)フェニル)−3,5−ジオキソ−2,3,4,5−テトラヒドロ−1,2,4−トリアジン−6−カルボニトリル(「化合物A」)の第1の用量を投与すること;(b)対象から得られた生物学的試料に対する遺伝子試験、バイオマーカー試験及び薬物動態学的試験、対象の理学的検査、並びにこれらの組合せからなる群から選択される試験を行って、ステップ(a)の後の化合物Aに対する対象の感受性を決定すること;並びに(c)ステップ(b)からの感受性結果に基づいて第2の期間対象に化合物Aの第2の用量を投与することを含む方法を提供する。一実施形態において、ステップ(b)の試験は、少なくとも1つのバイオマーカーの発現レベルを測定するバイオマーカー試験である。一実施形態において、方法は、(d)ステップ(a)の前に対象から得られた第1の生物学的試料に対して第1のバイオマーカー試験を行うことであって、ここで、第1のバイオマーカー試験は、ステップ(b)において測定されるべきである少なくとも1つのバイオマーカーの発現レベルを測定する、こと;並びに(e)ステップ(b)及び(d)における結果に基づいて少なくとも1つのバイオマーカーの発現レベルにおける変化又は変化の程度を決定することをさらに含む。一実施形態において、方法は、ステップ(f)ステップ(e)において決定された変化又は変化の程度に基づいて化合物Aの第2の用量を決定することをさらに含む。一実施形態において、ステップ(f)において化合物Aの第2の用量を決定することは、対象の少なくとも1つの人口統計学的特色、対象の薬歴、対象の身体情報、又はこれらの組合せにさらに基づく。
該研究は、2つの群の雄性SDラット(群1及び2)及び1つの群の雄性LEラット(群3)を利用した。これらは、Hilltop Lab Animals、Inc.(Scottdale、PA)から得た。群1を排泄物質量収支の評価のために使用し;群2を血漿総放射能PKの評価のために使用し;群3を総放射能の組織分布の評価のために使用した。全てのラットは、[14C]MGL−3196の単一PO用量を受けた。標的用量は、精製されたMilliQ水ビヒクル中4%のDMSO/96%の2% Klucel、0.1%ツイーン−80、0.09%メチルパラベン及び0.01%プロピルパラベン中で調製された製剤を使用して5mg/kgであった。
以下の研究を行った:(a)インビトロ薬物タンパク質結合輸送体(有機アニオン輸送ポリペプチド[OATP]、P−糖タンパク質[P−gp]、乳がん関連タンパク質[BCRP]、及び多剤耐性タンパク質1[MDR1])、並びに吸収、分布及び排泄を調査するためのシトクロムP−450酵素アッセイ;(b)インビボMGL−3196ラット及びイヌ経口PK及び生物学的利用能研究;(c)インビボ14C−MGL−3196ラット及びイヌ経口薬物動態、吸収、排泄、及び定量的全身オートラジオグラフィー(QWBA)研究による組織分布;並びに(d)イヌ(SCDH)及びヒト(SCHH)肝細胞においてインビトロでサンドイッチされた肝細胞モデル系(B−CLEAR(登録商標)科学技術)を使用するMGL−3196の肝臓処分。表1A〜1Bは、14C−MGL−3196ラットADME研究設計を示している。
・胆汁蓄積=総蓄積プラス(+)緩衝液−細胞蓄積マイナス(−)緩衝液
Claims (62)
- 肝臓障害又は脂質障害の治療を必要とする対象における肝臓障害又は脂質障害を治療する方法であって、
(a)第1の期間、毎日対象に2−(3,5−ジクロロ−4−((5−イソプロピル−6−オキソ−1,6−ジヒドロピリダジン−3−イル)オキシ)フェニル)−3,5−ジオキソ−2,3,4,5−テトラヒドロ−1,2,4−トリアジン−6−カルボニトリル(「化合物A」)の第1の用量を投与すること;
(b)対象から得られた生物学的試料に対する遺伝子試験、バイオマーカー試験及び薬物動態学的試験、対象の理学的検査、並びにこれらの組合せからなる群から選択される試験を行って、ステップ(a)の後の化合物Aに対する対象の感受性を決定すること;並びに
(c)ステップ(b)からの感受性結果に基づいて、第2の期間、対象に化合物Aの第2の用量を投与すること
を含む方法。 - ステップ(b)の試験が、少なくとも1つのバイオマーカーの発現レベルを測定するバイオマーカー試験である、請求項1に記載の方法。
- (d)ステップ(a)の前に対象から得られた第1の生物学的試料に対して第1のバイオマーカー試験を行うことであって、ここで、第1のバイオマーカー試験は、ステップ(b)において測定されるべきである少なくとも1つのバイオマーカーの発現レベルを測定すること;
