JP2008507477A - ポリペプチド延長タグ - Google Patents
ポリペプチド延長タグ Download PDFInfo
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- JP2008507477A JP2008507477A JP2007519766A JP2007519766A JP2008507477A JP 2008507477 A JP2008507477 A JP 2008507477A JP 2007519766 A JP2007519766 A JP 2007519766A JP 2007519766 A JP2007519766 A JP 2007519766A JP 2008507477 A JP2008507477 A JP 2008507477A
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- Prior art keywords
- glp
- xaa
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- peptide
- lys
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- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
- 235000010447 xylitol Nutrition 0.000 description 1
- 229960002675 xylitol Drugs 0.000 description 1
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Abstract
【解決手段】血漿中の化合物の半減期を増加するための方法及びその化合物の新規の誘導体。
【選択図】 なし。
Description
G、X、及びYは、独立して、
単結合、-S-、-O-、-NH-、-(CH2)1-10-、又は
一以上のアルキル、アミノ、シクロアルキル、アリール、ヘテロアリール、ハロゲン、ニトロ、低級アルコキシ、ヒドロキシ、MeCONH-、アルカノイル、又はシアノで任意に置換されたアリーレン、又は、
一以上のアルキル、アミノ、シクロアルキル、アリール、ヘテロアリール、ハロゲン、ニトロ、低級アルコキシ、ヒドロキシ、MeCONH-、アルカノイル、又はシアノで任意に置換されたヘテロアリーレン、
を表し、
Z は、単結合、又は
-(CH2)n-、-O-(CH2)n-、-S-(CH2)n-、-(OCH2CH2)n-、-(CF2)n-、-O-CH2-(CF2)n-、-S-CH2-(CF2)n-、
(式中 n は1-40である)
を表し、
A は、
-C(=O)-、-O-C(=O)-、-NH-C(=O)-、-C(C=O)NH-S(=O)2-、-S(=O)2NH-C(=O)-、-(CH2)1-5-、-O-(CH2)1-5-、又は-O-(CH2)1-5-C(=O)-、
を表し、及び、
Q は、単結合、又は
-[NH-(CH2CH2O)m-(CH2)p-E-C(=O)]q-、又は
-O-(CH2CH2O)m-(CH2)p-E-C(=O)-、又は
-S-(CH2CH2O)m-(CH2)p-E-C(=O)-、(式中 E は、単結合、O、S、又はNHであり、及び、m、p、及びq は独立して1-40である)
を表し、及び、
R は、単結合又は[-NH(CH2)4CH(NH-)-C(=O)-]1-5のようなポリラジカルを表し、及び、
t は1-40であり、及び、
「分子」という用語は、該基A又はQが共有結合的に結合される、アミノ基又はメルカプト基を含む化合物を表す。
G、X、及びYは、独立して、
単結合、-S-、-O-、-NH-、-(CH2)1-10-、又は
一以上のアルキル、アミノ、シクロアルキル、アリール、ヘテロアリール、ハロゲン、ニトロ、低級アルコキシ、ヒドロキシ、MeCONH-、アルカノイル、又はシアノで任意に置換されたアリーレン、又は、
一以上のアルキル、アミノ、シクロアルキル、アリール、ヘテロアリール、ハロゲン、ニトロ、低級アルコキシ、ヒドロキシ、MeCONH-、アルカノイル、又はシアノで任意に置換されたヘテロアリーレン、
を表し、
Z は、単結合、又は
-(CH2)n-、-O-(CH2)n-、-S-(CH2)n-、-(OCH2CH2)n-、-(CF2)n-、-O-CH2-(CF2)n-、-S-CH2-(CF2)n-、
(式中 n は1-40である)
を表し、
A は、
-C(=O)-、-O-C(=O)-、-NH-C(=O)-、-C(C=O)NH-S(=O)2-、-S(=O)2NH-C(=O)-、-(CH2)1-5-、-O-(CH2)1-5-、又は-O-(CH2)1-5-C(=O)-、
を表し、及び、
Q は、単結合、又は
-[NH-(CH2CH2O)m-(CH2)p-E-C(=O)]q-、又は
-O-(CH2CH2O)m-(CH2)p-E-C(=O)-、又は
-S-(CH2CH2O)m-(CH2)p-E-C(=O)-、(式中 E は、単結合、O、S、又はNHであり、及び、m、p、及びq は独立して1-40である)
を表し、及び、
R は、単結合又は[-NH(CH2)4CH(NH-)-C(=O)-]1-5のようなポリラジカルを表し、及び、
t は1-40であり、及び、
「分子」という用語は、該基A又はQが共有結合的に結合される、アミノ基又はメルカプト基を含む化合物を表す。
「ポリラジカル」という用語は、二以上の非共有電子を有する分子又は分子部分を意味する。この定義に従ったポリラジカルは、二以上の(モノ-)ラジカルと共に共有結合的に結合するために用いられ得る。
HAEGTFTSDVSSYLEGQAAKEFIAWLVKGRG (配列番号:1)によるペプチドを指す。
一定分量のペプチド(5 nmol)を、100 μLの0.1 M トリエチルアミン-HCl 緩衝液、pH 7.4中で、5 mUの酵素活性に相当する1 μLの精製されたジペプチジルアミノペプチダーゼIVと共に、37℃で10〜180 分インキュベートする。酵素反応を、5 μLの10% トリフルオロ酢酸の添加によって終結させ、ペプチド分解産物を分離しHPLC分析を用いて定量する。この分析を実行するための一つの方法は:「Siegel et al.、Regul. Pept. 1999;79:93-102」及び「Mentlein et al. Eur. J.ビochem. 1993;214:829-35」に従って、該混合物をVydac C18 広管孔 (30 nm管孔、5 μm粒子) 250 x 4.6 mmカラム中にアプライし、0.1% トリフルオロ酢酸中のアセトニトリルの直線状の段階的な勾配(0% アセトニトリル、3分間、0-24% アセトニトリル、17分間、24-48% アセトニトリル、1分間) で、1 ml/minの流速で溶出する。ペプチド及びその分解産物は、それらの吸光度220 nm (ペプチド結合)又は280 nm (芳香族アミノ酸)でモニターされ、また、基準のものに関するそれらのピーク領域の積分によって定量される。ジペプチジルアミノペプチダーゼIVによるペプチドの加水分解の速度は、加水分解されたペプチドの10%未満をもたらすインキュベーション時間で評価される。
「生物学的等価性(bioisostere)」という用語は、他の分子断片の生物学的性質を擬態する、分子断片の能力を指す。カルボン酸の典型的なバイオアイソスターは、テトラゾール、フェノール、N-アシルスルホンアミド、或いは、酸性NH-又はOH-基を有する他の化合物を含む。
「ハロゲン」という用語は、 F、Cl、Br又はIを意味する。
「アルキル」という用語は、本明細書で用いられるように、直鎖状の、分枝の、又は環状のC1-C10 アルキルを意味するように意図される。
「低級アルキル」という用語は、C1-C6アルキルを指す。
G、X、及びYは独立して、
単結合、-S-、-O-、-NH-、-(CH2)1-15-、-C(O)NH-、又は
一以上のアルキル、アミノ、シクロアルキル、アリール、ヘテロアリール、ハロゲン、ニトロ、低級アルコキシ、ヒドロキシ、MeCONH-、アルカノイル、又はシアノで任意に置換されたアリーレン、又は
一以上のアルキル、アミノ、シクロアルキル、アリール、ヘテロアリール、ハロゲン、ニトロ、低級アルコキシ、ヒドロキシ、MeCONH-、アルカノイル、又はシアノで任意に置換されたヘテロアリーレン、
を表し、及び、
Zは、単結合又は
-(CH2)n-、-O-(CH2)n-、-S-(CH2)n-、-(OCH2CH2)n-、-(CF2)n-、-O-CH2-(CF2)n-、-S-CH2-(CF2)n-、
(式中 nは1-40である)
を表し、及び、
Aは、
-C(=O)-、-O-C(=O)-、-NH-C(=O)-、-C(C=O)NH-S(=O)2-、-S(=O)2NH-C(=O)-、-(CH2)1-5-、-O-(CH2)1-5-、又は-O-(CH2)1-5-C(=O)-、
を表し、及び、
Q は、単結合又は
-[NH-(CH2CH2O)m-(CH2)p-E-C(=O)]q-、又は
-O-(CH2CH2O)m-(CH2)p-E-C(=O)-、又は
-S-(CH2CH2O)m-(CH2)p-E-C(=O)-、
(式中 Eは単結合、O、S、又はNHであり、及びm、p、及びqは独立して1-40である)
を表し、及び、
