JP2020525548A - 炎症反応を伴う疼痛状態における鎮痛のための末梢限局的二重作用性κおよびδオピオイドアゴニスト - Google Patents
炎症反応を伴う疼痛状態における鎮痛のための末梢限局的二重作用性κおよびδオピオイドアゴニスト Download PDFInfo
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Abstract
Description
本出願は、2017年7月6日に出願された米国特許仮出願第62/529,285号の優先権および恩恵を主張し、その内容は、その全体が参照により本明細書に組み入れられる。
本開示は、疼痛(例えば、炎症性疼痛)の処置のための二重作用性オピオイドアゴニストの使用を教示する。オピオイドは、κオピオイド受容体とδオピオイド受容体の両方を活性化して、疼痛の相乗的低減、すなわち二重アゴニズムをもたらす。
オピオイド鎮痛剤は、疼痛の処置に有用な鎮痛剤であり得る。ヘロインおよびモルヒネなどのこれらの薬物は、中枢神経系のμオピオイド受容体(MOR)におけるアゴニストである。しかし、これらの薬物は中枢神経系への血液脳関門を通過することができるので、それらの使用は、嗜癖などの望まれない副作用を引き起こし得る。さらに、すべての疼痛がMORによって媒介されるとは限らないので、これらの薬物は、ある特定のタイプの疼痛の処置にとっては部分的にしか有効でない可能性もある。したがって、モルヒネなどの従来のオピオイドの副作用を来さない、疼痛(例えば、慢性および/または炎症性疼痛)の処置のための安全かつ有効な鎮痛剤が必要である。
本開示の一局面は、その必要がある対象において疼痛を処置する方法であって、治療的有効量の化合物1
またはその薬学的に許容される塩、プロドラッグ、溶媒和化合物、水和物、互変異性体、もしくは異性体を対象に投与することを含む方法に関する。
またはその薬学的に許容される塩、プロドラッグ、溶媒和化合物、水和物、互変異性体、もしくは異性体を対象に投与することを含む方法に関する。
オピオイド鎮痛剤は、利用可能な最も重要かつ強力な鎮痛剤の1つである。多くの既存の調製物はそれらの活性を、中枢神経系(すなわち、脳および脊髄)中のμオピオイド受容体に依存している。残念ながら、中枢神経系におけるμオピオイドのアゴニズムは、命に関わる呼吸抑制および嗜癖を含む、オピオイド鎮痛と関連する重大な有害作用の原因であり得る。さらに、μオピオイドのアゴニズムは、精神機能障害、傾眠、悪心および便秘を含む、他の厄介な副作用の原因であり得る。
便宜上、本明細書、実施例および特許請求の範囲で用いられるある特定の用語を、ここに集める。別段規定されない限り、本開示で使用されるすべての技術用語および科学用語は、本開示が属する分野の当業者が一般に理解するものと同じ意味を有する。別段指示がない限り、本開示で提供されるある群または用語について提供される最初の定義は、本開示の全体を通して、個々にまたは別の群の一部として、その群または用語に適用する。
本明細書において使用する場合、化合物1は、4-(((2S,5S,8S)-2-イソブチル-8-イソプロピル-1-フェネチル-2,3,5,6,8,9-ヘキサヒドロ-1H-ジイミダゾ[1,2-d:2',1'-g][1,4]ジアゼピン-5-イル)メチル)フェノールとして理解される。化合物1は、κ受容体およびδ受容体に対してアゴニスト活性を有する末梢限局的オピオイドであり、化合物1の構造を以下に示す:
。
図1は、化合物1に関する提案される作用機構を記載する。理論に拘束されることを望むものではないが、図1Aは、非炎症組織についての提案されるネイティブ状態を示す。図1Aに示すように、Gタンパク質共役受容体キナーゼ-2(GRK2)はδオピオイド受容体(DOR)に結合することができ、DORを不活性化する。したがって、DORは非炎症状態における疼痛の感覚に影響を及ぼさない。
理論に拘束されることを望むものではないが、実施例1に記載のように、マウスにおける疼痛評価の標準モデルで、マウスをホルマリンで処理した。理論に拘束されることを望むものではないが、マウスにおけるホルマリン試験は、2相で疼痛を評価する。第1相は、マウスの後足に注射した後、約5〜10分間続く可能性がある。第1相は、ホルマリン(刺激性物質)注射の直後の急性疼痛に対するマウスの応答を評価することができる。したがって、いくつかの態様では、ホルマリンモデルの第1相は、侵害受容器の刺激によって引き起こされる疼痛を評価することができる(すなわち、第1相は侵害受容性または急性の疼痛を評価することができる)。
