JP5583635B2 - ペプチドのトランスグルタミナーゼ媒介性の結合 - Google Patents
ペプチドのトランスグルタミナーゼ媒介性の結合 Download PDFInfo
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- JP5583635B2 JP5583635B2 JP2011115773A JP2011115773A JP5583635B2 JP 5583635 B2 JP5583635 B2 JP 5583635B2 JP 2011115773 A JP2011115773 A JP 2011115773A JP 2011115773 A JP2011115773 A JP 2011115773A JP 5583635 B2 JP5583635 B2 JP 5583635B2
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- human insulin
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- peptide
- mpeg
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- C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
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Description
i)1以上の工程で、ペプチドを、前記ペプチドを構成しているアミノ酸の何れとも接触可能ではない(not accessible)1以上の官能基または潜在的な官能基(latent functional groups)を具備する第1化合物と、前記第1化合物を前記ペプチドへと導入することを触媒する能力を有するトランスグルタミナーゼの存在下で反応させて、機能化ペプチドを形成する工程と、
ii)任意に、前記潜在的な官能基を活性化させる工程と、
iii)1以上の工程で、前記機能化ペプチドを、前記ペプチドを構成しているアミノ酸残基における接触可能な官能基と反応せず、かつ前記第1化合物中の前記官能基と反応する能力を有する1以上の官能基を具備する第2化合物と反応させて、前記機能化ペプチドと前記第2化合物との間に共有結合を形成する工程。
上記式中のDは、結合または酸素を表し;
Rは、リンカーまたは結合を表し;
Xは、ペプチド P-C(O)-NH2を構成しているアミノ酸残基に接触可能ではない1以上の官能基又は潜在的な官能基を具備しているラジカルを表し;
Yは、Xに存在する官能基と反応し、かつペプチド P-C(O)-NH2における接触可能な官能基と反応しない1以上の官能基を具備しているラジカルを表し;
Eは、リンカーまたは結合を表し;
Aは、XおよびYに具備された官能基のペア間の反応によって形成される成分(moiety)を表し;並びに
Zは、前記ペプチドに結合される成分(moiety)である。
ヒドラジン誘導体 -NH-NH2,
ヒドラジンカルボキシレート誘導体 -O-C(O)-NH-NH2,
セミカルバジド誘導体 -NH-C(O)-NH-NH2,
チオセミカルバジド誘導体 -NH-C(S)-NH-NH2,
炭酸ジヒドラジド誘導体 -NHC(O)-NH-NH-C(O)-NH-NH2,
カルバジド誘導体 -NH-NH-C(O)-NH-NH2,
チオカルバジド誘導体 -NH-NH-C(S)-NH-NH2,
アリールヒドラジン誘導体 -NH-C(O)-C6H4-NH-NH2,および
ヒドラジド誘導体 -C(O)-NH-NH2;または
オキシルアミン誘導体(例えば、-O-NH2, -C(O)-O-NH2, -NH-C(O)-O-NH2 および -NH-C(S)-O-NH2)である。
NεB28-(CO-(CH2)14-COOH) LysB28ProB29-ヒトインシュリン; NεB28-(CO-(CH2)16-COOH) LysB28ProB29-ヒトインシュリン; NεB28-(CO-(CH2)18-COOH) LysB28ProB29-ヒトインシュリン; NεB28-(CO-(CH2)20-COOH) LysB28ProB29-ヒトインシュリン; NεB28-(CO-(CH2)22-COOH) LysB28ProB29-ヒトインシュリン; NεB29-(CO-(CH2)14-COOH) desB30 ヒトインシュリン; NεB29-(CO-(CH2)16-COOH) desB30 ヒトインシュリン; NεB29-(CO-(CH2)18-COOH) desB30 ヒトインシュリン; NεB29-(CO-(CH2)20-COOH) desB30 ヒトインシュリン; および NεB29-(CO-(CH2)22COOH) desB30 ヒトインシュリン。
Gly(A1),Lys(B29) ジガラクトースヒトインシュリン, Phe(B1),Gly(A1)ジイソマルトースヒトインシュリン, Phe(B1),Lys(B29) ジイソマルトースヒトインシュリン, Gly(A1),Lys(B29) ジイソマルトースヒトインシュリン, Phe(B1)グルコース[AspB10]ヒトインシュリンおよびGly(A1),Phe(B1)ジグルコース[AspB10]ヒトインシュリンに関してなされる。
GlyA21,LysB27,ThrB30-NH2 ヒトインシュリン, SerA21,LysB27 ,ThrB30-NH2 ヒトインシュリン,
ThrA21,LysB27,ThrB30-NH2 ヒトインシュリン, AlaB21,LysB27,ThrB30-NH2 ヒトインシュリン,
HisB30,LysB27,ThrB30-NH2 ヒトインシュリン, AspB21,LysB27,ThrB30-NN2 ヒトインシュリン,
