JP5744844B2 - 副甲状腺ホルモン(pth)受容体アゴニストとしての短鎖ペプチド - Google Patents
副甲状腺ホルモン(pth)受容体アゴニストとしての短鎖ペプチド Download PDFInfo
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- JP5744844B2 JP5744844B2 JP2012506651A JP2012506651A JP5744844B2 JP 5744844 B2 JP5744844 B2 JP 5744844B2 JP 2012506651 A JP2012506651 A JP 2012506651A JP 2012506651 A JP2012506651 A JP 2012506651A JP 5744844 B2 JP5744844 B2 JP 5744844B2
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- amino acid
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Description
本発明は、一般式(I)のPTH受容体アゴニストとしての新規の短鎖ペプチド、それらの医薬的に許容される塩、及びそれらを含む医薬組成物に関する。
骨粗鬆症は、減少した骨量、減少した骨ミネラル密度(BMD)、減少した骨強度により特徴付けられ、骨折の増大したリスクに関連する骨疾患である(Lane J. M., et al., Clin. Orthop. Relat. Res., 372, 2000, 139-150)。骨粗鬆症性骨折は、しばしば脊椎骨、寛骨、大腿骨首で起こる。これらの骨折は、痛み、長期にわたる不動性、及び乏しい回復により、生活の質を著しく損なう。骨は、いくつかの異なる細胞型を含む。骨芽細胞(骨形成)は、細胞の周りの細胞外環境に存在するミネラルから新しい骨を横たえる。破骨細胞(骨損失)は、古い骨を取り除き、骨内の蓄積されたミネラルを放出し、細胞外マトリックスに戻す。蓄えられる新しい骨と除去される古い骨の間の適切なバランスは、骨にその極めて有益な特性を与えるものである。骨粗鬆症は、骨形成の速度より骨吸収の速度が大きくなるときに起こる(Seeman E., et al., N. Engl. J. Med., 354(21), 2006, 2250-2261)。閉経後のエストロゲン減少は、エストロゲンは破骨細胞の寿命を破壊するので、女性の骨粗鬆症の最も一般的な原因である。骨粗鬆症の進行の他の主なリスク要因は以下:低カルシウム摂取、ビタミンD不足、1型糖尿病、関節リウマチ、抗けいれん剤及びコルチコステロイドなどの薬物の長期使用、男性のテストステロンの低いレベル、を含む(Cole Z. A., et al., Curr. Rheumatol. Rep., 10(2), 2008, 92-96; Harvey, N., et al., Curr. Rheumatol. Rep., 5(1), 2003, 75-81)。
PTH (1-34): 1SVSEIQLMHNLGKH14LNSMERVEWLRKKLQDVHNF34 (配列番号1)
PTH (1-11): 1SVSEIQLMHNL11 (配列番号2)
PTH (1-14): 1SVSEIQLMHNLGKH14 (配列番号3)
PTH (1-15): 1SVSEIQLMHNLGKHL15 (配列番号4)
アミノ酸の1文字略記は、Zubay, G著、Biochemistry 第2版、1988, MacMillan Publishing, New York, p. 33 で見られる。
一連の構造的に制御された副甲状腺ホルモンペプチド(PTH)アナログ、及び誘導体は、一般式Xaa1-Xaa11及び/又はXaa1-Xaa14であって、Xaa1-Xaa11及び/又はXaa1-Xaa14は、PTHペプチドの最初の1〜11及び/又は1〜14のN末端の残基を表し(SVSEIQLMHNL;配列番号2、及びSVSEIQLMHNLGKH;配列番号3)、Xaa1 及びXaa3は、Aib 又はAC5Cを表し, Xaa8はNleを表し、Xaa10はQを表し、Xaa11はHarを表し、Xaa12はAlaを表し、及びXaa14はWを表す、いくつかのアナログを伴う、と報告されている(WO 03 / 009804 A2; US 2006 / 7153951 B2; US 2007 / 0117157 A1; US 2007 / 0203071 A1; US 2006 / 0019902 A1; US 2007 / 0161569 A1; US 2007 / 0111946 A1; Gardella T. J., et al., J. Biol. Chem. 2000, 275, 21836-21843; Gardella T. J., et al., Endocrinology, 2001, 142, 3068-3074; Gardella T. J., et al., J. Biol. Chem., 2001, 52, 49003-49012)。近年、いくつかの非ペプチドPTHアゴニストはまた、文献において報告されているが、しかし、それらの中でインビボ動物モデルにおいて、可能性を有するものはないとみられた(US 2007 / 0099940 A1; WO 2005 / 077918 A1)。