(e)ステップ(b)及び(d)における結果に基づいて、少なくとも1つのバイオマーカーの発現レベルにおける変化又は変化の程度を決定すること;並びに
(f)ステップ(e)において決定された変化又は変化の程度に基づいて、化合物Aの第2の用量を決定すること
をさらに含む、請求項1又は2に記載の方法。 - 化合物Aの第2の用量を決定することが、対象の少なくとも1つの人口統計学的特色、対象の薬歴、対象の身体情報、又はこれらの組合せにさらに基づく、請求項3に記載の方法。
- 肝臓障害又は脂質障害の治療を必要とする対象における肝臓障害又は脂質障害を治療する方法における使用のための、2−(3,5−ジクロロ−4−((5−イソプロピル−6−オキソ−1,6−ジヒドロピリダジン−3−イル)オキシ)フェニル)−3,5−ジオキソ−2,3,4,5−テトラヒドロ−1,2,4−トリアジン−6−カルボニトリル(「化合物A」)であって、前記方法が、
(a)第1の期間、毎日対象に化合物Aの第1の用量を投与すること;
(b)対象から得られた生物学的試料に対する遺伝子試験、バイオマーカー試験及び薬物動態学的試験、対象の理学的検査、並びにこれらの組合せからなる群から選択される試験を行って、ステップ(a)の後の化合物Aに対する対象の感受性を決定すること;並びに
(c)ステップ(b)からの感受性結果に基づいて、第2の期間、対象に化合物Aの第2の用量を投与すること
を含む、2−(3,5−ジクロロ−4−((5−イソプロピル−6−オキソ−1,6−ジヒドロピリダジン−3−イル)オキシ)フェニル)−3,5−ジオキソ−2,3,4,5−テトラヒドロ−1,2,4−トリアジン−6−カルボニトリル(「化合物A」)。 - ステップ(b)の試験が、少なくとも1つのバイオマーカーの発現レベルを測定するバイオマーカー試験である、請求項5に記載の使用のための化合物A。
- 前記方法が、
(d)ステップ(a)の前に対象から得られた第1の生物学的試料に対して第1のバイオマーカー試験を行うことであって、ここで、第1のバイオマーカー試験は、ステップ(b)において測定されるべきである少なくとも1つのバイオマーカーの発現レベルを測定すること;
(e)ステップ(b)及び(d)における結果に基づいて、少なくとも1つのバイオマーカーの発現レベルにおける変化又は変化の程度を決定すること;並びに
(f)ステップ(e)において決定された変化又は変化の程度に基づいて、化合物Aの第2の用量を決定すること
をさらに含む、請求項5又は6に記載の使用のための化合物A。 - 化合物Aの第2の用量を決定することが、対象の少なくとも1つの人口統計学的特色、対象の薬歴、対象の身体情報、又はこれらの組合せにさらに基づく、請求項7に記載の使用のための化合物A。
- 肝臓障害又は脂質障害の治療を必要とする対象における肝臓障害又は脂質障害を治療する方法における使用のための医薬の製造における、2−(3,5−ジクロロ−4−((5−イソプロピル−6−オキソ−1,6−ジヒドロピリダジン−3−イル)オキシ)フェニル)−3,5−ジオキソ−2,3,4,5−テトラヒドロ−1,2,4−トリアジン−6−カルボニトリル(「化合物A」)の使用であって、前記方法が、
(a)第1の期間、毎日対象に化合物Aの第1の用量を投与すること;
(b)対象から得られた生物学的試料に対する遺伝子試験、バイオマーカー試験及び薬物動態学的試験、対象の理学的検査、並びにこれらの組合せからなる群から選択される試験を行うことで、ステップ(a)の後の化合物Aに対する対象の感受性を決定すること;並びに
(c)ステップ(b)からの感受性結果に基づいて、第2の期間、対象に化合物Aの第2の用量を投与すること
を含む、使用。 - ステップ(b)の試験が、少なくとも1つのバイオマーカーの発現レベルを測定するバイオマーカー試験である、請求項9に記載の使用。
- 前記方法が、
(d)ステップ(a)の前に対象から得られた第1の生物学的試料に対して第1のバイオマーカー試験を行うことであって、ここで、第1のバイオマーカー試験は、ステップ(b)において測定されるべきである少なくとも1つのバイオマーカーの発現レベルを測定すること;
(e)ステップ(b)及び(d)における結果に基づいて、少なくとも1つのバイオマーカーの発現レベルにおける変化又は変化の程度を決定すること;並びに
(f)ステップ(e)において決定された変化又は変化の程度に基づいて、化合物Aの第2の用量を決定すること