GlyA21,ArgB21,ThrB30-NH2 ヒトインシュリン, SerA21,ArgB27, ThrB30-NH2 ヒトインシュリン,
ThrA21,ArgB27,ThrB30-NH2 ヒトインシュリン, AlaB21,ArgB27,ThrB30-NH2 ヒトインシュリン,
HisA21,ArgB27,ThrB30-NH2 ヒトインシュリン, AspB21,ArgB27,ThrB30-NH2 ヒトインシュリン,
GlnB13,GlyA21,ArgB27,ThrB30-NH2 ヒトインシュリン, GlnB13,SerA21,ThrB30-NH2 ヒトインシュリン,
GlnB13,SerA21,ArgB27,ThrB30-NH2 ヒトインシュリン, GlnB13,ThrA21,ArgB27,ThrB30-NH2 ヒトインシュリン,
GlnB13,AlaA21,ArgB27,ThrB30-NH2 ヒトインシュリン, GlnB13,HisA21,ArgB27,ThrB30-NH2 ヒトインシュリン,
GlnB13,AspA21,ArgB27,ThrB30-NH2 ヒトインシュリン, GlnB13,GlyA21,LysB27,ThrB30-NH2 ヒトインシュリン,
GlnB13,SerA21,LysB27,ThrB30-NH2 ヒトインシュリン, GlnB13,ThrA21,LysB27,ThrB30-NH2 ヒトインシュリン,
GlnB13,AlaA21,LysB27,ThrB30-NH2 ヒトインシュリン, GlnB13,HisA21,LysB27,ThrB30-NH2 ヒトインシュリン,
GlnB13,AspA21,LysB27,ThrB30-NH2 ヒトインシュリン, AsnA21,LysB27 ヒトインシュリン, SerA21,LysB27 ヒトインシュリン, ThrA21,LysB27 ヒトインシュリン, AlaA21,LysB27 ヒトインシュリン, HisA21,LysB27 ヒトインシュリン, AspA21,LysB27 ヒトインシュリン, GlyA21,LysB27 ヒトインシュリン, AsnA21,ArgB27 ヒトインシュリン,
SerA21,ArgB27ヒトインシュリン, ThrA21,ArgB27 ヒトインシュリン, AlaA21,ArgB27ヒトインシュリン,
HisA21,ArgB27 ヒトインシュリン, AspA21,ArgB27ヒトインシュリン, GlyA21,ArgB27 ヒトインシュリン,
GlnA17,AsnA21,ArgB27ヒトインシュリン, GlnA17,SerA21,ArgB27ヒトインシュリン, GlnA17,ThrA21,ArgB27ヒトインシュリン, GlnA17,AlaA21,ArgB27ヒトインシュリン, GlnA17,HisA21,ArgB27ヒトインシュリン,
GlnA17,AspA21,ArgB27ヒトインシュリン, GlnA17,GlyA21,ArgB27ヒトインシュリン,
GlnA17,AsnA21,GlnB13ヒトインシュリン, GlnA17,SerA21,GlnB13ヒトインシュリン, GlnA17,ThrA21,GlnB13ヒトインシュリン, GlnA17,AlaA21,GlnB13ヒトインシュリン, GlnA17,HisA21,GlnB13ヒトインシュリン,
GlnA17,AspA21,GlnB13ヒトインシュリン, GlnA17,GlyA21,GlnB13ヒトインシュリン,
ArgA27,AsnA21,GlnB13ヒトインシュリン, ArgA27,SerA21,GlnB13ヒトインシュリン, ArgA27,ThrA21,GlnB13ヒトインシュリン, ArgA27,AlaA21,GlnB13ヒトインシュリン, ArgA27,HisA21,GlnB13ヒトインシュリン,
ArgA27,AspA21,GlnB13ヒトインシュリン, ArgA27,GlyA21,GlnB13ヒトインシュリン,
GlnA17,AsnA21,LysB27ヒトインシュリン, GlnA17,SerA21,LysB27ヒトインシュリン, GlnA17,ThrA21,LysB27ヒトインシュリン, GlnA17,AlaA21,LysB27ヒトインシュリン, GlnA17,HisA21,LysB27ヒトインシュリン,
GlnA17,AspA21,LysB27ヒトインシュリン, GlnA17,GlyA21,LysB27ヒトインシュリン,
GlnB13,AsnA21,LysB27ヒトインシュリン, GlnB13,SerA21,LysB27ヒトインシュリン, GlnB13,ThrA21,LysB27ヒトインシュリン, GlnB13,AlaA21,LysB27ヒトインシュリン, GlnB13,HisA21,LysB27ヒトインシュリン,
GlnB13,AspA21,LysB27ヒトインシュリン, およびGlnB13,GlyA21,LysB27ヒトインシュリン。
i. ポジションB28がAsp, Lys, Leu, Val, またはAlaであり、ポジションB29がLysまたはProであるアナログ;および
ii. des(B28-B30), des(B27)またはdes(B30)ヒトインシュリン、
は、同様に本発明の方法に適用可能であり、特に、ポジションB28がAspまたはLysであり、ポジションB29がLysまたはProであるインシュリン化合物である。
S5K(3-(ヘキサデカノイルアミノ)プロピオニル)-GLP-2(1-33);
S7K(3-(ヘキサデカノイルアミノ)プロピオニル)-GLP-2(1-33);
D8K(3-(ヘキサデカノイルアミノ)プロピオニル)-GLP-2(1-33);
E9K(3-(ヘキサデカノイルアミノ)プロピオニル)-GLP-2(1-33);
M10K(3-(ヘキサデカノイルアミノ)プロピオニル)-GLP-2(1-33);
N11K(3-(ヘキサデカノイルアミノ)プロピオニル)-GLP-2(1-33);