Rは、単結合又は[-NH(CH2)4CH(NH-)-C(=O)-]1-5のようなポリラジカルを表し、及び
t は1-40であり、及び
「分子」という用語は、該基A又はQが共有結合的に結合される、アミノ基又はメルカプト基を含む化合物を指す。
G、X、及びYは独立して、
単結合、-S-、-O-、-NH-、-(CH2)1-10-、又は
一以上のアルキル、アミノ、シクロアルキル、アリール、ヘテロアリール、ハロゲン、ニトロ、低級アルコキシ、ヒドロキシ、MeCONH-、アルカノイル、又はシアノで任意に置換されたアリーレン、又は
一以上のアルキル、アミノ、シクロアルキル、アリール、ヘテロアリール、ハロゲン、ニトロ、低級アルコキシ、ヒドロキシ、MeCONH-、アルカノイル,又はシアノで任意に置換されたヘテロアリーレン、
を表し、及び
Z は、単結合又は
-(CH2)n-、-O-(CH2)n-、-S-(CH2)n-、-(OCH2CH2)n-、-(CF2)n-、-O-CH2-(CF2)n-、-S-CH2-(CF2)n-、
(式中 nは1-40である)
を表し、及び、
A は、
-C(=O)-、-O-C(=O)-、-NH-C(=O)-、-C(C=O)NH-S(=O)2-、-S(=O)2NH-C(=O)-、-(CH2)1-5-、-O-(CH2)1-5-、又は-O-(CH2)1-5-C(=O)-
を表し、及び
Q は、単結合又は
-[NH-(CH2CH2O)m-(CH2)p-E-C(=O)]q-、又は
-O-(CH2CH2O)m-(CH2)p-E-C(=O)-、又は
-S-(CH2CH2O)m-(CH2)p-E-C(=O)-、
(式中 Eは単結合、O、S、又はNHであり、及びm、p、及びqは独立して1-40である)
を表し、及び
R は、単結合又は[-NH(CH2)4CH(NH-)-C(=O)-]1-5のようなポリラジカルを表し、及び
t は1-40であり、及び
「分子」という用語は、該基A又はQが共有結合的に結合される、アミノ基又はメルカプト基を含む化合物を指す。
4-[N-(16-{5-テトラゾリル}ヘキサデカノイル)スルファモイル]ブチリル、
2-(2-(2-(16-(テトラゾール-5-イル)(ヘキサデカノイルアミノ)エトキシ)エトキシ)アセチル)又は
16-(1H-テトラゾール-5-イル)ヘキサデカン酸 [2-(2-{[2-(2-カルバモイルメトキシエトキシ)エチルカルバモイル]メトキシ}エトキシ)エチル]アミドである。
Xaa7-Xaa8-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Xaa16-Ser-Xaa18-Xaa19-Xaa20-Glu-Xaa22-Xaa23-Ala-Xaa25-Xaa26-Xaa27-Phe-Ile-Xaa30-Trp-Leu-Xaa33-Xaa34-Xaa35-Xaa36-Xaa37-Xaa38-Xaa39-Xaa40-Xaa41-Xaa42-Xaa43-Xaa44-Xaa45-Xaa46
式 (III) (配列番号:3)
式中、
Xaa7 はL-ヒスチジン、D-ヒスチジン、desアミノ-ヒスチジン、2-アミノ-3-(2-アミノイミダゾール-4-イル)プロピオン酸、β-ヒドロキシ-ヒスチジン、ホモヒスチジン、Nα-アセチル-ヒスチジン、α-フルオロメチル-ヒスチジン、α-メチル-ヒスチジン、3-ピリジルアラニン、2-ピリジルアラニン又は4-ピリジルアラニンであり;
Xaa8 はAla、Gly、Val、Leu、Ile、Lys、Aib、1-アミノシクロプロパンカルボン酸、1-アミノシクロブタンカルボン酸、1-アミノシクロペンタンカルボン酸、1-アミノシクロヘキサンカルボン酸、1-アミノシクロヘプタンカルボン酸、又は1-アミノシクロオクタンカルボン酸であり;
Xaa16 はVal又はLeuであり;
Xaa18 はSer、Lys又はArgであり;
Xaa19 はTyr又はGlnであり;
Xaa20 はLeu又はMetであり;
Xaa22 はGly、Glu又はAibであり;
Xaa23 はGln、Glu、Lys又はArgであり;
Xaa25 はAla又はValであり;
Xaa26 はLys、Glu又はArgであり;
Xaa27 はGlu又はLeuであり;
Xaa30 はAla、Glu又はArgであり;
Xaa33 はVal又はLysであり;
Xaa34 はLys、Glu、Asn又はArgであり;
Xaa35 はGly又はAibであり;
Xaa36 はArg、Gly又はLysであり;
Xaa37 はGly、Ala、Glu、Pro、Lys、アミド又は欠失であり;
Xaa38 はLys、Ser、アミド又は欠失であり;
Xaa39 はSer、Lys、アミド又は欠失であり;
Xaa40 はGly、アミド又は欠失であり;
Xaa41 はAla、アミド又は欠失であり;
Xaa42 はPro、アミド又は欠失であり;
Xaa43 はPro、アミド又は欠失であり;
Xaa44 はPro、アミド又は欠失であり;
Xaa45 はSer、アミド又は欠失であり;
Xaa46 はアミド又は欠失であり;
Xaa38、Xaa39、Xaa40、Xaa41、Xaa42、Xaa43、Xaa44、Xaa45又はXaa46 が欠失である場合、各アミノ酸残基の下流も欠失である。
Xaa7-Xaa8-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Xaa18-Tyr-Leu-Glu-Xaa22-Xaa23-Ala-Ala-Xaa26-Glu-Phe-Ile-Xaa30-Trp-Leu-Val-Xaa34-Xaa35-Xaa36-Xaa37-Xaa38
式 (IV) (配列番号:4)
式中
Xaa7 はL-ヒスチジン、D-ヒスチジン、desアミノ-ヒスチジン、2-アミノヒスチジン、β-ヒドロキシ-ヒスチジン、ホモヒスチジン、Nα-アセチル-ヒスチジン、α-フルオロメチル-ヒスチジン、α-メチル-ヒスチジン、3-ピリジルアラニン、2-ピリジルアラニン又は4-ピリジルアラニンであり;
Xaa8 はAla、Gly、Val、Leu、Ile、Lys、Aib、1-アミノシクロプロパンカルボン酸、1-アミノシクロブタンカルボン酸、1-アミノシクロペンタンカルボン酸、1-アミノシクロヘキサンカルボン酸、1-アミノシクロヘプタンカルボン酸、又は1-アミノシクロオクタンカルボン酸であり;
Xaa18 はSer、Lys又はArgであり;
Xaa22 はGly、Glu又はAibであり;
Xaa23 はGln、Glu、Lys又はArgであり;
Xaa26 はLys、Glu又はArgであり;
Xaa30 はAla、Glu又はArgであり;
Xaa34 はLys、Glu又はArgであり;
Xaa35 はGly又はAibであり;
Xaa36 はArg又はLysであり;
Xaa37 はGly、Ala、Glu又はLysであり;
Xaa38 はLys、アミド又は欠失である。
ポリペプチドである。
Aib8,22,35 GLP-1(7-37)、Aib8,35 GLP-1(7-37)、Aib8,22 GLP-1(7-37)、
Aib8,22,35 Arg26,34Lys38GLP-1(7-38)、Aib8,35 Arg26,34Lys38GLP-1(7-38)、
Aib8,22 Arg26,34Lys38GLP-1(7-38)、Aib8,22,35 Arg26,34Lys38GLP-1(7-38)、
Aib8,35 Arg26,34Lys38GLP-1(7-38)、Aib8,22,35 Arg26Lys38GLP-1(7-38)、
Aib8,35 Arg26Lys38GLP-1(7-38)、Aib8,22 Arg26Lys38GLP-1(7-38)、
Aib8,22,35 Arg34Lys38GLP-1(7-38)、Aib8,35Arg34Lys38GLP-1(7-38)、Aib8,22Arg34Lys38GLP-1(7-38)、
Aib8,22,35Ala37Lys38GLP-1(7-38)、Aib8,35Ala37Lys38GLP-1(7-38)、Aib8,22Ala37Lys38GLP-1(7-38)、
Aib8,22,35 Lys37GLP-1(7-37)、Aib8,35Lys37GLP-1(7-37)及びAib8,22Lys37GLP-1(7-38)からなる群より選択されるGLP-1(7-37)類似体である。
N-ε-26-(16-[5-テトラゾリル]ヘキサデカノイル)Arg34GLP-1-(7-37)、
Gly8,Arg26,34GLP-1(7-37)Lys(16-(5-テトラゾリル)ヘキサデカノイル)、Gly8,Arg26,34GLP-1(7-37)Lys{4-[N-(16-{5-テトラゾリル}ヘキサデカノイル)スルファモイル]ブチリル}、N-ε-26-{4-[N-(16-{5-テトラゾリル}ヘキサデカノイル)スルファモイル]ブチリル} Arg34GLP-1(7-37)、
N-ε-37-(2-(2-(2-(16-(テトラゾール-5-イル)(ヘキサデカノイルアミノ)エトキシ)エトキシ)アセチル)) Aib8,22,35Lys37GLP-1(7-37)、