をさらに含む、請求項9又は10に記載の使用。 - 化合物Aの第2の用量を決定することが、対象の少なくとも1つの人口統計学的特色、対象の薬歴、対象の身体情報、又はこれらの組合せにさらに基づく、請求項11に記載の使用。
- 肝臓障害又は脂質障害の治療を必要とする対象における肝臓障害又は脂質障害を治療する方法であって、
(a)対象から得られた生物学的試料に対する遺伝子試験、バイオマーカー試験及び薬物動態学的試験、対象の理学的検査、並びにこれらの組合せからなる群から選択される試験を行うこと;
(b)試験の結果に基づいて、対象のための2−(3,5−ジクロロ−4−((5−イソプロピル−6−オキソ−1,6−ジヒドロピリダジン−3−イル)オキシ)フェニル)−3,5−ジオキソ−2,3,4,5−テトラヒドロ−1,2,4−トリアジン−6−カルボニトリル(「化合物A」)の治療有効量を決定すること;並びに
(c)対象に化合物Aの治療有効量を投与すること
を含む方法。 - 予測アルゴリズムが、化合物Aの治療有効量を決定するためにステップ(b)において使用される、請求項13に記載の方法。
- 化合物Aの治療有効量を決定することが、対象の少なくとも1つの人口統計学的特色、対象の薬歴、対象の身体情報、又はこれらの組合せにさらに基づく、請求項13又は14に記載の方法。
- 肝臓障害又は脂質障害の治療を必要とする対象における肝臓障害又は脂質障害を治療する方法における使用のための、2−(3,5−ジクロロ−4−((5−イソプロピル−6−オキソ−1,6−ジヒドロピリダジン−3−イル)オキシ)フェニル)−3,5−ジオキソ−2,3,4,5−テトラヒドロ−1,2,4−トリアジン−6−カルボニトリル(「化合物A」)であって、前記方法が、
(a)対象から得られた生物学的試料に対する遺伝子試験、バイオマーカー試験及び薬物動態学的試験、対象の理学的検査、並びにこれらの組合せからなる群から選択される試験を行うこと;並びに
(b)試験の結果に基づいて対象のための化合物Aの治療有効量を決定すること
を含む、2−(3,5−ジクロロ−4−((5−イソプロピル−6−オキソ−1,6−ジヒドロピリダジン−3−イル)オキシ)フェニル)−3,5−ジオキソ−2,3,4,5−テトラヒドロ−1,2,4−トリアジン−6−カルボニトリル(「化合物A」)。 - 予測アルゴリズムが、化合物Aの治療有効量を決定するためにステップ(b)において使用される、請求項16に記載の使用のための化合物A。
- 化合物Aの治療有効量を決定することが、対象の少なくとも1つの人口統計学的特色、対象の薬歴、対象の身体情報、又はこれらの組合せにさらに基づく、請求項16又は17に記載の使用のための化合物A。
- 肝臓障害又は脂質障害の治療を必要とする対象における肝臓障害又は脂質障害を治療する方法における使用のための医薬の製造における、2−(3,5−ジクロロ−4−((5−イソプロピル−6−オキソ−1,6−ジヒドロピリダジン−3−イル)オキシ)フェニル)−3,5−ジオキソ−2,3,4,5−テトラヒドロ−1,2,4−トリアジン−6−カルボニトリル(「化合物A」)の使用であって、前記方法が、
(a)対象から得られた生物学的試料に対する遺伝子試験、バイオマーカー試験及び薬物動態学的試験、対象の理学的検査、並びにこれらの組合せからなる群から選択される試験を行うこと;並びに
(b)試験の結果に基づいて対象のための化合物Aの治療有効量を決定すること
を含む、使用。 - 予測アルゴリズムが、化合物Aの治療有効量を決定するためにステップ(b)において使用される、請求項19に記載の使用。
- 化合物Aの治療有効量を決定することが、対象の少なくとも1つの人口統計学的特色、対象の薬歴、対象の身体情報、又はこれらの組合せにさらに基づく、請求項19又は20に記載の使用。
- 肝臓障害が非アルコール性脂肪性肝炎である、請求項1〜21のいずれか一項に記載の方法、使用のための化合物A、又は使用。
- 脂質障害が高脂質血症又は高コレステロール血症である、請求項1〜21のいずれか一項に記載の方法、使用のための化合物A、又は使用。
- 遺伝子試験が、薬物輸送体、薬物代謝酵素、若しくは甲状腺軸ホルモン、甲状腺経路遺伝子、脂質経路遺伝子、又はこれらの組合せをコードするポリヌクレオチドにおける多型を検出することを含む、請求項1〜23のいずれか一項に記載の方法、使用のための化合物A、又は使用。
- 薬物輸送体が、溶質担体輸送体又はATP結合カセット輸送体である、請求項1〜24のいずれか一項に記載の方法、使用のための化合物A、又は使用。