T12K(3-(ヘキサデカノイルアミノ)プロピオニル)-GLP-2(1-33);
I13K(3-(ヘキサデカノイルアミノ)プロピオニル)-GLP-2(1-33);
L14K(3-(ヘキサデカノイルアミノ)プロピオニル)-GLP-2(1-33);
D15K(3-(ヘキサデカノイルアミノ)プロピオニル)-GLP-2(1-33);
N16K(3-(ヘキサデカノイルアミノ)プロピオニル)-GLP-2(1-33);
L17K(3-(オクタノイルアミノ)プロピオニル)-GLP-2(1-33);
L17K(3-(ノナノイルアミノ)プロピオニル)-GLP-2(1-33);
L17K(3-(デカノイルアミノ)プロピオニル)-GLP-2(1-33);
L17K(3-(ウンデカノイルアミノ)プロピオニル)-GLP-2(1-33);
L17K(3-(ドデカノイルアミノ)プロピオニル)-GLP-2(1-33);
L17K(3-(トリデカノイルアミノ)プロピオニル)-GLP-2(1-33);
L17K(3-(テトラデカノイルアミノ)プロピオニル)-GLP-2(1-33);
L17K(3-(ペンタデカノイルアミノ)プロピオニル)-GLP-2(1-33);
L17K(3-(ヘキサデカノイルアミノ)プロピオニル)-GLP-2(1-33);
L17K(3-(ヘプタデカノイルアミノ)プロピオニル)-GLP-2(1-33);
L17K(3-(オクタデカノイルアミノ)プロピオニル)-GLP-2(1-33);
L17K(3-(ノナデカノイルアミノ)プロピオニル)-GLP-2(1-33);
L17K(3-(エイコサノイルアミノ)プロピオニル)-GLP-2(1-33);
L17K((S)-4-カルボキシル-4-(オクタノイルアミノ)ブタノイル)-GLP-2(1-33);
L17K((S)-4-カルボキシル-4-(ノナノイルアミノ)ブタノイル)-GLP-2(1-33);
L17K((S)-4-カルボキシル-4-(デカノイルアミノ)ブタノイル)-GLP-2(1-33);
L17K((S)-4-カルボキシル-4-(ウンデカノイルアミノ)ブタノイル)-GLP-2(1-33);
L17K((S)-4-カルボキシル-4-(ドデカノイルアミノ)ブタノイル)-GLP-2(1-33);
L17K((S)-4-カルボキシル-4-(トリデカノイルアミノ)ブタノイル)-GLP-2(1-33);
L17K((S)-4-カルボキシル-4-(テトラデカノイルアミノ)ブタノイル)-GLP-2(1-33);
L17K((S)-4-カルボキシル-4-(ペンタデカノイルアミノ)ブタノイル)-GLP-2(1-33);
L17K((S)-4-カルボキシル-4-(ヘキサデカノイルアミノ)ブタノイル)-GLP-2(1-33);
L17K((S)-4-カルボキシル-4-(ヘプタデカノイルアミノ)ブタノイル)-GLP-2(1-33);
L17K((S)-4-カルボキシル-4-(オクタデカノイルアミノ)ブタノイル)-GLP-2(1-33);
L17K((S)-4-カルボキシル-4-(ノナデカノイルアミノ)ブタノイル)-GLP-2(1-33);
L17K((S)-4-カルボキシル-4-(エイコサノイルアミノ)ブタノイル)-GLP-2(1-33);
L17K(4-(オクタノイルアミノ)ブタノイル)-GLP-2(1-33);
L17K(4-(ノナノイルアミノ)ブタノイル)-GLP-2(1-33);
L17K(4-(デカノイルアミノ)ブタノイル)-GLP-2(1-33);
L17K(4-(ウンデカノイルアミノ)ブタノイル)-GLP-2(1-33);
L17K(4-(ドデカノイルアミノ)ブタノイル)-GLP-2(1-33);
L17K(4-(トリデカノイルアミノ)ブタノイル)-GLP-2(1-33);
L17K(4-(テトラデカノイルアミノ)ブタノイル)-GLP-2(1-33);
L17K(4-(ペンタデカノイルアミノ)ブタノイル)-GLP-2(1-33);
L17K(4-(ヘキサデカノイルアミノ)ブタノイル)-GLP-2(1-33);
L17K(4-(ヘプタデカノイルアミノ)ブタノイル)-GLP-2(1-33);
L17K(4-(オクタデカノイルアミノ)ブタノイル)-GLP-2(1-33);
L17K(4-(ノナデカノイルアミノ)ブタノイル)-GLP-2(1-33);
L17K(4-(エイコサノイルアミノ)ブタノイル)-GLP-2(1-33);
A18K(3-(ヘキサデカノイルアミノ)プロピオニル)-GLP-2(1-33);
D21K(3-(ヘキサデカノイルアミノ)プロピオニル)-GLP-2(1-33);
N24K(3-(ヘキサデカノイルアミノ)プロピオニル)-GLP-2(1-33);
Q28K(3-(ヘキサデカノイルアミノ)プロピオニル)-GLP-2(1-33);
S5K(3-(ヘキサデカノイルアミノ)プロピオニル)/K30R-GLP-2(1-33);
S7K(3-(ヘキサデカノイルアミノ)プロピオニル)/K30R-GLP-2(1-33);
D8K(3-(ヘキサデカノイルアミノ)プロピオニル)/K30R-GLP-2(1-33);
E9K(3-(ヘキサデカノイルアミノ)プロピオニル)/K30R-GLP-2(1-33);
M10K(3-(ヘキサデカノイルアミノ)プロピオニル)/K30R-GLP-2(1-33);
N11K(3-(ヘキサデカノイルアミノ)プロピオニル)/K30R-GLP-2(1-33);
T12K(3-(ヘキサデカノイルアミノ)プロピオニル)/K30R-GLP-2(1-33);
I13K(3-(ヘキサデカノイルアミノ)プロピオニル)/K30R-GLP-2(1-33);
L14K(3-(ヘキサデカノイルアミノ)プロピオニル)/K30R-GLP-2(1-33);
D15K(3-(ヘキサデカノイルアミノ)プロピオニル)/K30R-GLP-2(1-33);
