JP2019536758A - アシル化インスリン化合物 - Google Patents
アシル化インスリン化合物 Download PDFInfo
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- JP2019536758A JP2019536758A JP2019520536A JP2019520536A JP2019536758A JP 2019536758 A JP2019536758 A JP 2019536758A JP 2019520536 A JP2019520536 A JP 2019520536A JP 2019520536 A JP2019520536 A JP 2019520536A JP 2019536758 A JP2019536758 A JP 2019536758A
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- insulin
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Landscapes
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Abstract
Description
式中、Xaaは、アミノ酸のグリシンまたはアスパラギンである、化合物を含む。
化合物12および19ならびに対照化合物(生合成ヒトインスリン、およびインスリン様成長因子1(IGF−1))を、ヒトインスリン受容体(hIR)およびヒトIGF−1受容体(hIGF−1R)シンチレーション近接アッセイ(SPA)組換えhIR−A、hIR−BまたはhIGF−1Rを過剰発現させて安定にトランスフェクトした293HEK細胞からの分画遠心分離工程を使用して調製された膜を使用した競合放射性リガンド結合アッセイで試験する。
インスリン受容体は、リガンド結合時にそれ自体のチロシン残基を自己リン酸化して、インスリンシグナル伝達経路を誘導するように作用するアダプタータンパク質の動員を可能にする細胞内チロシンキナーゼドメインを含有する。受容体の刺激チロシン残基上の自己リン酸化についての機能的細胞活性は、それぞれがC末端C9エピトープ(TETSQVAPA、配列番号5)を有する、hIR−A、hIR−B、またはhIGF−1Rを過剰発現する293HEK細胞のリガンド処理後に測定される。
化合物12および19の効果を、ストレプトゾトシン(STZ)で処理されたラット糖尿病モデルにおいて検証する。400〜425グラムの体重の雄のSprague−Dawleyラットを、Envigo、Indianapolis、Indianaから入手する。約1週間、馴化させた後、ラットをイソフルランで麻酔し、Zanosar(登録商標)(商品番号89256、Teva Parenteral Medicines、40mg/kg、IV)を1回注射する。Zanosarの注射から3日後に、ラットを試験に使用し、非空腹時の血糖値が400〜550mg/dlである動物のみ、これらの試験に使用する。
糖尿病(アロキサン誘発)の、去勢された、事前に血管アクセスを装着した雄のユカタンミニブタを拘束のためにスリングに入れ、アクセスし(血液採取のために備え)、かつ開通性をチェックしたそれらの血管アクセスポートを有する。動物を無作為に処置群に入れ、それらのペンに戻す。2つのベースライン血液試料を採取した後(−30分および0分)、動物は、試験物を1.8nmol/kgで、インシュリン注射器(0.3ml5/16インチの針)を用いて側腹部に皮下注射される(0分)。全ての試験動物は、残りの採血期間を通して、清潔で新鮮な水を自由に摂取する。
試料は、化合物12および19の凍結乾燥粉末を20mM NaOHに目標濃度約6mMで溶解することによって調製される。次いで、この溶液を10mMトリスに対して透析し、5.6mMの原液濃度を得る。次いで、この原液を使用して、pH7.5で、10mMのトリス、19mg/mLのグリセロール、3.15mg/mLのm−クレゾール、および4つの亜鉛/インスリン六量体(モル基準)を含有する目標濃度の溶液を調製する。目標濃度は、U200(200単位/mL、これは1.2mMに相当する)、U400(2.4mM)、U600(3.6mM)およびU800(4.8mM)であった。溶液の実際の濃度は、目標濃度レベルの0.1mM以内であった。安定性試験のための化合物12および19の試料と同じ方法で、比較剤であるインスリンデグルデックの試料を調製する。
A鎖の一般構造(配列番号1)
GIVEQCCTSICSLYQLENYCXaa
ここで、配列番号1の21位のXaaは、GまたはNである。
GIVEQCCTSICSLYQLENYCG
GIVEQCCTSICSLYQLENYCN
FVNQHLCGSHLVEALYLVCGERGFFYTPKT
TETSQVAPA
Claims (13)
- 下記式:
(式中、Xaaは、アミノ酸のグリシンまたはアスパラギンである)の化合物。 - Xaaが、アミノ酸のグリシンである、請求項1に記載の化合物。
- Xaaが、アミノ酸のアスパラギンである、請求項1に記載の化合物。
- 請求項1〜3に記載の化合物と1つ以上の薬学的に許容される賦形剤とを含む薬学的組成物。
- 患者における糖尿病を治療する方法であって、それを必要とする患者に、有効量の、請求項1〜3に記載の化合物または請求項4に記載の組成物を投与することを含む、方法。
- 患者における高血糖症を治療する方法であって、それを必要とする患者に、有効量の、請求項1〜3に記載の化合物または請求項4に記載の組成物を投与することを含む、方法。
- 治療に使用するための、請求項1〜3に記載の化合物。
- 糖尿病の治療に使用するための、請求項1〜3に記載の化合物。
- 高血糖症の治療に使用するための、請求項1〜3に記載の化合物。
- 下記式を有する化合物。
- 糖尿病の治療のための薬剤の製造における、請求項1〜3に記載の化合物の使用。
- 高血糖症の治療のための薬剤の製造における、請求項1〜3に記載の化合物の使用。
- 請求項1〜3のいずれか一項に記載の化合物の調製または製造における、請求項10に記載の化合物の使用。
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