JP2020535142A - 血清コレステロールおよびpcsk9を低減する組成物および方法 - Google Patents
血清コレステロールおよびpcsk9を低減する組成物および方法 Download PDFInfo
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Abstract
Description
この出願は、2017年9月25日に出願された米国仮出願第62/562,784号の優先権を主張し、その主題は参照によりその全体が本明細書に組み込まれる。
AKR1A1−/−マウスはDeltagen、Inc.によって作成された。C57BL6/JおよびApoE−/−マウスはジャクソン研究所から購入した。CETP−ApoB100トランスジェニックマウスは、Taconic Biosciencesから購入した。すべてのマウスは12時間の明/暗サイクルの下で維持した。イミレスタット治療研究のために、マウスには、対照食または0.0125%w/wイミレスタット(125mgイミレスタット/1kg食餌)を自由に含む食餌を与えた。C57BL6/JおよびApoE−/−マウスには、20週令から開始して4週間、対照飼料またはイミレスタット飼料を与え、CETP−ApoB100トランスジェニックマウスには、10週令から開始して8週間、対照飼料またはイミレスタット飼料を与えた。
安楽死の前に、マウスを示された時間断食させた。マウスを、下大静脈からの末期失血および重要臓器の除去を介して、イソフルラン麻酔下で安楽死させた。収集された血液は、小児用血清セパレーターチューブ内で、室温で20分間凝固させた。4℃、2000gで20分間遠心分離して血清を分離した。血清は分析まで−80℃で保存した。一晩絶食した12週令のAKR1A1−/−マウス(図5)については、コレステロール分析のために全血を大学病院の臨床研究所(OH、クリーブランド)に提供した。組織を液体窒素で急速冷凍し、分析まで−80℃で保存した。
総血清コレステロールは、標準的な酵素アッセイによって決定した。リポタンパク質コレステロールの定量化については、リポタンパク質画分をゲル濾過カラムクロマトグラフィーにより分離した。約70つの画分を収集し、各画分のコレステロールを標準的な酵素アッセイで定量化した。精製されたリポタンパク質画分を用いたカラムのキャリブレーションにより、様々なリポタンパク質種類のコレステロールの定量が可能になった。血清PCSK9は、固相サンドイッチELISAによって定量化した。
ヒトAKR1A1コード配列をpET21b細菌発現ベクターにクローニングした。pET21b−AKR1A1はRosetta2(DE3)pLysS大腸菌に変換され、A600nm=0.4で100μMイソプロピル−β−D−1−チオガラクトピラノシドを添加することにより発現を誘導した。細菌を25℃で4時間増殖させ、組換えHisタグ付きSCoRをNiアフィニティー精製により精製した。200nM組換えAKR1A1、100μM NADPH、100μM SNO−CoA、およびジメチルスルホキシド(DMSO)に溶解したイミレスタットの濃度を上げて、3回の反応を行った。SNO−CoAは、100μM EDTAと100μ MDTPAを含む1M HClと0.1M NaNO2水中で等量の0.1M CoAを反応させることで調製した。初期速度は、340nmでの吸光度の減少を使用して計算した。IC50は、非線形回帰分析を使用してGraphPad Prism7で計算した。食事療法後のイミレスタット治療後のAKR1A1肝臓活性について、凍結した肝臓組織を、100μMエチレンジアミン四酢酸(EDTA)とジエチレントリアミン五酢酸(DTPA)と150mM塩化ナトリウムを添加した50mMリン酸緩衝液、pH7.0で細かく均質化した(30オンス)。組織溶解物を20000gで45分間、4℃で遠心分離することにより清澄化した。清澄化した上澄みを収集し、遠心分離を繰り返した。肝臓溶解物における比活性のアッセイは、100μMSNO−CoA、100μM NADPH、100μM EDTA、および100μM DPTAを含む50mMリン酸緩衝液、pH7.0で行った。肝臓溶解物の添加により反応が開始され、340nmでの吸光度、タンパク質濃度、7.06mM−1・cm−1(SNO−CoAとNADPHの合計)の消衰係数の変化から比活性が計算された。
Claims (24)
- 血清コレステロールおよび/またはPCSK9レベルの低下を必要としている対象における血清コレステロールおよび/またはPCSK9レベルを低下させる方法であって、
ADH阻害剤、AKR阻害剤、および/またはSNO−CoAR阻害剤を、血清コレステロールおよび/またはPCSK9レベルを低下させるために有効な量で前記対象に投与することを含む、方法。 - 前記対象に投与される前記ADH阻害剤、AKR阻害剤、および/またはSNO−CoAR阻害剤が、(i)総血清コレステロールを、投与前レベルに対して、少なくとも約5%、約10%、約20%、約25%、約30%、約35%、約40%、約45%、約50%またはそれ以上減少させ、(ii)血清LDL−Cを、投与前レベルに対して、少なくとも約5%、約10%、約20%、約25%、約30%、約35%、約40%、約45%、約50%、約60%、約65%、約70%、約75%、約80%またはそれ以上減少させ、(iii)血清トリグリセリドを、投与前レベルに対して、少なくとも約5%、約10%、約20%、約25%、約30%、約35%、約40%、約45%、約50%減少させ、かつ/あるいは(iv)血清HDL−Cを減少させないか、または、血清HDL−Cを投与前レベルに対して約5%、約10%、約20%、約25%、約30%を超て減少させない、請求項1に記載の方法。