Gly8,Glu22,23,30Arg18,26,34 GLP-1(7-37)Lys(16-(1H-テトラゾール-5-イル)ヘキサデカン酸 [2-(2-{[2-(2-カルバモイルメトキシエトキシ)エチルカルバモイル]メトキシ}エトキシ)エチル]アミド)-NH2、及びGly8Arg26,34GLP-1(7-37)Lys(4-(4-(4-(4-(5-テトラゾリル)フェニル)フェニル)フェノキシ)ブチリル). N-ε38-(2-(2-(2-(16-(4-(5-テトラゾリル)フェノキシ)ヘキサデカノイル)エトキシ)エトキシ)アセチル) [Gly8,Arg26,34,Lys38]GLP-1(7-37) ペプチド
(ヘキサデカノイルアミノ)エトキシ)エトキシ)アセチル))[3-(4-イミダゾリル)プロピオニル7,Aib22,35,Arg26,34,Lys37] GLP-1 (7-37) ペプチド
NB29ε-4-[4''-(1H-テトラゾール-5-イル)-[1,1';4',1'']テルフェニル-4-イルオキシ]-ブチロイル des(B30) インスリン
治療的ポリペプチドをコードするDNA配列は、適切にはゲノムか又はcDNA由来のものであり、例えば、ゲノム又はcDNAライブラリーを調製し、標準的な技術(例えば、Sambrook、J、Fritsch、EF and Maniatis、T、Molecular Cloning: A Laboratory Manual、Cold Spring Harbor Laboratory Press、New York、1989を参照されたい)にしたがって合成オリゴヌクレオチドプローブを用いてハイブリダイゼーションすることによってペプチドの全部又は一部をコードするDNA配列をスクリーニングすることによって得られる。ポリペプチドをコードするDNA配列は、また、確立された標準的な方法、例えば、「Beaucage and Caruthers、Tetrahedron Letters 22 (1981)、1859−1869」に記載されたホスホアミジト方法、又は「Matthes et al.、EMBO Journal 3 (1984)、801−805」」に記載された方法によっても調製できる。DNA配列は、例えば、US 4,683,202又は「Saiki et al.、Science 239 (1988)、487-491」に記載されたような特異的なプライマーを用いたポリメラーゼ・チェーン・リアクションによっても調製できる。
本発明の他の態様において、本発明の化合物を含有する該薬学的製剤は、4週間を超える使用及び3年間を超える貯蔵に安定である。
本発明のさらなる態様において、本発明の化合物を含有する該薬学的製剤は、4週間を超える使用及び2年間を超える貯蔵に安定である。
本発明のさらなる態様において、該化合物を含有する該薬学的製剤は、2週間を超える使用及び2年間を超える貯蔵に安定である。
本発明の一つの態様において、前記治療的薬剤がGLP-1 ペプチドである本発明の化合物は、高血糖、2型糖尿病、耐糖能障害、1型糖尿病、肥満症、高血圧症、X症候群、異脂肪血症、毒性多血に関する疾患、認知性疾患、アテローム性動脈硬化症、心筋梗塞、冠状動脈心疾患、脳卒中及び他の循環器病、炎症性腸症候群、消化不良及び胃潰瘍の治療又は予防のための薬剤の調製のために用いられる。
Boc: tert-ブチルオキシカルボニル
Bt: 1-ベンゾトリアゾニル
DBU: 1,8-ジアザビシクロ[5.4.0]ウンデカ-7-エン
DCM: ジクロロメタン、メチレン塩化物
Dde: 1-(4,4-ジメチル-2,6-ジオキソシクロヘキシリデン)エチル
DIC: ジイソプロピルカルボジイミド
DMA: N,N-ジメチルアセトアミド
DMF: N,N-ジメチルホルムアミド
DMSO: ジメチルスルホキシド
DMAP: 4-ジメチルアミノピリジン
DMPU: 1,3-ジメチルテトラヒドロピリミジン-2-オン
EDC又はEDAC N-エチル-N’-(3-ジメチルアミノプロピル)カルボジイミドハイドロクロライド
Fmoc: 9-フルオレニルメチルオキシカルボニル
HBTU: 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ヘキサフルオロホスフェート
HOAt: 3-ヒドロキシ-3H-[1,2,3]トリアゾールo[4,5-b]ピリジン、4-アザ-3-ヒドロキシベンゾトリアゾール
HOBt: N-ヒドロキシベンゾトリアゾール、1-ヒドロキシベンゾトリアゾール
HONSu: N-ヒドロキシスクシンイミド
NMP: N-メチルピロリドン
HPLC: 高速液体クロマトグラフィー
Pmc 2,2,5,7,8-ペンタメチルクロマン-6-スルホニル
r.t. 室温
Su: スクシンイミジル
TIS トリイソプロピルサリン
Trt: トリチル、トリフェニルメチル
Ts: トルエンスルホニル
TSTU O-(1-スクシンイミジル)-N,N,N',N'-テトラメチルウロニウムヘキサフルオロホスフェート
DIEA ジイソプロピルエチルアミン
H2O 水
CH3CN アセトニトリル
OtBu t-ブチルエステル
tBu t-ブチル
Trt トリフェニルメチル
Pmc 2,2,5,7,8-ペンタメチル-クロマン-6-スルホニル
Dde 1-(4,4-ジメチル-2,6-ジオキソシクロヘキシリデン)エチル
DCM ジクロロメタン
TFA: トリフルオロ酢酸
Et2O: ジエチルエーテル
NMRスペクトルは、Bruker 300 MHz及び400 MHz機器で記録した。HPLC-MSはPerkin Elmer機器(API 100)で行った。
メルク-ヒタチ(Merck-Hitachi)(Hibar(TM) RT 250-4、Lichrosorb(TM) RP 18、5.0 μm、4.0 x 250 mm、勾配溶出、水中20%〜80% アセトニトリル、30分以内、1.0 ml/min、254 nmで検出)及びウォーターズ (Symmetry(TM) 、C18、3.5 μm、3.0 x 150 mm、勾配溶出、水中5%〜90% アセトニトリル、15分以内、1.0 ml/min、214 nmで検出)のHPLC-システムを用いた。
逆相分析を、218TP54 4.6 mm x 150 mm C-18シリカカラムで、214、254、276及び301 nmでのUV検出を用いて行った。これは、1 ml/min、42 ℃で溶出した。このカラムは5%のアセトニトリル、85%の水、及び10%の、水中0.5%のトリフルオロ酢酸の溶液で平衡化し、5%のアセトニトリル、85%の水及び10%の、0.5%のトリフルオロ酢酸の溶液から、90%のアセトニトリル及び10%の、0.5%のトリフルオロ酢酸の溶液の直線状の勾配によって15 分で溶出した。
RP-分析を、ウォーターズ996ダイオードアレイ検出器に適合されたウォーターズ2690システムを用いて行った。218TP54 4.6 mm x 250 mm 5μC-18シリカカラム(The Seperations group, Hesperia)で、214、254、276、及び301 nmでUV検出を収集し、これは1 ml/min、42℃で溶出した。カラムは水中のTFA(0.1%)水溶液中の、5% アセトニトリル(+0.1% TFA)で平衡化した。注入後、サンプルを、50分の間、水中のTFA(0.1%)の水溶液中の、0%〜90% アセトニトリル(+0.1% TFA)の勾配で溶出した。
K2CO3又はDBUのような塩基の存在下において、DMF、DMSO、アセトン、又はアルコールのような適切な溶媒で、シアノフェノール、シアノチオフェノール、ジシアノフェノール、シアノビフェニルオール、シアノテルフェニルオール、シアノアニリン、シアノヒドロキシヘテロアレーン、又は、少なくとも一つのシアノ基及び一つのアレーン-又はヘテロアレーン-結合ヒドロキシル基を含有する関連する試薬で処理される。この反応に続いて、サンプルは1H NMRによって分析される。得られたω-アリールオキシ-、ω-アリールチオ-、又はω-アリールアミノアルカン酸又はエステルは、水で希釈されて単離され、AcOEt又はDCMで抽出される。この産物を、AcOH及びNEt3 の存在下において、DMF中、140 ℃で、全ての開始物質が消費されるまで(1H NMRによって決定される)、NaN3 で処理することによって、対応するω-(5-テトラゾリル)アリールオキシ-、ω-(5-テトラゾリル)アリールチオ-、又はω-(5-テトラゾリル)アリールアミノアルカン酸又はエステルが産する。エステルの場合は、水及びアルコールの混合物で、過剰量のNaOH又はKOHで処理することによって、酸に転換される。アルコール及び追加の希HCl水溶液を蒸発させて、ω-(5-テトラゾリル)アリール官能性を持たせた(functionalize)アルカン酸が産し、これは濾過によって単離される。
ペプチドは、Fmoc保護されたリンク(Rink)アミド樹脂(Novabiochem)、Fmoc保護されたワン(Wang)樹脂又はクロロトリチル樹脂上で、NMP中のHBTUが媒介するカップリング、及び、Fmoc保護基の脱保護のUVモニタリングを用いる、製造者の供給したFastMoc UVプロトコールを用いて、0.25 mmolスケールで、Applied biosystems 433Aペプチド合成機で、Fmocストラテジーを用いて合成された。用いた保護されたアミノ酸誘導体は、Fmoc-Aib-OH (Fmoc-アミノイソ酪酸)のような非天然アミノ酸を除外すると、ABI 433A 合成機に適した予め秤量された(preweighed)カートリッジ中に供給された、標準のFmoc-アミノ酸 (Anaspec)であった。