N16K(3-(ヘキサデカノイルアミノ)プロピオニル)/K30R-GLP-2(1-33);
L17K(3-(オクタノイルアミノ)プロピオニル)/K30R-GLP-2(1-33);
L17K(3-(ノナノイルアミノ)プロピオニル)/K30R-GLP-2(1-33);
L17K(3-(デカノイルアミノ)プロピオニル)/K30R-GLP-2(1-33);
L17K(3-(ウンデカノイルアミノ)プロピオニル)/K30R-GLP-2(1-33);
L17K(3-(ドデカノイルアミノ)プロピオニル)/K30R-GLP-2(1-33);
L17K(3-(トリデカノイルアミノ)プロピオニル)/K30R-GLP-2(1-33);
L17K(3-(テトラデカノイルアミノ)プロピオニル)/K30R-GLP-2(1-33);
L17K(3-(ペンタデカノイルアミノ)プロピオニル)/K30R-GLP-2(1-33);
L17K(3-(ヘキサデカノイルアミノ)プロピオニル)/K30R-GLP-2(1-33);
L17K(3-(ヘプタデカノイルアミノ)プロピオニル)/K30R-GLP-2(1-33);
L17K(3-(オクタデカノイルアミノ)プロピオニル)/K30R-GLP-2(1-33);
L17K(3-(ノナデカノイルアミノ)プロピオニル)/K30R-GLP-2(1-33);
L17K(3-(エイコサノイルアミノ)プロピオニル)/K30R-GLP-2(1-33);
L17K((S)-4-カルボキシル-4-(オクタノイルアミノ)ブタノイル)/K30R-GLP-2(1-33);
L17K((S)-4-カルボキシル-4-(ノナノイルアミノ)ブタノイル)/K30R-GLP-2(1-33);
L17K((S)-4-カルボキシル-4-(デカノイルアミノ)ブタノイル)/K30R-GLP-2(1-33);
L17K((S)-4-カルボキシル-4-(ウンデカノイルアミノ)ブタノイル)/K30R-GLP-2(1-33);
L17K((S)-4-カルボキシル-4-(ドデカノイルアミノ)ブタノイル)/K30R-GLP-2(1-33);
L17K((S)-4-カルボキシル-4-(トリデカノイルアミノ)ブタノイル)/K30R-GLP-2(1-33);
L17K((S)-4-カルボキシル-4-(テトラデカノイルアミノ)ブタノイル)/K30R-GLP-2(1-33);
L17K((S)-4-カルボキシル-4-(ペンタデカノイルアミノ)ブタノイル)/K30R-GLP-2(1-33);
L17K((S)-4-カルボキシル-4-(ヘキサデカノイルアミノ)ブタノイル)/K30R-GLP-2(1-33);
L17K((S)-4-カルボキシル-4-(ヘプタデカノイルアミノ)ブタノイル)/K30R-GLP-2(1-33);
L17K((S)-4-カルボキシル-4-(オクタデカノイルアミノ)ブタノイル)/K30R-GLP-2(1-33);
L17K((S)-4-カルボキシル-4-(ノナデカノイルアミノ)ブタノイル)/K30R-GLP-2(1-33);
L17K((S)-4-カルボキシル-4-(エイコサノイルアミノ)ブタノイル)/K30R-GLP-2(1-33);
L17K(4-(オクタノイルアミノ)ブタノイル)/K30R-GLP-2(1-33);
L17K(4-(ノナノイルアミノ)ブタノイル)/K30R-GLP-2(1-33);
L17K(4-(デカノイルアミノ)ブタノイル)/K30R-GLP-2(1-33);
L17K(4-(ウンデカノイルアミノ)ブタノイル)/K30R-GLP-2(1-33);
L17K(4-(ドデカノイルアミノ)ブタノイル)/K30R-GLP-2(1-33);
L17K(4-(トリデカノイルアミノ)ブタノイル)/K30R-GLP-2(1-33);
L17K(4-(テトラデカノイルアミノ)ブタノイル)/K30R-GLP-2(1-33);
L17K(4-(ペンタデカノイルアミノ)ブタノイル)/K30R-GLP-2(1-33);
L17K(4-(ヘキサデカノイルアミノ)ブタノイル)/K30R-GLP-2(1-33);
L17K(4-(ヘプタデカノイルアミノ)ブタノイル)/K30R-GLP-2(1-33);
L17K(4-(オクタデカノイルアミノ)ブタノイル)/K30R-GLP-2(1-33);
L17K(4-(ノナデカノイルアミノ)ブタノイル)/K30R-GLP-2(1-33);
L17K(4-(エイコサノイルアミノ)ブタノイル)/K30R-GLP-2(1-33);
A18K(3-(ヘキサデカノイルアミノ)プロピオニル)/K30R-GLP-2(1-33);
D21K(3-(ヘキサデカノイルアミノ)プロピオニル)/K30R-GLP-2(1-33);
N24K(3-(ヘキサデカノイルアミノ)プロピオニル)/K30R-GLP-2(1-33);
Q28K(3-(ヘキサデカノイルアミノ)プロピオニル)/K30R-GLP-2(1-33);
D3E/S5K(3-(ヘキサデカノイルアミノ)プロピオニル)/K30R/D33E-GLP-2(1-33);
D3E/S7K(3-(ヘキサデカノイルアミノ)プロピオニル)/K30R/D33E-GLP-2(1-33);
D3E/D8K(3-(ヘキサデカノイルアミノ)プロピオニル)/K30R/D33E-GLP-2(1-33);
D3E/E9K(3-(ヘキサデカノイルアミノ)プロピオニル)/K30R/D33E-GLP-2(1-33);
D3E/M10K(3-(ヘキサデカノイルアミノ)プロピオニル)/K30R/D33E-GLP-2(1-33);
D3E/N11K(3-(ヘキサデカノイルアミノ)プロピオニル)/K30R/D33E-GLP-2(1-33);
D3E/T12K(3-(ヘキサデカノイルアミノ)プロピオニル)/K30R/D33E-GLP-2(1-33);
D3E/I13K(3-(ヘキサデカノイルアミノ)プロピオニル)/K30R/D33E-GLP-2(1-33);