- ATP結合カセット輸送体が、ABCC1、ABCC2、ABCC3、ABCC4、ABCC5、ABCG2及びABCB11からなる群から選択される、請求項25に記載の方法、使用のための化合物A、又は使用。
- 溶質担体輸送体が、SLC22A1、SLC22A2、SLC22A3、SLC22A6、SLC22A8、SLC22A11、SLCO1B1、SLCO1B3、SLCO2B1、SLC47A1及びSLC47A2からなる群から選択される、請求項25に記載の方法、使用のための化合物A、又は使用。
- バイオマーカー試験が、甲状腺軸ホルモン、チロキシン結合グロブリン(TBG)、性ホルモン結合グロブリン(SHBG)、及び脂質バイオマーカーからなる群から選択されるバイオマーカーの発現レベルを測定することを含む、請求項1〜27のいずれか一項に記載の方法、使用のための化合物A、又は使用。
- 甲状腺軸ホルモンが、トリヨードチロニン(遊離T3)若しくはその代謝物、リバースT3若しくはその代謝物、遊離チロキシン(T4)若しくはその代謝物、チロトロピン(TSH)若しくはその代謝物、チロトロピン放出ホルモン(TRH)若しくはその代謝物、又はこれらの組合せである、請求項28に記載の方法、使用のための化合物A、又は使用。
- 脂質バイオマーカーが、総コレステロール、トリグリセリド、低密度リポタンパク質コレステロール(LDL−C)、高密度リポタンパク質コレステロール(HDL−C)、非HDL−C、リポタンパク質(a)、アポリポタンパク質A1(ApoA−1)及びアポリポタンパク質B(ApoB)からなる群から選択される、請求項28に記載の方法、使用のための化合物A、又は使用。
- 生物学的試料が、血液又は血清の試料である、請求項1〜30のいずれか一項に記載の方法、使用のための化合物A、又は使用。
- 有効量が、5mg〜300mgの範囲である、請求項1〜31のいずれか一項に記載の方法、使用のための化合物A、又は使用。
- 有効量が、約40mg、約50mg、約80mg、約100mg、約120mg、約140mg、約160mg、約180mg又は約200mgである、請求項1〜32のいずれか一項に記載の方法、使用のための化合物A、又は使用。
- 第1の用量が、約5mg〜300mgの範囲である、請求項1〜33のいずれか一項に記載の方法、使用のための化合物A、又は使用。
- 第1の用量が、約40mg、約50mg、約80mg、約100mg、約120mg、約140mg、約160mg、約180mg又は約200mgである、請求項1〜34のいずれか一項に記載の方法、使用のための化合物A、又は使用。
- 第2の用量が、第1の用量よりも低い、請求項1〜35のいずれか一項に記載の方法、使用のための化合物A、又は使用。
- 第2の用量が、第1の用量と同じである、請求項1〜35のいずれか一項に記載の方法、使用のための化合物A、又は使用。
- 第2の用量が、第1の用量よりも高い、請求項1〜35のいずれか一項に記載の方法、使用のための化合物A、又は使用。
- 第2の用量が、約5mg〜300mgの範囲である、請求項1〜38のいずれか一項に記載の方法、使用のための化合物A、又は使用。
- 第2の用量が、約40mg、約50mg、約80mg、約100mg、約120mg、約140mg、約160mg、約180mg又は約200mgである、請求項1〜39のいずれか一項に記載の方法、使用のための化合物A、又は使用。
- 化合物Aが、約10.5、18.7、22.9、23.6、及び24.7度2θでのピークを含むX線粉末回折パターンを特徴とする形態型である、請求項1〜40のいずれか一項に記載の方法、使用のための化合物A、又は使用。
- 第1の期間が、2〜21日の範囲である、請求項1〜41のいずれか一項に記載の方法、使用のための化合物A、又は使用。
- 化合物Aが、ゲル、錠剤、丸剤又はカプセル中に製剤化される、請求項1〜42のいずれか一項に記載の方法、使用のための化合物A、又は使用。
- 化合物Aが経口的に投与される、請求項1〜43のいずれか一項に記載の方法、使用のための化合物A、又は使用。
- 化合物Aが毎日投与される、請求項1〜44のいずれか一項に記載の方法、使用のための化合物A、又は使用。
- 脂質障害が、ヘテロ接合型家族性高コレステロール血症(HeFH)又はホモ接合型家族性高コレステロール血症(HoFH)である、請求項1〜45のいずれか一項に記載の方法、使用のための化合物A、又は使用。
- 薬物代謝酵素が、酸化的薬物代謝酵素又は共役的薬物代謝酵素である、請求項1〜46のいずれか一項に記載の方法、使用のための化合物A、又は使用。