ペプチドを、TFA、水及びトリイソプロピルサリン(95:2.5:2.5)と共に、180分、室温で撹拌することによって樹脂から切断した。切断混合物を濾過し該濾液を、窒素の流れによって油に濃縮した。粗製ペプチドを45 mlのジエチルエーテルでこの油から沈殿させ、45 mlのジエチルエーテルで3回洗浄した。
半調製用HPLCによって精製した。
乾燥後、粗製ペプチドを5 mlの50% 酢酸 H2Oに溶解し、H2Oで20 mlに希釈し、カラムに注入し、これは次いで0.1% TFA 中の40-60 % CH3CN勾配で、10 ml/minで、50分の間、40 ℃で溶出された。そのペプチド含有画分を集めた。精製ペプチドを、溶出液を水で希釈した後、凍結乾燥した。得られた最終産物を、分析的RP-HPLC (保持時間)及びLCMSによって性質決定した。
A1: 0.1M (NH4)2SO4からなる緩衝液(これは、濃H2SO4でpH 2.5に調整された)中でのカラムの平衡化、及び、同じ緩衝液中0%〜60% CH3CN の勾配、50分間の溶出。
A:水中10mM NH4OH
B:90% アセトニトリル中10mM NH4OH
分析は、23℃で、適切な容量のサンプル(好ましくは 20 μl)をカラム中へ注入することによって行った。これはA及びBの勾配で溶出される。
勾配: 5% - 100% アセトニトリル 直線状、6.5分の間、1.5ml/minで
検出: 210 nm (類似体 DADからのアウトプット)
ELS: 類似体 ELSからのアウトプット
MS イオン化モード API-ES. Scan 100-1000 amu 工程 0.1 amu
典型的な方法:
樹脂(Fmoc-Gly-ワン樹脂、0.6 mmol/g Novabiochem 0.25 mmole)を、製造者のガイドラインに従ってABI 433Aマシーン上で一次配列を生成するために用いた。樹脂(0.25 mmole)を手動の振盪/濾過装置に配置し、NMP中2% ヒドラジン(2x12 分 2x20 ml)で処置してDde基を除去した。樹脂をNMP (4x20 ml)で洗浄した。Fmoc-8-アミノ-3,6-ジオキサオクタン酸 (Neosystem FA03202) (樹脂に対して4モーラー当量)をNMP/DCM (1:1、20 ml)に溶解した。HOBt(樹脂に対して4モーラー当量)及びDIC(樹脂に対して4モーラー当量)を加え、該溶液を15分撹拌した。該溶液を樹脂に加え、DIPEA(樹脂に対して4モーラー当量)を加えた。該樹脂を24時間、室温で振盪した。樹脂をNMP (4x20 ml)で洗浄した。NMP中20% ピペリジン溶液(3x20 ml、各10分)を樹脂に振盪しながら加えた。該樹脂を、NMP (4x20 ml)で洗浄した。16-(テトラゾール-5-イル)ヘキサデカノイル-ONSuエステル(樹脂に対して4モーラー当量)をNMP (20 ml)に溶解した。この溶液を樹脂に加え、DIPEA(樹脂に対して4モーラー当量)を加えた。この樹脂を24時間室温で振盪した。該樹脂をNMP (2x20 ml)、NMP/DCM (1:1) (2x20ml)及びDCM (2x20 ml)で洗浄した。ペプチドを、TFA、水及びトリイソプロピルサリン (95:2.5:2.5; 15 ml) の混合物と共に、室温で180分間撹拌することによって樹脂から切断した。切断混合物を濾過し、濾液を真空中で油に濃縮した。粗製ペプチドをこのオイルから、45 ml ジエチルエーテルで沈殿し、45 ml ジエチルエーテルで3回洗浄した。この粗製ペプチドを、7μC-18シリカ で充填された20 mm x 250 mm カラムでの調製用HPLCで精製した。粗製ペプチドを水中5 ml 50% 酢酸に溶解し、H2Oで20 mlに希釈し、カラムに注入した。これは40〜60 % (CH3CN in 水 with 0.1% TFA)の勾配で、10 ml/min、50分間、40℃で溶出された。そのペプチド含有画分を集めた。精製されたペプチドを、水で溶出液を希釈した後凍結乾燥した。
結合アッセイを、ヒトGLP-1受容体を含有する精製された血漿膜により行った。該受容体含有血漿膜を、安定に発現するBHK tk-ts 13細胞から精製した。該膜をアッセイ緩衝液 (50 mM HEPES、5 mM EGTA、5 mM MgCl2、0.005% Tween 20、pH=7.4)で希釈して最終濃度0.2 mg/mlのタンパク質にし、0.3 % PEI でプレコートされた96-ウェルマイクロタイタープレートに分配した。0.05 nM [125I]GLP-1、高濃度の非標識リガンド及び異なるHAS濃度 (0.005%、0.05%、及び2%)の存在下における膜を、30℃で2時間インキュベートした。インキュベーション後、未結合リガンドを減圧-マニフォールドを通した濾過によって結合リガンドから分離し、続いて、氷冷アッセイ緩衝液で2X100 μl洗浄した。濾液を一晩室温で乾燥し、γ計数器で打ち出し、定量化した。
16-ブロモヘキサデカン酸 (15.5 g、46.2 mmol)、MeOH (100 ml)、PhMe (30 ml)、トリメチルオルトギ酸(30 ml)、及びポリスチレン-結合ベンゼンスルホン酸 (3.6 g)の混合物を、55℃で撹拌した。69時間後、該混合物を、セライトを通して濾過し、該濾液を濃縮して16.85 gの油(100% 収率)を産した。
(4'-シアノビフェニル-4-イルオキシ)ヘキサデカン酸メチルエステル (2.75 g、5.93 mmol)、DMF (7.0 ml)、NEt3 (4.0 ml、28.9 mmol)、AcOH (1.75 ml、29.1 mmol)、及びNaN3 (2.50 g、38.5 mmol)の混合物を、140 ℃で撹拌した。17時間後、水 (50 ml)及び1N HCl (50 ml)を添加し、続いて濃HCl (約2 ml)で酸性化した。該産物を濾過し、MeCN/PhMe (約60 + 60 ml)から再結晶した。濾過及び減圧化の乾燥して、2.87 g (96%) の16-(4'-(5-テトラゾリル)ビフェニル-4-イルオキシ)ヘキサデカン酸メチルステルを産した。
16-(4'-(5-テトラゾリル)ビフェニル-4-イルオキシ)ヘキサデカン酸メチルエステル (2.87 g、5.66 mmol)、MeOH (30 ml)、及びNaOH (1.51 g、37.8 mmol)の水 (2.0 ml)中溶液の混合物を70 ℃で撹拌した。4日後、水 (100 ml)及び1N HCl (50 ml)を添加し、該産物を濾過し、水で洗浄し、MeCN/PhMeと共蒸発させ、減圧下で乾燥した。2.68 g (96%)の16-(4'-(5-テトラゾリル)ビフェニル-4-イルオキシ)ヘキサデカン酸を得た。
4-(4-ブロモフェニル)フェノール (3.74 g、15.0 mmol)、MeCN (20 ml)、エチル4-ブロモブチレート (4.42 g、22.7 mmol)、及びK2CO3 (3.12 g、22.6 mmol)の混合物を80 ℃で撹拌した。16時間後、水 (100 ml)及び1N HCl (40 ml) を添加し、該産物を抽出し(3 x AcOEt)、混合性抽出物を潅水(2 x)で洗浄し、乾燥し(MgSO4)、濃縮した。該残渣をEtOH (40 ml)から再結晶し、4.35 g (80%)の4-(4'-ブロモビフェニル-4-イルオキシ)酪酸エチルエステルを無色の平板(plates)として産した。
トルエン (30 ml)中の4-(4'-ブロモビフェニル-4-イルオキシ)酪酸エチルエステル (2.03 g、5.59 mmol)及びEtOH (20 ml)に、トリフェニルホスフィン (0.17 g、0.65 mmol)、4-シアノフェニルホウ素酸 (1.23 g、8.37 mmol)、Pd(OAc)2 (65 mg、0.29 mmol)、及び水 (10 ml)中のNa2CO3 (2.33 g、22.0 mmol) 溶液を加えた。該混合物を70 ℃ (オイルバス温度)で撹拌した。66時間後、水 (100 ml)及び1N HCl (50 ml)を添加し、産物を抽出した (3 x DCM)。混合性抽出物を水で洗浄し、次いで飽和水性NaHCO3で洗浄し、乾燥し、濃縮して、2.33 gの灰色固体を産した。これは、熱EtOHで洗浄し、減圧下で乾燥し、0.81 g (38%)の4-(4-シアノ-[1,1',4',1'']-テルフェニル-4''-イルオキシ)酪酸エチルエステルを産した。エタノール洗浄物からさらなる産物 (0.48 g、22%) が沈殿した。
4-(4-シアノ-[1,1',4',1'']-テルフェニル-4''-イルオキシ)酪酸エチルエステル (1.29 g、3.35 mmol)、DMF (4.0 ml)、NEt3 (2.3 ml、16.6 mmol)、AcOH (1.0 ml、16.7 mmol)、及びNaN3 (1.32 g、20.3 mmol)の混合物を140 ℃で撹拌した。20時間後、水 (50 ml)及び1N HCl (50 ml)を加え、産物を濾過して単離し、熱MeCNで洗浄し、減圧下で乾燥し、1.16 g (81%) の 4-(4-(5-テトラゾリル)-[1,1',4',1'']-テルフェニル-4''-イルオキシ)酪酸エチルエステルを灰色固体として産した。