D3E/L14K(3-(ヘキサデカノイルアミノ)プロピオニル)/K30R/D33E-GLP-2(1-33);
D3E/D15K(3-(ヘキサデカノイルアミノ)プロピオニル)/K30R/D33E-GLP-2(1-33);
D3E/N16K(3-(ヘキサデカノイルアミノ)プロピオニル)/K30R/D33E-GLP-2(1-33);
D3E/L17K(3-(オクタノイルアミノ)プロピオニル)/K30R/D33E-GLP-2(1-33);
D3E/L17K(3-(ノナノイルアミノ)プロピオニル)/K30R/D33E-GLP-2(1-33);
D3E/L17K(3-(デカノイルアミノ)プロピオニル)/K30R/D33E-GLP-2(1-33);
D3E/L17K(3-(ウンデカノイルアミノ)プロピオニル)/K30R/D33E-GLP-2(1-33);
D3E/L17K(3-(ドデカノイルアミノ)プロピオニル)/K30R/D33E-GLP-2(1-33);
D3E/L17K(3-(トリデカノイルアミノ)プロピオニル)/K30R/D33E-GLP-2(1-33);
D3E/L17K(3-(テトラデカノイルアミノ)プロピオニル)/K30R/D33E-GLP-2(1-33);
D3E/L17K(3-(ペンタデカノイルアミノ)プロピオニル)/K30R/D33E-GLP-2(1-33);
D3E/L17K(3-(ヘキサデカノイルアミノ)プロピオニル)/K30R/D33E-GLP-2(1-33);
D3E/L17K(3-(ヘプタデカノイルアミノ)プロピオニル)/K30R/D33E-GLP-2(1-33);
D3E/L17K(3-(オクタデカノイルアミノ)プロピオニル)/K30R/D33E-GLP-2(1-33);
D3E/L17K(3-(ノナデカノイルアミノ)プロピオニル)/K30R/D33E-GLP-2(1-33);
D3E/L17K(3-(エイコサノイルアミノ)プロピオニル)/K30R/D33E-GLP-2(1-33);
D3E/L17K((S)-4-カルボキシル-4-(オクタノイルアミノ)ブタノイル)/K30R/D33E-GLP-2(1-33);
D3E/L17K((S)-4-カルボキシル-4-(ノナノイルアミノ)ブタノイル)/K30R/D33E-GLP-2(1-33);
D3E/L17K((S)-4-カルボキシル-4-(デカノイルアミノ)ブタノイル)/K30R/D33E-GLP-2(1-33);
D3E/L17K((S)-4-カルボキシル-4-(ウンデカノイルアミノ)ブタノイル)/K30R/D33E-GLP-2(1-33);
D3E/L17K((S)-4-カルボキシル-4-(ドデカノイルアミノ)ブタノイル)/K30R/D33E-GLP-2(1-33);
D3E/L17K((S)-4-カルボキシル-4-(トリデカノイルアミノ)ブタノイル)/K30R/D33E-GLP-2(1-33);
D3E/L17K((S)-4-カルボキシル-4-(テトラデカノイルアミノ)ブタノイル)/K30R/D33E-GLP-2(1-33);
D3E/L17K((S)-4-カルボキシル-4-(ペンタデカノイルアミノ)ブタノイル)/K30R/D33E-GLP-2(1-33);
D3E/L17K((S)-4-カルボキシル-4-(ヘキサデカノイルアミノ)ブタノイル)/K30R/D33E-GLP-2(1-33);
D3E/L17K((S)-4-カルボキシル-4-(ヘプタデカノイルアミノ)ブタノイル)/K30R/D33E-GLP-2(1-33);
D3E/L17K((S)-4-カルボキシル-4-(オクタデカノイルアミノ)ブタノイル)/K30R/D33E-GLP-2(1-33);
D3E/L17K((S)-4-カルボキシル-4-(ノナデカノイルアミノ)ブタノイル)/K30R/D33E-GLP-2(1-33);
D3E/L17K((S)-4-カルボキシル-4-(エイコサノイルアミノ)ブタノイル)/K30R/D33E-GLP-2(1-33);
D3E/L17K(4-(オクタノイルアミノ)ブタノイル)/K30R/D33E-GLP-2(1-33);
D3E/L17K(4-(ノナノイルアミノ)ブタノイル)/K30R/D33E-GLP-2(1-33);
D3E/L17K(4-(デカノイルアミノ)ブタノイル)/K30R/D33E-GLP-2(1-33);
D3E/L17K(4-(ウンデカノイルアミノ)ブタノイル)/K30R/D33E-GLP-2(1-33);
D3E/L17K(4-(ドデカノイルアミノ)ブタノイル)/K30R/D33E-GLP-2(1-33);
D3E/L17K(4-(トリデカノイルアミノ)ブタノイル)/K30R/D33E-GLP-2(1-33);
D3E/L17K(4-(テトラデカノイルアミノ)ブタノイル)/K30R/D33E-GLP-2(1-33);
D3E/L17K(4-(ペンタデカノイルアミノ)ブタノイル)/K30R/D33E-GLP-2(1-33);
D3E/L17K(4-(ヘキサデカノイルアミノ)ブタノイル)/K30R/D33E-GLP-2(1-33);
D3E/L17K(4-(ヘプタデカノイルアミノ)ブタノイル)/K30R/D33E-GLP-2(1-33);
D3E/L17K(4-(オクタデカノイルアミノ)ブタノイル)/K30R/D33E-GLP-2(1-33);
D3E/L17K(4-(ノナデカノイルアミノ)ブタノイル)/K30R/D33E-GLP-2(1-33);
D3E/L17K(4-(エイコサノイルアミノ)ブタノイル)/K30R/D33E-GLP-2(1-33);
D3E/A18K(3-(ヘキサデカノイルアミノ)プロピオニル)/K30R/D33E-GLP-2(1-33);
D3E/D21K(3-(ヘキサデカノイルアミノ)プロピオニル)/K30R/D33E-GLP-2(1-33);
D3E/N24K(3-(ヘキサデカノイルアミノ)プロピオニル)/K30R/D33E-GLP-2(1-33); および