以下の実施例2は、ラットにおける関節リウマチのモデルで、化合物1の単回腹腔内(IP)注射の効力を評価した。実施例2で示すように、単回腹腔内用量の化合物1は、ラットにおいて、CFA誘導性関節リウマチが原因の確立された機械的痛覚過敏を、時間および用量依存的に、有意に低減した。
以下の実施例3は、ラットにおける神経障害性疼痛についての脊髄神経結紮(SNL)モデルで、化合物1および比較物であるガバペンチンの単回腹腔内注射の効力を評価した。実施例3で示すように、化合物1の腹腔内注射は、ラットのSNL誘導性神経障害性疼痛と関連する機械的痛覚過敏に対して、時間および用量依存的鎮痛効果を生じさせた。
理論に拘束されることを望むものではないが、以下の実施例4は、ラットにおける溶骨性癌の疼痛のMRMT-1モデルで、化合物1の単回腹腔内注射および比較物の皮下モルヒネの効力を評価した。実施例4に示すように、10mg/kg(IP)で投与された化合物1は、MRMT-1の播種によって誘導される溶骨性骨癌疼痛に対して有意な効果があり、モルヒネと比較して発症が遅くなった。
したがって、いくつかの態様では、化合物1は、疼痛の処置で使用することができる。疼痛は、対象における、炎症性疼痛、または炎症反応の開始によって引き起こされる疼痛であり得る。いくつかの態様では、疼痛は、自己免疫障害または他の炎症性障害が原因であり得る。いくつかの態様では、疼痛は関節炎が原因であり得る。例えば、疼痛は、関節リウマチ、変形性関節症(例えば、滑膜炎を伴う変形性関節症)、外傷後の関節炎、または炎症性関節炎が原因であり得る。
本開示は、本開示の化合物1のまたは化合物1を含む薬学的組成物の投与を含む処置方法にも関する。本明細書において記載される薬学的組成物または調製物は、例えば、疼痛(例えば、炎症性疼痛)または痛覚過敏の処置のために、本開示に従って使用することができる。
化合物1および/またはその薬学的に許容される塩の投与の量および回数は、患者の年齢、状態、およびサイズ、ならびに処置される症状の重症度などの因子を考慮して、担当臨床医の判断に従って調節される。化合物1の有効投薬量は、示される効果のために使用される場合、状態を処置する必要に応じて、約0.5mg〜約5000mgの化合物1の範囲にわたる。インビボまたはインビトロでの使用のための組成物は、約0.5、5、20、50、75、100、150、250、500、750、1000、1250、2500、3500、もしくは5000mgの化合物1、または用量のリストにおけるある量から別の量までの範囲の化合物1を含むことができる。経口投与のための典型的な推奨される1日の投薬レジメンは、単回用量で、または2〜4分割用量で、約1mg/日〜約500mg/日、または1mg/日〜200mg/日の範囲にわたり得る。一態様では、1日の用量レジメンは150mgである。
本研究の目的は、マウスにおけるホルマリン誘起性自発的侵害受容性行動に対する化合物1および末梢限局的κアゴニスト(ICI204448)の効果を評価することであった。本研究は、ホルマリン誘導性侵害受容性行動のビデオ記録、次いで、コンピューターを使用するオフラインのスコア化によって行った。
IACUCの承認および順化の後に、20〜30gのC57BL6マウス(Charles River Canada Inc.)を、表1に示すように、1群当たり8匹のマウスを有する群に無作為に割り当てた。
図2Aおよび2Bは、それぞれ、各用量のビヒクルまたは薬物が与えられたマウスが示す疼痛行動の折れ線グラフおよび棒グラフを示す。図2Aおよび2Bに示すように、不活性なビヒクルおよびICI204448と比較して、化合物1は、約20〜25分、25〜30分、および30〜35分(すなわち、第2相)において、ホルマリンで処理したマウスの疼痛行動を低減した。さらに、高用量のICI204448と同じ効果をもたらすのに、小用量の化合物1(1mg/kg)しか必要でなかった。さらに、高用量の化合物1(10mg/kg)は、マウスの疼痛応答を完全に取り除くことが示された。用量の関数としてのp値の比較を以下の表2に示す。