4-(4-(5-テトラゾリル)-[1,1',4',1'']-テルフェニル-4''-イルオキシ)酪酸エチルエステル (1.16 g、2.71 mmol)、EtOH (10 ml)、NaOH (0.75 g、18.8 mmol)、及び水 (1.5 ml) の不均一混合物を、80 ℃で撹拌した。18時間後、水 (50 ml)及び1N HCl (50 ml)を加えた。0.5時間の撹拌後、産物を濾過し、水で洗浄し、固体をMeCN及びPhMeと共蒸発させ、0.79 g (73%)の4-(4-(5-テトラゾリル)-[1,1',4',1'']-テルフェニル-4''-イルオキシ)酪酸を明るい茶色粉末として産した。
LCMS: m/z = 1231 (MH3 3+)。算出 (MH3 3+): 1231。
LCMS: m/z = 1279 (MH3 3+).算出 (MH3 3+): 1279
例7 Gly8,Arg26,34GLP-1(7-37)Lys{4-[N-(16-{5-テトラゾリル}ヘキサデカノイル)スルファモイル]ブチリル} ペプチド
LCMS: m/z = 1328 (MH3 3+). 算出 (MH3 3+): 1328
例8
N-ε-26-{4-[N-(16-{5-テトラゾリル}ヘキサデカノイル)スルファモイル]ブチリル} Arg34GLP-1(7-37)
LCMS: m/z = 1281 (MH3 3+). 算出(MH3 3+): 1281
例9
N-ε-37-(2-(2-(2-(16-(テトラゾール-5-イル)(ヘキサデカノイルアミノ)エトキシ)エトキシ)アセチル)) Aib8,22,35Lys37GLP-1(7-37)
LCMS: m/z = 988.7 (MH4)4+、1317.8 (MH3)3+. Calculated (MH)+: 3949.6。
ヒト成長ホルモン (100 mg、hGH) をH2O (6 ml)、DIEA (7.5 μl)、及びNMP (6 ml)に溶解し、0 ℃に冷却した。16-(テトラゾール-5-イル)ヘキサデカノイル-ONSu (3.5 mg、2 eq)のNMP (100 μl)に溶解したものを加えた。該反応混合物を1時間撹拌し、イオン交換クロマトグラフィーで精製した。
粗製反応混合物を50 mM Tris pH 8.5で5倍に希釈し、モノQカラムにアプライした。6 mlの粗製反応混合物の精製のために、10 mlの10/10 モノQカラム(Amersham Pharmcia)を用いた。 1000 CV 勾配を、天然の位置30/45/70におけるモノアシル化、位置140/145におけるモノアシル化、ジアシル化及びトリアシル化hGHを分離するために用いた。トリアシル化hGHの溶出後まもなく、急勾配が二量体のhGHの溶出に用いられた。溶出緩衝液として、 50 mM Tris、2 M NaCl、pH 8.5を用いた。精製は4℃で行った。
ピーク 1 天然のhGHを含む
ピーク2 位置38又は45又は70でのモノアシル化hGHを含む
ピーク3 位置140又は145でのモノアシル化hGHを含む
ピーク4 ジアシル化hGHを含む
ピーク5 トリアシル化hGHを含む。
Gly8,Glu22,23,30Arg18,26,34 GLP-1(7-37)Lys(16-(1H-テトラゾール-5-イル)ヘキサデカン酸 [2-(2-{[2-(2-カルバモイルメトキシエトキシ)エチルカルバモイル]メトキシ}エトキシ)エチル]アミド)-NH2
LCMS: m/z = 1441.8 (MH3)3+. Calculated (MH3)3+: 1439.6。
LCMS: m/z = 1304 (MH3)3+. Calculated (MH3)3+: 1304。
Maldi: m/z = 4071; Calculated: 4069.6。
N-イプシロン37-(2-(2-(2-(16-(4-(5-テトラゾリル)フェノキシ)ヘキサデカノイル)エトキシ)エトキシ)アセチル)[Aib8,22,35,Lys37]GLP-1 (7-37)
Maldi: m/z = 4042. Calculated: 4040.7。
Maldi: m/z = 4007. Calculated: 4009。
N-イプシロン37-(16-(4´-(テトラゾール-5-イル)ビフェニル)-4-イルオキシ)ヘキサデカノイル) [3-(4-イミダゾリル)プロピオニル7,Aib22,35,Arg26,34,Lys37]GLP-1 (7-37) ペプチド
LCMS: m/z = 1333.7 (MH3 3+). Calculated for (MH3 3+): 1334.2。
LCMS: m/z = 1277.9 (MH3 3+). Calculated for (MH3 3+): 1277.8。
N-イプシロン37-(16-(4-(テトラゾール-5-イル)フェノキシ)ヘキサデカノイル) [3-(4-イミダゾリル)プロピオニル7,Aib22,35,Arg26,34,Lys37]GLP-1 (7-37)
LCMS: m/z = 1309.2 (MH3 3+). Calculated for (MH3 3+): 1308.5。
N-イプシロン37-(4-(4-(テトラゾール-5-イル)[1,1`,4´,1´´]テルフェニル-4´´ylオキシ)ブチロイル) [3-(4-イミダゾリル)プロピオニル7,Aib22,35,Arg26,34,Lys37]GLP-1 (7-37)
LCMS: m/z = 1303.3 (MH3 3+). Calculated for (MH3 3+): 1303.1。
N-イプシロン37-(2-(2-(2-(16-(テトラゾール-5-イル)ヘキサデカノイル)アミノ)エトキシ)エトキシ)アセチル)[Aib8,22,35,Arg26,34,Lys37] GLP-1 (7-37)
LCMS: m/z = 1336.2 (MH3 3+). Calculated for (MH3 3+): 1335.9。
[3-(4-イミダゾリル)プロピオニル7,Aib22,35,Arg26,34,Lys37] GLP-1 (7-37) ペプチド
HPLC: (method B6): RT = 32.8 min (99%)
LCMS: m/z = 1326.3 (MH3 3+). Calculated for (MH3 3+): 1326.2。
LCMS: m/z = 1330.9 (MH3 3+). Calculated for (MH3 3+): 1330.9。
LCMS: m/z = 1634.3 (MH3 3+). Calculated for (MH3 3+): 1634.5。
N εB29 -(16-2H -テトラゾール-5-イル-ヘキサデカノイル) ガンマ-Glu-des(B30)ヒトインスリン
工程1:2-(16-2H-テトラゾール-5-イル-ヘキサデカノイルアミノ)ペンタン二酸1-tert-ブチルエステルの合成
工程3:N εB29 -(16-2H -テトラゾール-5-イル-ヘキサデカノイル) ガンマ-Glu-des(B30) ヒトインスリンの合成
A: アセトニトリル
B: 水
D: 水中1.0% TFA
勾配: 5 --> 95% A、15分、1.0 ml/分
シンメトリー300、C18、5 μm、3.9×150 mmカラム
カラムオーブン温度= 42 ℃; 214 nmで検出。
LCMS: m/z = 1335 (MH3 3+)。算出 (MH3 3+): 1334
例29.
Nε37-(4-(4-(4-(4-(5-テトラゾリル)フェニル)フェニル)フェノキシ)ブチリル)[Gly8,Arg26,34]GLP-1-(7-37) ペプチド
LCMS: m/z = 1303 (MH3 3+). 算出 (MH3 3+): 1303
例30.
17,17-ビス(5-テトラゾリル)ヘプタデカン酸
MeCN (20 ml)中の16-ブロモヘキサデカン酸メチルエステル (1.40 g、4.0 mmol)に、マロノジニトリル (1.01 g、15.3 mmol)及びK2CO3 (0.92 g、6.64 mmol)を加えた。該混合物を80 ℃で18.5時間撹拌した。水 (50 ml)及び1N HCl (50 ml)を加え、該産物をAcOEtで抽出した。併せた抽出物を潅水で洗浄し、MgSO4で乾燥し、減圧下で濃縮した。1.87 g (100%) の油を得た。これは、数時間後に完全に結晶化した。
17,17-ジシアノヘプタデカン酸メチルエステル (2.25 g、6.73 mmol)に、DMF (12 ml)、AcOH (4.1 ml、68.3 mmol)、NEt3 (9.0 ml、64.9 mmol)、及びNaN3 (5.25 g、80.8 mmol)を加えた。得られた混合物を140 ℃で19時間撹拌した。水 (90 ml)及び1N HCl (60 ml) を加え、該混合物に濃塩酸を加えて酸性化した。固体を濾過し、水で洗浄し、熱メタノールから再結晶し、1.70 g (60%)の表題化合物を固体として得た。
17,17-ビス(5-テトラゾリル)ヘプタデカン酸メチルエステル (1.70 g、4.04 mmol)をMeOH (40 ml)に溶解し、水 (3 ml)中のNaOH (1.17 g、29 mmol)溶液を加えた。室温で19時間撹拌した後はもはや開始エステルは1H NMRで検出されず、該混合物を水 (130 ml)と1N HCl (50 ml)の混合物で希釈した。この産物を濾過して単離し、水で洗浄し、沸騰MeCN (40 ml)から再結晶し、0.53 g (32%)の表題化合物を固体として得た。母液からさらなる産物(0.39 g)が得られた。総収量:0.92 g、56%。
LCMS: m/z = 1306 (MH3 3+)、1959 (MH2 2+). 算出 (MH3 3+): 1306
例32.