D3E/Q28K(3-(ヘキサデカノイルアミノ)プロピオニル)/K30R/D33E-GLP-2(1-33)。
V158D/M298Q-FVII, L305V/K337A-FVII, V158D/E296V/M298Q/L305V-FVII,
V158D/E296V/M298Q/K337A-FVII, V158D/E296V/M298Q/L305V/K337A-FVII, K157A-FVII,
E296V-FVII, E296V/M298Q-FVII, V158D/E296V-FVII, V158D/M298K-FVII, および S336G-FVII,
L305V/K337A-FVII, L305V/V158D-FVII, L305V/E296V-FVII, L305V/M298Q-FVII,
L305V/V158T-FVII, L305V/K337A/V158T-FVII, L305V/K337A/M298Q-FVII,
L305V/K337A/E296V-FVII, L305V/K337A/V158D-FVII, L305V/V158D/M298Q-FVII,
L305V/V158D/E296V-FVII, L305V/V158T/M298Q-FVII, L305V/V158T/E296V-FVII,
L305V/E296V/M298Q-FVII, L305V/V158D/E296V/M298Q-FVII,
L305V/V158T/E296V/M298Q-FVII, L305V/V158T/K337A/M298Q-FVII,
L305V/V158T/E296V/K337A-FVII, L305V/V158D/K337A/M298Q-FVII,
L305V/V158D/E296V/K337A-FVII, L305V/V158D/E296V/M298Q/K337A-FVII,
L305V/V158T/E296V/M298Q/K337A-FVII, S314E/K316H-FVII, S314E/K316Q-FVII,
S314E/L305V-FVII, S314E/K337A-FVII, S314E/V158D-FVII, S314E/E296V-FVII,
S314E/M298Q-FVII, S314E/V158T-FVII, K316H/L305V-FVII, K316H/K337A-FVII,
K316H/V158D-FVII, K316H/E296V-FVII, K316H/M298Q-FVII, K316H/V158T-FVII,
K316Q/L305V-FVII, K316Q/K337A-FVII, K316Q/V158D-FVII, K316Q/E296V-FVII,
K316Q/M298Q-FVII, K316Q/V158T-FVII, S314E/L305V/K337A-FVII, S314E/L305V/V158D-FVII, S314E/L305V/E296V-FVII, S314E/L305V/M298Q-FVII, S314E/L305V/V158T-FVII,
S314E/L305V/K337A/V158T-FVII, S314E/L305V/K337A/M298Q-FVII,
S314E/L305V/K337A/E296V-FVII, S314E/L305V/K337A/V158D-FVII,
S314E/L305V/V158D/M298Q-FVII, S314E/L305V/V158D/E296V-FVII,
S314E/L305V/V158T/M298Q-FVII, S314E/L305V/V158T/E296V-FVII,
S314E/L305V/E296V/M298Q-FVII, S314E/L305V/V158D/E296V/M298Q-FVII,
S314E/L305V/V158T/E296V/M298Q-FVII, S314E/L305V/V158T/K337A/M298Q-FVII,
S314E/L305V/V158T/E296V/K337A-FVII, S314E/L305V/V158D/K337A/M298Q-FVII,
S314E/L305V/V158D/E296V/K337A-FVII, S314E/L305V/V158D/E296V/M298Q/K337A-FVII,
S314E/L305V/V158T/E296V/M298Q/K337A-FVII, K316H/L305V/K337A-FVII,
K316H/L305V/V158D-FVII, K316H/L305V/E296V-FVII, K316H/L305V/M298Q-FVII,
K316H/L305V/V158T-FVII, K316H/L305V/K337A/V158T-FVII, K316H/L305V/K337A/M298Q-FVII, K316H/L305V/K337A/E296V-FVII, K316H/L305V/K337A/V158D-FVII,
K316H/L305V/V158D/M298Q-FVII, K316H/L305V/V158D/E296V-FVII,
K316H/L305V/V158T/M298Q-FVII, K316H/L305V/V158T/E296V-FVII,
K316H/L305V/E296V/M298Q-FVII, K316H/L305V/V158D/E296V/M298Q-FVII,
K316H/L305V/V158T/E296V/M298Q-FVII, K316H/L305V/V158T/K337A/M298Q-FVII,
K316H/L305V/V158T/E296V/K337A-FVII, K316H/L305V/V158D/K337A/M298Q-FVII,
K316H/L305V/V158D/E296V/K337A -FVII, K316H/L305V/V158D/E296V/M298Q/K337A-FVII, K316H/L305V/V158T/E296V/M298Q/K337A-FVII, K316Q/L305V/K337A-FVII,