- 化合物Aが、1日1回、1日2回、又は1日3回投与される、請求項1〜47のいずれか一項に記載の方法、使用のための化合物A、又は使用。
- 対象が、少なくとも1つの他の治療剤を投与される又は投与されたことがある、請求項1〜48のいずれか一項に記載の方法、使用のための化合物A、又は使用。
- 少なくとも1つの他の治療剤がスタチンである、請求項49に記載の方法、使用のための化合物A、又は使用。
- 薬物動態学的試験が、第1の用量の投与の後の所定の時間に生物学的試料中の化合物Aの代謝物のレベルを測定することを含む、請求項1〜50のいずれか一項に記載の方法、使用のための化合物A、又は使用。
- 所定の時間が少なくとも20分である、請求項51又は52に記載の方法、使用のための化合物A、又は使用。
- 代謝物が、約100ng/mL〜1000ng/mLの最大血漿濃度の相乗平均を有する、請求項51〜53のいずれか一項に記載の方法、使用のための化合物A、又は使用。
- 最大血漿濃度の相乗平均が、約150ng/mL〜700ng/mLである、請求項54に記載の方法、使用のための化合物A、又は使用。
- 肝臓障害又は脂質障害の治療を必要とする対象における肝臓障害又は脂質障害を治療治療する方法であって、対象に毎日2−(3,5−ジクロロ−4−((5−イソプロピル−6−オキソ−1,6−ジヒドロピリダジン−3−イル)オキシ)フェニル)−3,5−ジオキソ−2,3,4,5−テトラヒドロ−1,2,4−トリアジン−6−カルボニトリルの有効量を投与することを含み、ここで、対象は医薬の投与の後に臨床モニタリングを必要としない、方法。
- 有効量が、5mg〜300mgの範囲である、請求項56に記載の方法。
- 臨床モニタリングが、骨スキャン、心臓スキャン及び脳スキャンからなる群から選択される、請求項56又は57に記載の方法。
- 肝臓障害又は脂質障害の治療を必要とする対象における、肝臓障害又は脂質障害を治療する際における使用のための、2−(3,5−ジクロロ−4−((5−イソプロピル−6−オキソ−1,6−ジヒドロピリダジン−3−イル)オキシ)フェニル)−3,5−ジオキソ−2,3,4,5−テトラヒドロ−1,2,4−トリアジン−6−カルボニトリル(「化合物A」)であって、ここで、対象は医薬の投与の後に臨床モニタリングを必要としない、化合物A。
- 臨床モニタリングが、骨スキャン、心臓スキャン及び脳スキャンからなる群から選択される、請求項59に記載の使用のための化合物A。
- 肝臓障害又は脂質障害の治療を必要とする対象における肝臓障害又は脂質障害を治療する方法における使用のための医薬の製造における、2−(3,5−ジクロロ−4−((5−イソプロピル−6−オキソ−1,6−ジヒドロピリダジン−3−イル)オキシ)フェニル)−3,5−ジオキソ−2,3,4,5−テトラヒドロ−1,2,4−トリアジン−6−カルボニトリル(「化合物A」)の使用であって、ここで、対象は医薬の投与の後に臨床モニタリングを必要としない、使用。
- 臨床モニタリングが、骨スキャン、心臓スキャン及び脳スキャンからなる群から選択される、請求項61に記載の使用。
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Families Citing this family (24)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP3689853B1 (en) | 2012-09-17 | 2021-11-24 | Madrigal Pharmaceuticals, Inc. | Method of synthesizing thyroid hormone analogs and polymorphs thereof |
SI3730487T1 (sl) | 2016-06-13 | 2022-08-31 | Gilead Sciences, Inc. | Azetidinski derivati kot modulatorji FXR (NR1H4) |
CA2968836A1 (en) | 2016-06-13 | 2017-12-13 | Gilead Sciences, Inc. | Fxr (nr1h4) modulating compounds |