本発明は、PTH/PTH-1受容体に対して異なる程度の親和性を有し、骨粗鬆症の治療のための有用である、PTH受容体のアゴニストとして機能する新規短鎖ペプチドの群を記述する。これらの短鎖ペプチドは、下記に与えられたような一般式(I)により定義される。本発明の短鎖ペプチドは、副甲状腺機能低下症、及び骨量減少又は骨量損失、例えば骨粗鬆症、閉経後骨粗鬆症など、によって特徴付けられる疾患の治療又は予防のため、及び骨再生を刺激するために有用である。
本発明の好ましい実施形態は、一般式(I)の新規短鎖ペプチド、それらの合成に含まれる新規中間体、それらの医薬的に許容される塩、及びそれら又はそれらの混合物を含む医薬組成物を提供することであり、骨疾患の治療/緩和/制御のために好適である。
本発明に従って、PTH-1受容体アゴニスト活性を示す、構造式(I)を有する合成短鎖ペプチドは、開示される。これらの短鎖ペプチドは、タンパク質分解的切断への代謝的安定性を示し、多くの短鎖ペプチドはラットの血漿中(インビトロ)で24時間安定であることが分かったように、GIT酵素、例えばペプシン、酸性の胃pHに対して、及びまた肝臓ミクロソーム(インビトロ)に対して、増加した安定性を示した。増加した代謝安定性のために、これらの一部の短鎖ペプチドはまた、副甲状腺機能低下症、及び骨量の減少により特徴付けられる疾患、例えば、骨粗鬆症、閉経後の骨粗鬆症の治療/予防のために、及び骨修復を刺激するために、経口投与により送達が可能である。
-α-アルキル化、例えば、Alaのα-メチルAla(Aib)との置き換え、Metのα-メチルMetとの置き換えなど;
-アミノ酸の側鎖の置換、例えば、芳香族アミノ酸のハロゲン、(C1-C3)アルキル、アリール基への置換、より具体的には置換PheのハロPheとの置換など;
を表す。
a) 一つ又はそれ以上のアミノ酸が、その相当するD-アミノ酸によって置換された化合物。当業者は、逆-反転(retro-inverso)アミノ酸配列は標準手順;例、Chorev M., Acc. Chem. Res., 26, 1993, 266-273を参照;により合成され得ることを知っているだろう、
b) ペプチド結合が、代謝的分解に対してより耐性を有する構造で置き換えたペプチド模倣化合物。例、Olson G. L., et al., J. Med. Chem., 36(21), 1993, 3039-3049を参照、及び
c) 個別のアミノ酸が、アナログ構造、例えば、AlaをAibで;Metをα-Me-Metで、置き換えられた化合物。
を制限されることなく含む。
いくつかの合成経路は、本発明の短鎖ペプチドを調製するために用いられ、ペプチド合成の技術分野における当業者にはよく知られている。全ての記号は先に定義されている、式(I)の短鎖ペプチドは、ペプチド合成の分野の当業者に知られている従来の技術、又は当業者により認められているその変更とともに、下記の方法を用いて合成される。言及した方法は、後述のそれらを制限することなく含む。
レジン上での短鎖ペプチドの組み立て:
十分な量(50〜100 mg)のFmoc-PAL-PEG-PSレジン、又はFmoc-Rink アミド MBHA レジン、ローディング:0.5〜0.6 mmol/ gは、DMF(1〜10 mL/100 mgレジン)で2〜10分膨潤させた。レジン上のFmoc基は、DMF (10〜30 mL /100 mg レジン)中、10〜30%ピペリジンで10〜30分インキュベートすることにより、取り除いた。脱保護されたレジンは、濾過され、過剰のDMF、DCM及びエーテル(50 mL x 4)で洗浄された。洗浄されたレジンは、新鮮な蒸留されたDMF (1 mL/ 100 mg レジン)中、窒素雰囲気下で、5分インキュベートされた。DMF中のHOBt (1〜3当量)、及びDIPCDI(1〜2当量)で予備的活性化された最初のFmoc保護アミノ酸(1〜3当量)の0.5M溶液は、レジンに加えられ、レジンはそれから1〜3時間、窒素雰囲気下で振盪された。結合完了は、定性的なニンヒドリン試験を用いることにより、観察された。最初のアミノ酸の結合後、レジンはDMF、DCM、及びジメチルエーテル(50 mL x 4)で洗浄された。次のアミノ酸の結合のために、まず、10〜20%ピペリジン溶液を用いて、レジンと結合している最初のアミノ酸のFmoc保護をは保護され、続いて好適な結合試薬を用いて、上述のように、Fmoc保護された2番目のアミノ酸が結合される。