4-(4'-{5-[4-(5-テトラゾリル)フェニル]-[1,2,4]オキサジアゾール-3-イル}ビフェニル-4-イルオキシ)酪酸
Nε37-(4-(4'-{5-[4-(5-テトラゾリル)フェニル]-[1,2,4]オキサジアゾール-3-イル}ビフェニル-4-イルオキシ)ブチリル)[Gly8,Arg26,34]GLP-1-(7-37) ペプチド
LCMS: m/z = 1326 (MH3 3+). 算出 (MH3 3+): 1326。
LCMS: m/z = 1323 (MH3 3+). 算出 (MH3 3+): 1323。
LCMS: m/z = 1327 (MH3 3+). 算出 (MH3 3+): 1327。
LCMS: m/z = 1276 (MH3 3+). 算出 (MH3 3+): 1276。
LCMS: m/z = 1136 (MH3 3+). 算出 (MH3 3+): 1136。
Nε26-({2-[2-(4-(16-(テトラゾール-5-イル)ヘキサデカノイルスルファモイル)ブチリルアミノ)エトキシ]エトキシ}アセチル)-[Arg34] GLP-1 (7-37) ペプチド
LCMS: m/z = 1329 (MH3 3+). 算出 (MH3 3+): 1329。
Nε34-({2-[2-(4-(16-(テトラゾール-5-イル)ヘキサデカノイルスルファモイル)ブチリルアミノ)エトキシ]エトキシ}アセチル)-[Arg26] GLP-1 (7-34) ペプチドアミド
LCMS: m/z = 1234 (MH3 3+). 算出 (MH3 3+): 1234。
Nε26-({2-[2-(4-(16-(テトラゾール-5-イル)ヘキサデカノイルスルファモイル)ブチリルアミノ)エトキシ]エトキシ}アセチル)-[(3-(4-イミダゾリル)プロピオニル)7,Arg34]GLP-1 (7-37) ペプチド
LCMS: m/z = 1324 (MH3 3+). 算出 (MH3 3+): 1324。
LCMS: m/z = 1285 (MH3 3+). 算出 (MH3 3+): 1285。
LCMS: m/z = 1286 (MH3 3+). 算出 (MH3 3+): 1285。
LCMS: m/z = 1276 (MH3 3+). 算出 (MH3 3+): 1276。
LCMS: m/z = 1304 (MH3 3+). 算出 (MH3 3+): 1304。
例47.
Nε18-(4-(16-(テトラゾール-5-イル)ヘキサデカノイルスルファモイル)ブチリル)[Lys18;Arg26,34]GLP-1-(7-37) ペプチド
LCMS: m/z = 1304 (MH3 3+). 算出 (MH3 3+): 1304。
Nε18-(4-(16-(テトラゾール-5-イル)ヘキサデカノイルスルファモイル)ブチリル)[3-(4-イミダゾリル)プロピオニル7;Lys18;Arg26,34]GLP-1-(7-37) ペプチド
Nε26-((2-(2-(2-(2-(2-(4-(16-(テトラゾール-5-イル)ヘキサデカノイルスルファモイル)ブチリル)エトキシ)
エトキシ)アセチルアミノ)エトキシ)エトキシ)アセチル)-[Arg34]GLP-1-(7-37) ペプチド
Nε26-((2-(2-(2-(2-(2-(4-(16-(テトラゾール-5-イル)ヘキサデカノイルスルファモイル)ブチリル)エトキシ)エトキシ)アセチルアミノ)エトキシ)エトキシ)アセチル)[Gly8,Arg34]GLP-1-(7-37) ペプチド
Nε26-((2-(2-(2-(2-(2-(4-(16-(テトラゾール-5-イル)ヘキサデカノイルスルファモイル)ブチリル)エトキシ)エトキシ)アセチルアミノ)エトキシ)エトキシ)アセチル)-[Aib8,Arg34]GLP-1-(7-37) ペプチド
LCMS: m/z = 1330 (MH3 3+). 算出 (MH3 3+): 1330。
LCMS: m/z = 1305 (MH3 3+). 算出 (MH3 3+): 1305。
LCMS: m/z = 1301 (MH3 3+). 算出 (MH3 3+): 1301。
LCMS: m/z = 1319 (MH3 3+). 算出 (MH3 3+): 1319。
LCMS: m/z = 1290 (MH3 3+). 算出 (MH3 3+): 1290。
LCMS: m/z = 1313 (MH3 3+). 算出 (MH3 3+): 1313。
Nε26-[4(S)-4-(16-{4-[4-(1-H-テトラゾール-5-イル)フェニル]フェノキシ}ヘキサデカノイルアミノ)-4-カルボキシブチリル] [Aib8,Arg34] GLP-1(7-37)。
又は
Nε26-[4(S)-4-(2-(2-(2-(6-(N-(16-(1-H-テトラゾール-5-イル)ヘキサデカノイル)スルファモイル)ヘキサノイルアミノ)エトキシ)エトキシ)アセチルアミノ)-4-カルボキシブチリル] [Aib8,Arg34] GLP-1(7-37)。
又は
Nε26-[4(S)-4-(2-(2-(2-(2-(2-(2-(6-(N-(16-(1-H-テトラゾール-5-イル)ヘキサデカノイル)スルファモイル)ヘキサノイルアミノ)エトキシ)エトキシ)アセチルアミノ)エトキシ)エトキシ)アセチルアミノ)-4-カルボキシブチリル] [Aib8,Arg34] GLP-1(7-37)。
Claims (42)
- 分子の血漿半減期を増加する方法であって、該分子を複素環式カルボン酸バイオアイソスターに共有結合的に結合させることを含む方法。
- 分子の血漿半減期を増加する方法であって、該分子を1H-テトラゾールに共有結合的に結合させることを含む方法。
- 分子の血漿半減期を増加する方法であって、前記分子を一般式(I)の化合物に転換することを含む方法:
G、X、及びYは独立して、
単結合、-S-、-O-、-NH-、-(CH2)1-15-、-C(O)NH-、又は
一以上のアルキル、アミノ、シクロアルキル、アリール、ヘテロアリール、ハロゲン、ニトロ、低級アルコキシ、ヒドロキシ、MeCONH-、アルカノイル、又はシアノで任意に置換されたアリーレン、又は
一以上のアルキル、アミノ、シクロアルキル、アリール、ヘテロアリール、ハロゲン、ニトロ、低級アルコキシ、ヒドロキシ、MeCONH-、アルカノイル、又はシアノで任意に置換されたヘテロアリーレン、
を表し、及び、
Zは、単結合又は
-(CH2)n-、-O-(CH2)n-、-S-(CH2)n-、-(OCH2CH2)n-、-(CF2)n-、-O-CH2-(CF2)n-、-S-CH2-(CF2)n-、
(式中 nは1-40である)
を表し、及び、
Aは、
-C(=O)-、-O-C(=O)-、-NH-C(=O)-、-C(C=O)NH-S(=O)2-、-S(=O)2NH-C(=O)-、-(CH2)1-5-、-O-(CH2)1-5-、又は-O-(CH2)1-5-C(=O)-、
を表し、及び、
Q は、単結合又は
-[NH-(CH2CH2O)m-(CH2)p-E-C(=O)]q-、又は
-O-(CH2CH2O)m-(CH2)p-E-C(=O)-、又は
-S-(CH2CH2O)m-(CH2)p-E-C(=O)-、
(式中 Eは単結合、O、S、又はNHであり、及びm、p、及びqは独立して1-40である)
を表し、及び、
Rは、単結合又は[-NH(CH2)4CH(NH-)-C(=O)-]1-5のようなポリラジカルを表し、及び
t は1-40であり、及び
「分子」という用語は、該基A又はQが共有結合的に結合される、アミノ基又はメルカプト基を含む化合物を指す。 - 一般式(I)の化合物:
G、X、及びYは独立して、
単結合、-S-、-O-、-NH-、-(CH2)1-10-、又は
一以上のアルキル、アミノ、シクロアルキル、アリール、ヘテロアリール、ハロゲン、ニトロ、低級アルコキシ、ヒドロキシ、MeCONH-、アルカノイル、又はシアノで任意に置換されたアリーレン、又は
一以上のアルキル、アミノ、シクロアルキル、アリール、ヘテロアリール、ハロゲン、ニトロ、低級アルコキシ、ヒドロキシ、MeCONH-、アルカノイル,又はシアノで任意に置換されたヘテロアリーレン、
を表し、及び
Z は、単結合又は
-(CH2)n-、-O-(CH2)n-、-S-(CH2)n-、-(OCH2CH2)n-、-(CF2)n-、-O-CH2-(CF2)n-、-S-CH2-(CF2)n-、
(式中 nは1-40である)
を表し、及び、
A は、
-C(=O)-、-O-C(=O)-、-NH-C(=O)-、-C(C=O)NH-S(=O)2-、-S(=O)2NH-C(=O)-、-(CH2)1-5-、-O-(CH2)1-5-、又は-O-(CH2)1-5-C(=O)-
を表し、及び
Q は、単結合又は
-[NH-(CH2CH2O)m-(CH2)p-E-C(=O)]q-、又は
-O-(CH2CH2O)m-(CH2)p-E-C(=O)-、又は
-S-(CH2CH2O)m-(CH2)p-E-C(=O)-、
(式中 Eは単結合、O、S、又はNHであり、及びm、p、及びqは独立して1-40である)
を表し、及び
R は、単結合又は[-NH(CH2)4CH(NH-)-C(=O)-]1-5のようなポリラジカルを表し、及び
t は1-40であり、及び
「分子」という用語は、該基A又はQが共有結合的に結合される、アミノ基又はメルカプト基を含む化合物を指す。 - 前記G、X及びYが全て単結合である、請求項4に記載の化合物。