WO2018075650A1 (en) | 2016-10-18 | 2018-04-26 | Madrigal Pharmaceuticals, Inc. | Methods of treating liver disorders or lipid disorders with a thr-beta agonist |
CA3055581C (en) | 2017-03-28 | 2023-03-14 | Gilead Sciences, Inc. | Methods of treating liver disease |
JP7181386B2 (ja) * | 2018-06-12 | 2022-11-30 | スーチョワン ハイスコ ファーマスーティカル カンパニー リミテッド | 甲状腺ホルモン受容体アゴニスト及びその用途 |
US20210292304A1 (en) * | 2018-06-22 | 2021-09-23 | Hinova Pharmaceuticals Inc. | Deuterated mgl-3196 compound and use thereof |
AR115666A1 (es) * | 2018-07-02 | 2021-02-10 | Madrigal Pharmaceuticals Inc | Formas sólidas de 2-(3,5-dicloro-4-((5-isopropil-6-oxo-1,6-dihidropiridazin-3-il)oxi)fenil)-3,5-dioxo-2,3,4,5-tetrahidro-1,2,4-triazin-6-carbonitrilo |
KR20210057758A (ko) * | 2018-09-06 | 2021-05-21 | 갈메드 리서치 앤드 디벨롭먼트 리미티드 | 간 질환을 치료하기 위한 병용 요법 |
MA53868A (fr) | 2018-10-12 | 2021-08-18 | Terns Inc | Composés agonistes du récepteur bêta des hormones thyroïdiennes |
CN111320609A (zh) * | 2018-12-13 | 2020-06-23 | 拓臻股份有限公司 | 一种THRβ受体激动剂化合物及其制备方法和用途 |
HRP20240265T1 (hr) * | 2019-01-15 | 2024-05-10 | Gilead Sciences, Inc. | Spoj izoksazola kao fxr agonist i farmaceutski pripravci koji ga sadrže |
US11524005B2 (en) | 2019-02-19 | 2022-12-13 | Gilead Sciences, Inc. | Solid forms of FXR agonists |
WO2020169069A1 (en) | 2019-02-21 | 2020-08-27 | Nanjing Ruijie Pharma Co., Ltd. | Novel compounds and their uses as thyroid hormone receptor agonists |
US11091467B2 (en) | 2019-05-08 | 2021-08-17 | Aligos Therapeutics, Inc. | Modulators of THR-β and methods of use thereof |
CA3154488A1 (en) * | 2019-08-23 | 2021-03-04 | Terns Pharmaceuticals, Inc. | Thyroid hormone receptor beta agonist compounds |
WO2021050945A1 (en) * | 2019-09-12 | 2021-03-18 | Terns, Inc. | Thyroid hormone receptor beta agonist compounds |
WO2021063367A1 (zh) * | 2019-09-30 | 2021-04-08 | 苏州科睿思制药有限公司 | 一种Resmetirom晶型及其制备方法和用途 |
US20230089582A1 (en) * | 2019-11-26 | 2023-03-23 | Kpc Pharmaceuticals, Inc | 1,2,4-triazine-3,5-dione compound, preparation method therefor, and application thereof |