当業者の範囲の内の、上述の手順及びその好適な変更を用いて、本明細書で設計された短鎖ペプチドは、Fmoc-SPPS手法を用いて、調製された。最終的に、レジン結合短鎖ペプチドは、切断され、及び脱保護され、精製され、及び次の部分で記述される手順を用いて特徴付けられる。
直鎖の短鎖ペプチド、H2N-(AC5C)-V-(AC5C)-EIQLMHQ-Har-(αMe-Pro)-K-(α-Me-Phe)-PAL-PEG-PSは、Fmoc固相ペプチド合成(SPPS)手法(スキーム2)を用いて、自動化されたCS-Bio 536 PepSynthesiser(登録商標)で構築された。Fmocアミノ酸、及び2-(1H-ベンゾトリアゾール‐1‐イル)‐1,1,3,3-テトラメチルウロニウムテトラフルオロボレート(TBTU)は、バイアルに供に充填され、合成装置のアミノ酸モジュール中に置かれた。
所望の短鎖ペプチドは、下記のようなTFA切断混合物での処理によって、それらのそれぞれのペプチジルレジンから切断され、脱保護された。TFA /水/トリイソプロピルシラン(95: 2.5: 2.5) (10 mL/ペプチジルレジン100 mg)の溶液は、ペプチジルリジンに加えられ、混合物は周囲温度で、時折撹拌されて、保たれた。レジンは濾過され、切断混合物で洗浄され、結合した濾過液は、乾燥のために蒸発させた。得られた残余物は、10 mLの水に溶解され、水層は、エーテル(各20 mL)で3回抽出され、最終的に水層は凍結乾燥された。凍結乾燥後に得られた粗製ペプチドは、分取HPLCで下記のように精製された:
分取HPLCは、Shimadzu LC-8A液体クロマトグラフィーで行われた。DMF、又は水に溶解された粗製製ペプチドの溶液は、semi-Prepカラム(Luna 10μ;C18;100 A°)、寸法250 x 50 mmに注入され、水にACN(双方ともに0.1%TFAで緩衝化した)の直線的勾配をかけ、流速15〜50 mL/分、220 nmのPDA検出器により溶出液を監視し、溶出させた。0.1%TFAで緩衝化された水−ACN混合物の20〜70%典型的な勾配、50分間以上、1分につき1%勾配変化が用いられた。溶出された所望の生成物は、1つ10〜20 mL画分に回収され、精製短鎖ペプチドは、それぞれのHPLC画分の凍結乾燥により非結晶質の白色粉末として得られた。
上述の分取HPLCによる精製後、それぞれのペプチドは、Shimadzu LC-10AD 分析的 HPLCシステムで、分析的RP-HPLCにより分析された。短鎖ペプチドの分析的HPLC分析のために、0.1% TFA 及びACNバッファの直線的勾配で、Luna 5μ;C18;100 A°、寸法 250 x 4.6 mm カラムが用いられ、PDA検出器を用いて、クロマトグラムの収集は220 nmで行われた。
それぞれのペプチドは、フローインジェクション又はLC/MSモードで、エレクトロスプレイイオン化質量分析(ESI-MS)により、特性評価された。トリプル四重極質量分析(API-3000 (MDS-SCIES, Canada)は、正及び負イオンエレクトロスプレイモードで、全ての分析で用いられた。フルスキャンデータは、四重極の質量範囲をかけて得られ、分解能単位で行われた。全ての場合で、実験的に測定された分子量は、計算されたモノアイソトピック分子量の0.5 kDa以内であった。マスクロマトグラムの質量の「定量化は、Analyst 1.4.1ソフトウェアを用いて行われた。
他の一般的な既知の技術、及び好適なその変更とともに、本明細書で記述した合成方法の利用することによって、次の新規短鎖ペプチドは調製された[表2 (i-xix)]。この一覧は、短鎖ペプチドの様々な群を示し、それは、本発明により調製され、少なくともそれらの短鎖ペプチドの明らかな変更を含むことが予想される。しかしながら、そのような開示は、本発明の範囲をいかなる方法でも、制限するものとして解釈されない。表2 (i-xix)において、本発明の新規短鎖ペプチドは、それらの対応する配列番号とともに列挙する。
上述の調製された短鎖ペプチドは、以下:
a) インビボラットPTH−1 Rアゴニスト活性(UMR-106細胞中におけるサイクリックAMP測定);
b) ヒト血漿中、疑似胃液、腸液、及び肝臓ミクロソーム(エクスビボ)でのペプチド安定性;及び
c) OVXラットモデルにおける、インビボ抗−骨粗鬆症活性試験
の試験が行われた。