- 前記G、X及びY が全て-(CH2)1-10-から選択される、請求項4に記載の化合物。
- 前記t が1である、請求項4〜6の何れか一項に記載の化合物。
- 前記分子が、リジン残基のε-アミノ基を介してRに共有結合的に結合される、請求項4〜8の何れか一項に記載の化合物。
- 前記分子が、システイン残基のチオール基を介してRに共有結合的に結合される、請求項4〜8の何れか一項に記載の化合物。
- 前記分子が治療的薬剤である、請求項4〜10の何れか一項に記載の化合物。
- 前記治療的薬剤が生体高分子である、請求項11に記載の化合物。
- 前記治療的薬剤がポリペプチドである、請求項11に記載の化合物。
- 前記治療的薬剤が小分子薬物である、請求項11に記載の化合物。
- 前記ポリペプチドがインシュリン分泌性ペプチドである、請求項13に記載の化合物。
- 前記ポリペプチドがGLP-1(7-37)又はその変異体である、請求項15に記載の化合物。
- 前記ポリペプチドがGLP-1(7-37)又はその類似体である、請求項15に記載の化合物。
- 前記ポリペプチドが、式(IV)のアミノ酸配列:
Xaa7-Xaa8-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Xaa16-Ser-Xaa18-Xaa19-Xaa20-Glu-Xaa22-Xaa23-Ala-Xaa25-Xaa26-Xaa27-Phe-Ile-Xaa30-Trp-Leu-Xaa33-Xaa34-Xaa35-Xaa36-Xaa37-Xaa38-Xaa39-Xaa40-Xaa41-Xaa42-Xaa43-Xaa44-Xaa45-Xaa46
式 (III) (配列番号:3)
を含む、請求項16〜17の何れか一項に記載の化合物:
ここにおいて、
Xaa7 はL-ヒスチジン、D-ヒスチジン、desアミノ-ヒスチジン、2-アミノ-3-(2-アミノイミダゾール-4-イル)プロピオン酸、β-ヒドロキシ-ヒスチジン、ホモヒスチジン、Nα-アセチル-ヒスチジン、α-フルオロメチル-ヒスチジン、α-メチル-ヒスチジン、3-ピリジルアラニン、2-ピリジルアラニン又は4-ピリジルアラニンであり;
Xaa8 は Ala、Gly、Val、Leu、Ile、Lys、Aib、1-アミノシクロプロパンカルボン酸、1-アミノシクロブタンカルボン酸、1-アミノシクロペンタンカルボン酸、1-アミノシクロヘキサンカルボン酸、1-アミノシクロヘプタンカルボン酸、又は1-アミノシクロオクタンカルボン酸であり;
Xaa16 は Val又はLeuであり;
Xaa18 は Ser、Lys又はArgであり;
Xaa19 は Tyr又はGlnであり;
Xaa20 はLeu又はMetであり;
Xaa22 はGly、Glu又はAibであり;
Xaa23 はGln、Glu、Lys又はArgであり;
Xaa25 はAla又はValであり;
Xaa26 はLys、Glu又はArgであり;
Xaa27 はGlu又はLeuであり;
Xaa30 はAla、Glu又はArgであり;
Xaa33 はVal又はLysであり;
Xaa34 はLys、Glu、Asn又はArgであり;
Xaa35 はGly又はAibであり;
Xaa36 はArg、Gly又はLysであり;
Xaa37 はGly、Ala、Glu、Pro、Lys、アミド又は欠失であり;
Xaa38 はLys、Ser、アミド又は欠失であり;
Xaa39 はSer、Lys、アミド又は欠失であり;
Xaa40 はGly、アミド又は欠失であり;
Xaa41 はAla、アミド又は欠失であり;
Xaa42 はPro、アミド又は欠失であり;
Xaa43 はPro、アミド又は欠失であり;
Xaa44 はPro、アミド又は欠失であり;
Xaa45 はSer、アミド又は欠失であり;
Xaa46 はアミド又は欠失であり;
Xaa38、Xaa39、Xaa40、Xaa41、Xaa42、Xaa43、Xaa44、Xaa45又はXaa46 が欠失である場合、各アミノ酸残基の下流も欠失である。 - 前記ポリペプチドが、式(V):
Xaa7-Xaa8-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Xaa18-Tyr-Leu-Glu-Xaa22-Xaa23-Ala-Ala-Xaa26-Glu-Phe-Ile-Xaa30-Trp-Leu-Val-Xaa34-Xaa35-Xaa36-Xaa37-Xaa38
式 (IV) (配列番号:4)
のアミノ酸配列を含む、請求項18に記載の化合物:
ここにおいて、
Xaa7 はL-ヒスチジン、D-ヒスチジン、desアミノ-ヒスチジン、2-アミノヒスチジン、β-ヒドロキシ-ヒスチジン、ホモヒスチジン、Nα-アセチル-ヒスチジン、α-フルオロメチル-ヒスチジン、α-メチル-ヒスチジン、3-ピリジルアラニン、2-ピリジルアラニン又は4-ピリジルアラニンであり;
Xaa8 はAla、Gly、Val、Leu、Ile、Lys、Aib、1-アミノシクロプロパンカルボン酸、1-アミノシクロブタンカルボン酸、1-アミノシクロペンタンカルボン酸、1-アミノシクロヘキサンカルボン酸、1-アミノシクロヘプタンカルボン酸、又は1-アミノシクロオクタンカルボン酸であり;
Xaa18 はSer、Lys又はArgであり;
Xaa22 はGly、Glu又はAibであり;
Xaa23 はGln、Glu、Lys又はArgであり;
Xaa26 はLys、Glu又はArgであり;
Xaa30 はAla、Glu又はArgであり;
Xaa34 はLys、Glu又はArgであり;
Xaa35 はGly又はAibであり;
Xaa36 はArg又はLysであり;
Xaa37 はGly、Ala、Glu又はLysであり;
Xaa38 はLys、アミド又は欠失である。 - 請求項17〜19の何れか一項に記載の化合物であって、前記ポリペプチドが、GLP-1(7-35)、GLP-1(7-36)、GLP-1(7-36)-アミド、GLP-1(7-37)、GLP-1(7-38)、GLP-1(7-39)、GLP-1(7-40)、GLP-1(7-41)又はそれらの類似体から選択される化合物。
- 請求項17〜20の何れか一項に記載の化合物であって、前記ポリペプチドが、GLP-1(7-37) (配列番号:1)と比較して、交換され、追加され、又は欠失された、わずか15のアミノ酸残基、或いは、GLP-1(7-37) (配列番号:1)と比較して、交換され、追加され、又は欠失された、わずか10のアミノ酸残基を含む化合物。
- 請求項21に記載の化合物であって、前記ポリペプチドが、GLP-1(7-37) (配列番号:1)と比較して、交換され、追加され、又は欠失された、わずか6のアミノ酸残基を含む化合物。
- 請求項21〜22の何れか一項に記載の化合物であって、前記ポリペプチドが、遺伝コードによってコードされない、わずか4のアミノ酸残基を含む化合物。
- 前記ポリペプチドが、DPP-IV保護インシュリン分泌性ペプチドである、請求項17に記載の化合物。
- 前記ポリペプチドが、Aib残基を位置8に含む、請求項17〜24の何れか一項に記載の化合物。
- 請求項17〜25の何れか一項に記載の化合物であって、前記ポリペプチドの位置7のアミノ酸残基が、D-ヒスチジン、desアミノ-ヒスチジン、2-アミノ-3-(2-アミノイミダゾール-4-イル)プロピオン酸、β-ヒドロキシ-ヒスチジン、ホモヒスチジン、Nα-アセチル-ヒスチジン、α-フルオロメチル-ヒスチジン、α-メチル-ヒスチジン、3-ピリジルアラニン、2-ピリジルアラニン及び4-ピリジルアラニンから成る群より選択される化合物。
- 請求項17〜26の何れか一項に記載の化合物であって、前記ポリペプチドが、Arg34GLP-1(7-37)、Lys38Arg26,34GLP-1(7-38)、Lys38Arg26,34GLP-1(7-38)-OH、Lys36Arg26,34GLP-1(7-36)、Aib8,22,35 GLP-1(7-37)、Aib8,35 GLP-1(7-37)、Aib8,22 GLP-1(7-37)、Aib8,22,35 Arg26,34Lys38GLP-1(7-38)、Aib8,35 Arg26,34Lys38GLP-1(7-38)、Aib8,22 Arg26,34Lys38GLP-1(7-38)、Aib8,22,35 Arg26,34Lys38GLP-1(7-38)、Aib8,35 Arg26,34Lys38GLP-1(7-38)、Aib8,22,35 Arg26Lys38GLP-1(7-38)、Aib8,35 Arg26Lys38GLP-1(7-38)、Aib8,22 Arg26Lys38GLP-1(7-38)、Aib8,22,35 Arg34Lys38GLP-1(7-38)、Aib8,35Arg34Lys38GLP-1(7-38)、Aib8,22Arg34Lys38GLP-1(7-38)、Aib8,22,35Ala37Lys38GLP-1(7-38)、Aib8,35Ala37Lys38GLP-1(7-38)、Aib8,22Ala37Lys38GLP-1(7-38)、Aib8,22,35 Lys37GLP-1(7-37)、Aib8,35Lys37GLP-1(7-37)及びAib8,22Lys37GLP-1(7-38)から成る群より選択される化合物。