CN111562321B (zh) * | 2020-04-16 | 2022-10-28 | 广东省结核病控制中心 | 用于检测活动性肺结核的粪便代谢物及其检测系统 |
AU2021341182A1 (en) * | 2020-09-10 | 2023-04-27 | Crystal Pharmaceutical (Suzhou) Co., Ltd. | Crystal form of resmetirom, preparation method therefor, and use thereof |
US20230364099A1 (en) | 2020-10-19 | 2023-11-16 | Teva Pharmaceuticals International Gmbh | Solid state forms of resmetirom |
AU2022213405A1 (en) * | 2021-02-01 | 2023-08-03 | Madrigal Pharmaceuticals, Inc. | Therapeutic combinations of rosuvastatin and resmetirom for the treatment of liver disorders or lipid disorders |
EP4373476A1 (en) * | 2021-07-21 | 2024-05-29 | Cyta Therapeutics, Inc. | Particle delivery of thyroid hormone receptor agonists and antagonists |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2015123256A1 (en) * | 2014-02-14 | 2015-08-20 | Cempra Pharmaceuticals, Inc. | Compositions and methods for treating diabetes and liver diseases |
Family Cites Families (13)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS5615272A (en) | 1979-07-17 | 1981-02-14 | Ishihara Sangyo Kaisha Ltd | N-benzoyl-n'-phenylurea compound, its preparation, and insecticide containing the same |
US4522811A (en) | 1982-07-08 | 1985-06-11 | Syntex (U.S.A.) Inc. | Serial injection of muramyldipeptides and liposomes enhances the anti-infective activity of muramyldipeptides |
JP4485520B2 (ja) | 2003-03-24 | 2010-06-23 | エフ.ホフマン−ラ ロシュ アーゲー | 逆転写酵素阻害剤としてのベンジル−ピリダジノン類 |
ITRM20030363A1 (it) | 2003-07-24 | 2005-01-25 | Fernando Goglia | Composizioni comprendenti la 3, 5diiodotironina e uso farmaceutico di esse. |
US20060229267A1 (en) | 2004-06-01 | 2006-10-12 | Reza Sheikhnejad | Methods and compositions for the inhibition of gene expression |
US7807647B2 (en) | 2004-06-01 | 2010-10-05 | Pronai Therapeutics, Inc. | Methods and compositions for cancer therapy |
ATE480524T1 (de) | 2005-07-21 | 2010-09-15 | Hoffmann La Roche | Pyridazinonderivate als schilddrüsenhormon- rezeptoragonisten |