PTHRはGPCRであり、PTHRアゴニストはそれと結合し、直通のシグナル伝達は、アデニル化サイクルの活性化を引き起こし、細胞内cAMPレベルが上昇する。新規化合物のアゴニスト活性の観察のために、UMR-106ラット骨粗鬆症細胞(供給元ATCC)は、内生的にラットPTHR、特にPTH-1Rを発現し、PTH-1Rは、試験化合物の様々な濃度で処理され、放出されたcAMPの量が測定された。
異なる短鎖ペプチド(最終濃度2μM)は、プールヒト血漿(7.5μM)、又は疑似胃液(pH 1.5;組成HCl、NaCl、及びペプシン)、又は疑似腸液(pH 7.5)、又はヒト肝臓ミクロソームと、0、2、4、6、12及び24時間(37℃;50 mM トリエタノールアミン−HClバッファ;pH 7.8)インキュベーションされた。ヒト血漿/疑似胃液/疑似腸液/ヒト肝臓ミクロソームの濃度は、1時間以内でPTH(1-34)の約50%の分解を提供する、予備実験で選択され、それゆえ、24時間以上観察されるための時間依存的な分解が許容された。反応は、TFA/H2O (15 mL、10%(v/v))の添加により、終了される。反応生成物は、その後、Vydac C18分析カラム(4.6 x 250 mm)に適用され、主な分解断片は無傷の短鎖ペプチドから分離された。カラムは流速1 mL/minで、TFA/H2Oにより平衡化された。70%アセトニトリル/H2O中の0.1% (v/v) TFAの使用することで、溶出した溶媒中のアセトニトリルの濃度は、10分以上で0%から28%まで、30分以上で28%から42%まで上昇した。吸光度は、206 nmで、UV検出器を用いて観察され、ピークはESI-MS分析に先立って、手作業で回収された。曲線の下の面積は、試験ペプチド、及びそれらの代謝産物のために測定され、分解百分率は、24時間以上の各時間で計算された。ヒト血漿/疑似胃液/疑似腸液/肝臓ミクロソーム(インビトロ)における選択されたペプチドの安定性試験結果を、表4に列挙する。
卵巣摘出(OVX)ラットは、インビボでの試験化合物(短鎖ペプチド)の抗骨粗鬆症活性の試験のために用いられた。OVXラットは、卵巣ホルモン欠乏のため、骨減少が生じる。骨減少は、早ければ、OVXから14日後に発見され、100日後には増加し、その後安定化する(Wronski T. J., et al., Calcif. Tissue Int., 43(3), 1988, 179-183)。
10〜11週齢の雌性のウィスターラット(150〜200 g)が用いられた。動物は、制御された温度(23° ± 3°C)、照明(12:12時間 明暗サイクル)、相対湿度(55 ± 10%)を備える室内に、個別に換気されたケージ中に置かれた。動物は、標準のラットの食事及び水と自由に接触をもった。本試験を行うための動物の使用の手順は、動物倫理委員会(IAEC)により審査され、承認されている。
好ましい実施形態では、本発明は、UMR-106細胞において、親和性の異なる程度(1〜1000 nM 濃度)を有するPTH-1受容体のアゴニストとして機能する短鎖ペプチドを作製する方法を提供する。PTH-1受容体アゴニスト活性は、試験化合物(インビトロ)により放出されたcAMP量の推定により評価された。OVXマウス/ラットモデル(インビボ)において、一部の短鎖ペプチドは、骨成長パラメータの改善を示し、それゆえ、それらは骨粗鬆症の治療及び予防のための、理想的な治療候補となる。
本発明の新規短鎖ペプチドは、上昇した安定性、及び短い鎖長により、様々なタンパク質分解酵素に対して上昇した安定性を示し、そのような短鎖ペプチドはまた、他の侵襲(invensive)及び、非侵襲経路(non-invensive)の投与とともに、経口投与により送達される。
Claims (7)
- 骨粗鬆症の治療のための、請求項1に記載の化合物、及び医薬的に許容される賦形剤、担体又は希釈剤を含む医薬組成物。
- 骨粗鬆症の進行又は発病を治療又は遅延するのに有用な、PTH-1受容体のアゴニストとして作用する、請求項2に記載の医薬組成物。
- 前記骨粗鬆症が、原発性骨粗鬆症、内分泌性骨粗鬆症、閉経後骨粗鬆症、又は遺伝的若しくは先天性型の骨粗鬆症である、請求項3に記載の医薬組成物。
- 原発性骨粗鬆症;内分泌性骨粗鬆症;遺伝的若しくは先天性型の骨粗鬆症;固定化、慢性閉塞性肺疾患若しくはリウマチ性疾患による骨粗鬆症;又は骨損失合併症につながる骨髄炎若しくは骨の感染病巣;により引き起こされる疾患を予防又は治療するための医薬組成物であって、有効で、毒性を示さない量の請求項1に記載の化合物を含む、請求項2に記載の医薬組成物。
- 請求項1に記載の化合物、及び医薬的に許容される担体、希釈剤、賦形剤又は溶媒和物を含む、請求項3〜5のいずれか1項に記載したいずれかの病状を治療/減少させるための医薬。
- 請求項3〜5のいずれか1項に記載の疾患の治療のための医薬の製造における、請求項1に記載の化合物の使用。
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