K316Q/L305V/V158D-FVII, K316Q/L305V/E296V-FVII, K316Q/L305V/M298Q-FVII,
K316Q/L305V/V158T-FVII, K316Q/L305V/K337A/V158T-FVII, K316Q/L305V/K337A/M298Q-FVII, K316Q/L305V/K337A/E296V-FVII, K316Q/L305V/K337A/V158D-FVII,
K316Q/L305V/V158D/M298Q-FVII, K316Q/L305V/V158D/E296V-FVII,
K316Q/L305V/V158T/M298Q-FVII, K316Q/L305V/V158T/E296V-FVII,
K316Q/L305V/E296V/M298Q-FVII, K316Q/L305V/V158D/E296V/M298Q-FVII,
K316Q/L305V/V158T/E296V/M298Q-FVII, K316Q/L305V/V158T/K337A/M298Q-FVII,
K316Q/L305V/V158T/E296V/K337A-FVII, K316Q/L305V/V158D/K337A/M298Q-FVII,
K316Q/L305V/V158D/E296V/K337A -FVII, K316Q/L305V/V158D/E296V/M298Q/K337A-FVII, K316Q/L305V/V158T/E296V/M298Q/K337A-FVII, F374Y/K337A-FVII, F374Y/V158D-FVII, F374Y/E296V-FVII, F374Y/M298Q-FVII, F374Y/V158T-FVII, F374Y/S314E-FVII,
F374Y/L305V-FVII, F374Y/L305V/K337A-FVII, F374Y/L305V/V158D-FVII,
F374Y/L305V/E296V-FVII, F374Y/L305V/M298Q-FVII, F374Y/L305V/V158T-FVII,
F374Y/L305V/S314E-FVII, F374Y/K337A/S314E-FVII, F374Y/K337A/V158T-FVII,
F374Y/K337A/M298Q-FVII, F374Y/K337A/E296V-FVII, F374Y/K337A/V158D-FVII,
F374Y/V158D/S314E-FVII, F374Y/V158D/M298Q-FVII, F374Y/V158D/E296V-FVII,
F374Y/V158T/S314E-FVII, F374Y/V158T/M298Q-FVII, F374Y/V158T/E296V-FVII,
F374Y/E296V/S314E-FVII, F374Y/S314E/M298Q-FVII, F374Y/E296V/M298Q-FVII,
F374Y/L305V/K337A/V158D-FVII, F374Y/L305V/K337A/E296V-FVII,
F374Y/L305V/K337A/M298Q-FVII, F374Y/L305V/K337A/V158T-FVII,
F374Y/L305V/K337A/S314E-FVII, F374Y/L305V/V158D/E296V-FVII,
F374Y/L305V/V158D/M298Q-FVII, F374Y/L305V/V158D/S314E-FVII,
F374Y/L305V/E296V/M298Q-FVII, F374Y/L305V/E296V/V158T-FVII,
F374Y/L305V/E296V/S314E-FVII, F374Y/L305V/M298Q/V158T-FVII,
F374Y/L305V/M298Q/S314E-FVII, F374Y/L305V/V158T/S314E-FVII,
F374Y/K337A/S314E/V158T-FVII, F374Y/K337A/S314E/M298Q-FVII,
F374Y/K337A/S314E/E296V-FVII, F374Y/K337A/S314E/V158D-FVII,
F374Y/K337A/V158T/M298Q-FVII, F374Y/K337A/V158T/E296V-FVII,
F374Y/K337A/M298Q/E296V-FVII, F374Y/K337A/M298Q/V158D-FVII,
F374Y/K337A/E296V/V158D-FVII, F374Y/V158D/S314E/M298Q-FVII,
F374Y/V158D/S314E/E296V-FVII, F374Y/V158D/M298Q/E296V-FVII,
F374Y/V158T/S314E/E296V-FVII, F374Y/V158T/S314E/M298Q-FVII,
F374Y/V158T/M298Q/E296V-FVII, F374Y/E296V/S314E/M298Q-FVII,
F374Y/L305V/M298Q/K337A/S314E-FVII, F374Y/L305V/E296V/K337A/S314E-FVII,
F374Y/E296V/M298Q/K337A/S314E-FVII, F374Y/L305V/E296V/M298Q/K337A-FVII,
F374Y/L305V/E296V/M298Q/S314E-FVII, F374Y/V158D/E296V/M298Q/K337A-FVII,
F374Y/V158D/E296V/M298Q/S314E-FVII, F374Y/L305V/V158D/K337A/S314E-FVII,
F374Y/V158D/M298Q/K337A/S314E-FVII, F374Y/V158D/E296V/K337A/S314E-FVII,