- 請求項17〜27の何れか一項に記載の化合物であって、前記ポリペプチドが、配列番号:1のアミノ酸配列に関して位置23、26、34、36又は38のアミノ酸残基を介してRに結合する化合物。
- 前記ポリペプチドが、エクセンディン-4又はその類似体である、請求項13及び15の何れか一項に記載の化合物。
- 請求項29に記載の化合物であって、前記ポリペプチドが、エクセンディン-4(1-39) (配列番号:2)と比較して交換され、追加され、又は欠失された、わずか12のアミノ酸残基、或いは、エクセンディン-4(1-39) (配列番号:2)と比較して交換され、追加され、又は欠失された、わずか8のアミノ酸残基を含む、エクセンディン-4類似体である化合物。
- 請求項13、15又は30の何れか一項に記載の化合物であって、前記ポリペプチドが、ZP-10、即ちHGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPSKKKKKK-アミド (配列番号:5)である化合物。
- 請求項4に記載の化合物であって、前記化合物が、下記からなる群より選択される化合物:
N-ε-26-(16-[5-テトラゾリル]ヘキサデカノイル)Arg34GLP-1-(7-37)、
Gly8,Arg26,34GLP-1(7-37)Lys(16-(5-テトラゾリル)ヘキサデカノイル)、Gly8,Arg26,34GLP-1(7-37)Lys{4-[N-(16-{5-テトラゾリル}ヘキサデカノイル)スルファモイル]ブチリル}、N-ε-26-{4-[N-(16-{5-テトラゾリル}ヘキサデカノイル)スルファモイル]ブチリル} Arg34GLP-1(7-37)、
N-ε-37-(2-(2-(2-(16-(テトラゾール-5-イル)(ヘキサデカノイルアミノ)エトキシ)エトキシ)アセチル)) Aib8,22,35Lys37GLP-1(7-37)、
Gly8,Glu22,23,30Arg18,26,34 GLP-1(7-37)Lys(16-(1H-テトラゾール-5-イル)ヘキサデカン酸 [2-(2-{[2-(2-カルバモイルメトキシエトキシ)エチルカルバモイル]メトキシ}エトキシ)エチル]アミド)-NH2、及びGly8Arg26,34GLP-1(7-37)Lys(4-(4-(4-(4-(5-テトラゾリル)フェニル)フェニル)フェノキシ)ブチリル).N-ε38-(2-(2-(2-(16-(4-(5-テトラゾリル)フェノキシ)ヘキサデカノイル)エトキシ)エトキシ)アセチル) [Gly8,Arg26,34,Lys38]GLP-1(7-37) ペプチド
(ヘキサデカノイルアミノ)エトキシ)エトキシ)アセチル))[3-(4-イミダゾリル)プロピオニル7,Aib22,35,Arg26,34,Lys37] GLP-1 (7-37) ペプチド
NB29ε-4-[4''-(1H-テトラゾール-5-イル)-[1,1';4',1'']テルフェニル-4-イルオキシ]-ブチロイル des(B30) インスリン
エトキシ)エトキシ)アセチル)[Gly8,Arg26,34]GLP-1-(7-37) ペプチド
- 請求項13に記載の化合物であって、前記治療的薬剤がヒト成長ホルモン又はその類似体である化合物。
- 請求項13に記載の化合物であって、前記治療的薬剤がヒトインスリン又はその類似体である化合物。
- 請求項13に記載の化合物であって、前記治療的薬剤がVII因子又はその類似体である化合物。
- 請求項4〜35の何れか一項の化合物の合成のための、請求項36に記載の化合物の使用。
- 請求項4〜35の何れか一項に記載の化合物、及び、薬学的に許容される賦形剤を含む薬学的組成物。
- 非経口投与に適する、請求項38に記載の薬学的組成物。
- 高血糖、2型糖尿病、耐糖能障害、1型糖尿病、肥満症、高血圧症、X症候群、異脂肪血症、毒性多血に関する疾患、認知性疾患、アテローム性動脈硬化症、心筋梗塞、冠状動脈心疾患、脳卒中及び他の循環器病、炎症性腸症候群、消化不良及び胃潰瘍の治療又は予防のための薬剤の調製のための、請求項15〜32の何れか一項に記載の化合物の使用。
- 2型糖尿病における疾病の進行を遅延させるか又は予防するための薬剤の調製のための、請求項15〜32の何れか一項に記載の化合物の使用。
- 食物摂取を減少させるため、β-細胞アポトーシスを減少させるため、β-細胞機能及びβ-細胞質量を上昇させるため、β-細胞再生を刺激するため及び/又はグルコース感受性をβ-細胞に回復させるための薬剤の調製のための、請求項15〜32の何れか一項に記載の化合物の使用。
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BR (1) | BRPI0512988A (ja) |
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ES (2) | ES2564167T3 (ja) |
MX (1) | MXPA06015049A (ja) |
RU (1) | RU2006144821A (ja) |
WO (1) | WO2006005667A2 (ja) |
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JP2012515747A (ja) * | 2009-01-23 | 2012-07-12 | ノヴォ・ノルディスク・アー/エス | アルブミンバインダーa−b−c−d−e−を有するfgf21誘導体及びそれらの使用 |
US9480753B2 (en) | 2009-01-23 | 2016-11-01 | Novo Nordisk A/S | FGF21 derivatives with albumin binder A-B-C-D-E- and their use |
JP2013532644A (ja) * | 2010-07-20 | 2013-08-19 | ノヴォ ノルディスク アー/エス | N末端が修飾されたfgf21化合物 |
US9655974B2 (en) | 2010-07-20 | 2017-05-23 | Novo Nordisk A/S | N-terminal modified FGF21 compounds |
KR20170095256A (ko) * | 2014-12-23 | 2017-08-22 | 노보 노르디스크 에이/에스 | Fgf21 유도체 및 그것의 용도 |
US9744213B2 (en) | 2014-12-23 | 2017-08-29 | Novo Nordisk A/S | FGF21 derivatives and uses thereof |
US9895417B2 (en) | 2014-12-23 | 2018-02-20 | Novo Nordisk A/S | FGF21 derivatives and uses thereof |
US10124039B2 (en) | 2014-12-23 | 2018-11-13 | Novo Nordisk A/S | FGF21 derivatives and uses thereof |
KR102427527B1 (ko) | 2014-12-23 | 2022-08-01 | 노보 노르디스크 에이/에스 | Fgf21 유도체 및 그것의 용도 |
Also Published As
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CN101005857A (zh) | 2007-07-25 |
EP1765408B1 (en) | 2015-12-09 |
EP2289560A2 (en) | 2011-03-02 |
EP2289560B1 (en) | 2015-04-22 |
WO2006005667A3 (en) | 2006-10-12 |
ES2564167T3 (es) | 2016-03-18 |
KR20070029247A (ko) | 2007-03-13 |
EP1765408A2 (en) | 2007-03-28 |
WO2006005667A2 (en) | 2006-01-19 |
EP2292272A3 (en) | 2011-10-26 |
MXPA06015049A (es) | 2007-02-08 |
RU2006144821A (ru) | 2008-08-20 |
AU2005261740A1 (en) | 2006-01-19 |
EP2292272A2 (en) | 2011-03-09 |
US20090111730A1 (en) | 2009-04-30 |
EP2289560A3 (en) | 2011-10-19 |
US9061067B2 (en) | 2015-06-23 |
US20120088716A1 (en) | 2012-04-12 |
BRPI0512988A (pt) | 2008-04-22 |
ES2542228T3 (es) | 2015-08-03 |
CA2572770A1 (en) | 2006-01-19 |
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