EA019084B1 (ru) | 2007-06-06 | 2014-01-30 | Торрент Фармасьютикалс Лтд. | Новые тиреоидные соединения для лечения заболеваний, связанных с нарушением обмена веществ |
US8076334B2 (en) | 2007-09-20 | 2011-12-13 | Hoffmann-La Roche Inc. | Prodrugs of thyroid hormone analogs |
EP3689853B1 (en) | 2012-09-17 | 2021-11-24 | Madrigal Pharmaceuticals, Inc. | Method of synthesizing thyroid hormone analogs and polymorphs thereof |
US8858502B2 (en) | 2012-10-10 | 2014-10-14 | Alcon Research, Ltd. | Systems and methods for external pressure sensing |
WO2018075650A1 (en) | 2016-10-18 | 2018-04-26 | Madrigal Pharmaceuticals, Inc. | Methods of treating liver disorders or lipid disorders with a thr-beta agonist |
AR115666A1 (es) | 2018-07-02 | 2021-02-10 | Madrigal Pharmaceuticals Inc | Formas sólidas de 2-(3,5-dicloro-4-((5-isopropil-6-oxo-1,6-dihidropiridazin-3-il)oxi)fenil)-3,5-dioxo-2,3,4,5-tetrahidro-1,2,4-triazin-6-carbonitrilo |
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Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2015123256A1 (en) * | 2014-02-14 | 2015-08-20 | Cempra Pharmaceuticals, Inc. | Compositions and methods for treating diabetes and liver diseases |
Non-Patent Citations (2)
Title |
---|
JOURNAL OF MEDICINAL CHEMISTRY, vol. 57, JPN6021030590, 2014, pages 3912 - 3923, ISSN: 0005063663 * |
THE NEW ENGLAND JOURNAL OF MEDICINE, vol. 361, JPN7022001702, 2009, pages 1152 - 1163, ISSN: 0005063664 * |
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IL302336A (en) | 2023-06-01 |
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WO2018075650A1 (en) | 2018-04-26 |
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KR20190109387A (ko) | 2019-09-25 |
US20210330675A1 (en) | 2021-10-28 |
CN110167557A (zh) | 2019-08-23 |
EP4112056A1 (en) | 2023-01-04 |
US11806353B2 (en) | 2023-11-07 |
US20240156826A1 (en) | 2024-05-16 |
AU2017346871A1 (en) | 2019-05-02 |
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