本研究は、ラットにおける関節リウマチ性疼痛のCFA(完全フロイントアジュバント)モデルの痛覚過敏性侵害受容性行動に対する、化合物1の単回腹腔内注射の効力を評価した。
動物の選択
統計的検定力計算機(statistical power calculator)(Massachusetts General Hospital on-line power calculator, http://hedwig.mgh.harvard.edu/sample_size/size.html)を使用して、解釈可能かつ再現性のある結果を保証するのに適切な群サイズを決定した。以前の研究由来のデータを計算機に入力し、80%の検定力および51gの標準偏差で、68gの関節圧迫閾値差に基づいて群サイズを計算した。これらのパラメーターにより、10という群サイズの計算になった。
IACUCの承認および順化の後に、50μLの100%完全フロイントアジュバント(CFA)を左後脚の脛骨足根骨関節中へ滑液包内注射することによって、55匹の雄のSprague-Dawleyラットにおいて炎症性関節炎痛を誘導した。機械的痛覚過敏は関節圧迫閾値(JCT)によって評価した。JCTは、研究物の投与に先立って、CFA注射の前およびCFA後14日目に決定した。その時に、組み入れ基準を満たした50匹の動物を、1群当たり10匹の動物を有する5群に無作為に割り当てた(表3)。関節炎痛のモデルとしての妥当性をさらに確認するために、抗炎症性シクロオキシゲナーゼ-2阻害剤、セレコキシブを活性対照として使用した。
機械的痛覚過敏の発生:
CFA誘導性関節リウマチ性疼痛が原因の機械的痛覚過敏の発生を検証するために、CFA注射より前、0日目の投薬前、ならびに投薬後の1、2、および4時間目に、同側および対側の関節圧迫閾値(JCT)を評価した。以下の図4および表4に示すように、各時点で、独立t検定を使用して、同側JCTを対側JCTと比較した。図4に示すように、同側JCTはCFA後のすべての時点で有意に低く、これは、CFA注射が原因の持続性機械的痛覚過敏を示す。
CFA注射から14日後、0日目に、投薬前ベースライン(試験物および対照物の投与の前)、ならびに試験物および対照物の投薬後の1、2、および4時間目で、機械的痛覚過敏を評価した。ビヒクルもしくは化合物1のいずれかの腹腔内注射、またはセレコキシブの経口的強制投与を動物に行った。図5に示すように、化合物1の3用量(1、5、および10mg/kg)のすべては、2時間および4時間の時点で機械的痛覚過敏を有意に逆転させたが、10mg/kg用量は、試験した3時点(投与後1、2、および4時間)のすべてで機械的痛覚過敏を有意に逆転させた。
本研究は、ラットにおける神経障害性疼痛についての脊髄神経結紮(SNL)モデルで、化合物1および比較物であるガバペンチンの単回腹腔内注射の効力を評価した。ラットは、ラットおよびヒトの末梢および中枢神経系の多くの類似性が理由で、疼痛の研究のための信頼できる動物モデルとして使用されている。これらの類似性は、両方の種における、有痛性状態に対する行動性応答の点と様々な治療剤(すなわち、オピエートおよび非ステロイド性抗炎症薬物)の疼痛軽減効果の点との両方から明らかである。さらに、ラットは、神経障害性疼痛の効果を調べる場合に必要な脊椎動物である。
動物の選択
統計的検定力計算機(Massachusetts General Hospital on-line power calculator, http://hedwig.mgh.harvard.edu/sample_size/size.html)を使用して、解釈可能かつ再現性のある結果を保証するのに適切な群サイズを決定した。以前の研究由来のデータを計算機に入力し、80%の検定力(対照の平均=3.42、処置の平均=7.92、標準偏差=2.1)で、4.5グラムの閾値差に基づいて群サイズを計算した。これらの入力データにより、10という群サイズの計算になった。