- 前記対象に投与される前記ADH阻害剤、AKR阻害剤、および/またはSNO−CoAR阻害剤が、HDL−Cレベルを低下させないか、または実質的に低下させない、請求項1に記載の方法。
- 前記ADH阻害剤、AKR阻害剤、および/またはSNO−CoAR阻害剤が、肝臓における脂質の蓄積をもたらさない、請求項1に記載の方法。
- 前記AKR阻害剤が選択的または部分的に選択的なAKR1A1阻害剤である、請求項1に記載の方法。
- 前記AKR1A1阻害剤が、2,7−ジフルオロ−2’H,5’H−スピロ[フルオレン−9,4’−イミダゾリジン]−2’,5’−ジオンおよびその類似体を含む、請求項5に記載の方法。
- イミレスタット類似体が、以下からなる群から選択される化合物であって、
- 前記AKR1A1阻害剤が、AKR1B1に対して、≧2倍、≧5倍、≧10倍、≧20倍、≧30倍、≧40倍、≧50倍またはそれ以上のAKR1A1の選択性を有することができる、請求項1に記載の方法。
- 前記対象が糖尿病を患っているかまたは糖尿病のリスクがあり、前記AKR阻害剤が選択的または部分的に選択的なAKR1B1阻害剤である、請求項1に記載の方法。
- 選択的または部分的に選択的なAKR1A1阻害剤が、選択的または部分的に選択的なAKR1B1阻害剤と組み合わせて投与される、請求項1に記載の方法。
- 前記AKR1B1阻害剤が、AKR1A1に対して、≧2倍、≧5倍、≧10倍、≧20倍、≧30倍、≧40倍、≧50倍またはそれ以上のAKR1B1の選択性を有することができる、請求項10に記載の方法。
- 血清コレステロールレベルが上昇している、または上昇するリスクがある対象を治療する方法であって、
前記対象の血清コレステロールおよび/またはPCSK9レベルを低下させるために有効な量で、AKR1A1阻害剤および/またはAKR1B1阻害剤を前記対象に投与することを含む、方法。 - 前記対象が、高コレステロール血症、多遺伝子性高コレステロール血症、混合型脂質異常症、冠状動脈性心疾患、急性冠症候群、早期発症型冠状動脈性心疾患、I型糖尿病、II型糖尿病、脂質異常症を伴うII型糖尿病、脂肪肝、非アルコール性脂肪性肝炎、非アルコール性脂肪肝疾患、高トリグリセリド血症、高脂肪酸血症、高脂血症、メタボリックシンドローム、アテローム性動脈硬化症、ApoBの上昇、コレステロールの上昇、LDLコレステロールの上昇、VLDLコレステロールの上昇、もしくは非HDLコレステロールの上昇、末梢血管疾患または脳卒中を有するか、またはそのリスクがある、請求項12に記載の方法。
- 前記上昇したLDLコレステロールレベルが、少なくとも約70mg/dL、100mg/dL、130mg/dL、160mg/dL、または190mg/dLの目標レベルを超える、請求項12に記載の方法。
- 前記AKR1A1阻害剤を投与することにより、少なくとも約190mg/dL、160mg/dL、130mg/dL、100mg/dL、70mg/dL、50mg/dL、または30mg/dLの目標レベルを下回るLDLコレステロールレベルがもたらされる、請求項12に記載の方法。
- AKR1A1阻害剤を投与することにより、ApoB、LDLコレステロール、VLDLコレステロール、非HDLコレステロール、肝臓トリグリセリドレベル、血清トリグリセリド、血清リン脂質、またはそれらの任意の組み合わせの減少がもたらされる、請求項12に記載の方法。
- 前記ApoB低下、前記LDLコレステロール低下、前記VLDLコレステロール低下、前記非HDLコレステロール低下、前記肝臓トリグリセリドレベル低下、前記血清トリグリセリド低下、または血清リン脂質低下のうちの少なくとも1つが、少なくとも10%、少なくとも15%、少なくとも20%、少なくとも25%、少なくとも30%、少なくとも35%、少なくとも40%、少なくとも45%、少なくとも50%、少なくとも55%、少なくとも60%、少なくとも65%、少なくとも70%、少なくとも75%、少なくとも80%、少なくとも85%、少なくとも90%、少なくとも95%、または少なくとも100%である、請求項16に記載の方法。
- 前記AKR阻害剤が選択的または部分的に選択的なAKR1A1阻害剤である、請求項12に記載の方法。
- 前記AKR1A1阻害剤が、2,7−ジフルオロ−2’H,5’H−スピロ[フルオレン−9,4’−イミダゾリジン]−2’,5’−ジオン、およびその類似体を含む、請求項18に記載の方法。
- 前記イミレスタット類似体が、以下からなる群から選択される化合物であって、
- 前記AKR1A1阻害剤が、AKR1B1に対して、≧2倍、≧5倍、≧10倍、≧20倍、≧30倍、≧40倍、≧50倍またはそれ以上のAKR1A1の選択性を有することができる、請求項18に記載の方法。
- 前記対象が糖尿病を有するかまたは糖尿病のリスクがあり、前記AKR阻害剤が選択的または部分的に選択的なAKR1B1阻害剤である、請求項12に記載の方法。
- 選択的または部分的に選択的なAKR1A1阻害剤が、選択的または部分的に選択的なAKR1B1阻害剤と組み合わせて投与される、請求項22に記載の方法。
- AKR1B1阻害剤が、AKR1A1に対して、≧2倍、≧5倍、≧10倍、≧20倍、≧30倍、≧40倍、≧50倍またはそれ以上のAKR1B1の選択性を有することができる、請求項23に記載の方法。
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