IACUCの承認および順化の後に、脊髄神経結紮(SNL)としても公知の手順である、第5および第6腰椎神経(L5およびL6)を外科的に結紮することによって、55匹の雄のSprague-Dawleyラットにおいて神経障害を誘導した。デジタルRandall-Selitto装置を使用して、機械的感度を足圧迫閾値によって評価した。閾値は、研究物の投与に先立って、手術前および手術後15日目に決定した。その時に、組み入れ基準を満たした50匹の動物を、1群当たり10匹の動物を有する5群に割り当てた(表5)。神経障害性疼痛のモデルとしての妥当性をさらに確認するために、ガバペンチンを活性対照として使用した。
痛覚過敏の発生:
SNL手術が原因の機械的痛覚過敏の発生を検証するために、SNL手術より前、0日目の投薬より前のSNL手術後、ならびに0日目の投薬後の1、2、および4時間目に、同側および対側の足圧迫閾値を評価した。各時点で、独立t検定を使用して、同側足圧迫閾値を対側足圧迫閾値と比較した。図6および表6に示すように、同側足圧迫閾値は、SNL後のすべての時点で有意に低く、これは、SNL手術が原因の持続性機械的痛覚過敏を示す。
SNL手術から15日後、研究0日目に、投薬前ベースライン(試験物および対照物の投与の前)、ならびに試験物および対照物の投薬後の1、2、および4時間目で、機械的痛覚過敏を評価した。ビヒクル([1部]エタノール、[1部]Tween 80、[8部]通常の0.9%生理食塩水)、化合物1、またはガバペンチンのいずれかの腹腔内注射を動物に行った。1mg/kg用量の化合物1は、試験した時点のいずれにおいても、機械的痛覚過敏を有意には逆転させなかった。図7に示すように、5mg/kgおよび10mg/kg用量の化合物1は、投薬後1時間の時点で、機械的痛覚過敏を有意には逆転させなかったが、投薬後2および4時間の時点で機械的痛覚過敏を有意に逆転させた。
本研究では、雌のSprague-Dawleyラットにおいて、MRMT-1モデルで誘導される溶骨性骨癌疼痛に対する試験物である化合物1の効果を研究した。本研究は、ラットにおける溶骨性癌の疼痛のMRMT-1癌細胞モデルで、化合物1の単回腹腔内注射および比較物の皮下モルヒネの効力を評価した。ラットは、ラットおよびヒトの末梢および中枢神経系の多くの類似性が理由で、疼痛の研究のための信頼できる動物モデルとして使用されている。これらの類似性は、両方の種における、有痛性状態に対する行動性応答の点と様々な治療剤(例えば、オピオイド、非ステロイド性抗炎症薬物、抗けいれん薬、および抗うつ剤)の点との両方から明らかである。ラットは、ヒトにおける治療剤の効力の予測可能性を判定するための最良の種の1つである。さらに、ラットは、手術後疼痛の影響の調査を可能にする脊椎動物である。
動物の選択
統計的検定力計算機(Massachusetts General Hospital on-line power calculator, http://hedwig.mgh.harvard.edu/sample_size/size.html)を使用して、90%の検定力および9の標準偏差で、体重負荷スコア(WBS)によって測定された14%の閾値差に基づいて、適切な群サイズを決定した(定量測定を用いる並行研究)。これらのパラメーターおよび以前の研究由来の入力データにより、1群当たり10匹の動物という群サイズの計算になった。
3000個の乳腺癌腫細胞(MRMT-1)を脛骨の髄内腔中に注射することによって、溶骨性骨癌を生じさせた。0日目に、ビヒクルまたは化合物1(10mg/kg)のいずれかを腹腔内投与で動物に与えた。モルヒネ(6mg/kg)は本研究の陽性対照として働き、これは、皮下注射によって投与した。骨癌疼痛は、播種前(研究日-21)、ならびに0日目の投与前(BL)、投与してから1、2、および4時間後に後肢の体重負荷スコア%(%WBS)を測定することによって評価した。
モデル作成:%WBSの有意な低下。
薬理学的評価期間全体を通して体重負荷の非対称性が存在することを評価するために、独立両側t検定を使用して、ビヒクル群の0日目の処置前ベースライン由来の後肢体重負荷スコアを播種前ベースラインと比較した。
本発明を上記の特定の態様と併せて説明してきたが、それらの多くの代替物、修正、および他の変形が当業者には明らかであろう。すべてのそのような代替物、修正、および変形は、本発明の趣旨および範囲の中に入ることが意図される。
Claims (25)
- 前記疼痛が、炎症反応の開始によって引き起こされる、請求項1記載の方法。
- 前記疼痛が痛覚過敏と関連する、前記請求項のいずれか一項記載の方法。
- 前記疼痛が慢性疼痛または亜急性疼痛である、前記請求項のいずれか一項記載の方法。
- 前記慢性疼痛が、関節炎痛、腰痛、神経障害性疼痛、内臓痛、癌が原因の疼痛、損傷が原因の疼痛、関節の炎症が原因の疼痛、背部障害が原因の疼痛、または頚部痛である、前記請求項のいずれか一項記載の方法。
- 癌が原因の前記疼痛が、腹腔内、腹部、および骨盤内器官に関与する癌、または骨癌もしくは骨転移によって引き起こされる、請求項5記載の方法。
- 損傷が原因の前記疼痛が、骨、靱帯、または腱の損傷によって引き起こされる、請求項5記載の方法。
- 化合物1が中枢神経系作用性オピオイドと同程度まで疼痛を低減させる、前記請求項のいずれか一項記載の方法。
- 前記中枢神経系作用性オピオイドがμ受容体を活性化する、請求項8記載の方法。
- 前記中枢神経系作用性オピオイドがモルヒネである、請求項8記載の方法。
- 化合物1の投与がいかなる中枢神経系副作用ももたらさない、前記請求項のいずれか一項記載の方法。
- 前記中枢神経系副作用が、嗜癖、便秘、鎮静、精神機能障害、傾眠、呼吸抑制、悪心、不快気分、または発作である、請求項11記載の方法。
- 化合物1の投与が便秘をもたらさない、請求項12記載の方法。
- 化合物1の投与が嗜癖をもたらさない、請求項12記載の方法。
- 化合物1が、κオピオイド受容体とδオピオイド受容体との相乗的活性化をもたらす、前記請求項のいずれか一項記載の方法。
- 相乗作用が、δ受容体活性によるκ受容体のアロステリック調節に起因する、請求項16記載の方法。
- 化合物1の投与が、急性疼痛の処置について、κ受容体アゴニストと同様であるか、またはそれより優れている、前記請求項のいずれか一項記載の方法。
- 化合物1の投与が、痛覚過敏の処置について、κ受容体アゴニストと同様であるか、またはそれより優れている、前記請求項のいずれか一項記載の方法。
- 化合物1の投与が、κ受容体アゴニストと比較して、低減した尿量をもたらす、前記請求項のいずれか一項記載の方法。
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CLIN J PAIN, vol. 26, no. 1, JPN6022013602, 2010, pages 10 - 15, ISSN: 0004874869 * |
JOURNAL OF MEDICINAL CHEMISTRY, vol. 58, JPN6022013607, 2015, pages 4905 - 4917, ISSN: 0004874865 * |
MEDCHEM NEWS, JPN6022013603, 2014, pages 22 - 26, ISSN: 0004874868 * |
THE JOURNAL OF NEUROSCIENCE, vol. 11, no. 4, JPN6022013596, 1991, pages 928 - 932, ISSN: 0004874870 * |
奥羽大歯学誌, vol. 30, no. 2, JPN6022013606, 2003, pages 115 - 126, ISSN: 0004874866 * |
歯学療法, vol. 33, no. 1, JPN6022013604, 2014, pages 1 - 9, ISSN: 0004874867 * |
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AU2018297214B2 (en) | 2022-09-01 |
JP7233741B2 (ja) | 2023-03-07 |
US20220288089A1 (en) | 2022-09-15 |
EP3649132A1 (en) | 2020-05-13 |
CN111278831A (zh) | 2020-06-12 |
IL271772A (en) | 2020-02-27 |
WO2019010014A1 (en) | 2019-01-10 |
CA3067398A1 (en) | 2019-01-10 |
US20210161912A1 (en) | 2021-06-03 |
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