F374Y/L305V/V158D/E296V/M298Q-FVII, F374Y/L305V/V158D/M298Q/K337A-FVII,
F374Y/L305V/V158D/E296V/K337A-FVII, F374Y/L305V/V158D/M298Q/S314E-FVII,
F374Y/L305V/V158D/E296V/S314E-FVII, F374Y/V158T/E296V/M298Q/K337A-FVII,
F374Y/V158T/E296V/M298Q/S314E-FVII, F374Y/L305V/V158T/K337A/S314E-FVII,
F374Y/V158T/M298Q/K337A/S314E-FVII, F374Y/V158T/E296V/K337A/S314E-FVII,
F374Y/L305V/V158T/E296V/M298Q-FVII, F374Y/L305V/V158T/M298Q/K337A-FVII,
F374Y/L305V/V158T/E296V/K337A-FVII, F374Y/L305V/V158T/M298Q/S314E-FVII,
F374Y/L305V/V158T/E296V/S314E-FVII, F374Y/E296V/M298Q/K337A/V158T/S314E-FVII,
F374Y/V158D/E296V/M298Q/K337A/S314E-FVII,
F374Y/L305V/V158D/E296V/M298Q/S314E-FVII, F374Y/L305V/E296V/M298Q/V158T/S314E-FVII, F374Y/L305V/E296V/M298Q/K337A/V158T-FVII,
F374Y/L305V/E296V/K337A/V158T/S314E-FVII, F374Y/L305V/M298Q/K337A/V158T/S314E-FVII, F374Y/L305V/V158D/E296V/M298Q/K337A-FVII,
F374Y/L305V/V158D/E296V/K337A/S314E-FVII, F374Y/L305V/V158D/M298Q/K337A/S314E-FVII, F374Y/L305V/E296V/M298Q/K337A/V158T/S314E-FVII,
F374Y/L305V/V158D/E296V/M298Q/K337A/S314E-FVII, S52A-VII因子, S60A-VII因子;
R152E-VII因子, S344A-VII因子, Glaドメインを欠いているVIIa因子; およびP11Q/K33E-FVII, T106N-FVII, K143N/N145T-FVII, V253N-FVII, R290N/A292T-FVII, G291N-FVII,
R315N/V317T-FVII, K143N/N145T/R315N/V317T-FVII;およびアミノ酸配列の233Thr〜240Asnに置換、付加、又は欠失を有しているFVII, アミノ酸配列の304Arg 〜 329Cysに置換、付加、又は欠失を有しているFVIIである。
Nε141-[2-(4-(4-(mPEG(20k)イルブタノイル)-アミノ-ブチルオキシイミノ)-エチル]hGH,
Nε141-[2-(1-(ヘキサデカノイル)ピペリジン-4-イル)エチルオキシイミノ)-エチル]hGH,
Nε141(2-(4-(4-(1,3-ビス(mPEG(20k)イルアミノカルボニルオキシ)プロパ-2-イルオキシ)ブチリルアミノ)ブチルオキシイミノ)エチル)hGH,
Nε141(2-(4-(2,6-ビス(mPEG(20k)イルオキシカルボニルアミノ)ヘキサノイルアミノ)ブチルオキシイミノ)エチル)hGH,
Nε141(2-(4-(4-(mPEG(30k)イルオキシ)ブチリルアミノ)ブチルオキシイミノ)エチル)hGH,
Nε141(2-(4-(4-(mPEG(20k)イルオキシ)ブチリルアミノ)ブチルオキシイミノ)エチル)hGH, および
Nε141(2-(4-(3-(mPEG(30k)イルオキシ)プロパノイルアミノ)ブチルオキシイミノ)エチル)hGH;並びに、その薬学的に許容される塩、溶媒和物(solvates)およびプロドラッグ。
TGase: US5156956に記載のStreptoverticillium mobaraenaeからの又はWO9606931-A1に記載のStreptomyces Lydicusからの微生物のトランスグルタミナーゼ。
Maldi-Tof質量分析。
RP-HPLC分析を、Waters996ダイオードアレイ検出器を備えたWaters 2690 Separation Module上で実施した。A Vydac 218TP54 4.6mm x 250mm 5μm C-18 シリカ カラム(The Separations Group, Hesperia)を使用し、検出をUVで214 nm、254 nm、280 nmおよび301nmで行った。前記カラムを、0.1% トリフルオロ酢酸 / H2Oで平衡化し、0.1% トリフルオロ酢酸 /H2Oに対して0から90%アセトニトリルのグラジエントで、50 min、42゜C、0.5ml/minの流速で溶出した。
LC-MS分析を、2つのPerkin Elmerシリーズ200マイクロポンプ、Perkin Elmerシリーズ200オートサンプラー、アプライドバイオシステム785A UV検出器およびSedex 75 蒸発光散乱検出器(Evaporative Light scattering detector)を備えるPE-Sciex API 100質量分析計で実施した。Waters Xterra 3.0 mm x 50 mm 5μ C-18シリカカラムを、1.5 ml/minで室温で溶出した。それを5 % アセトニトリル / 0.1% トリフルオロ酢酸 / H2O で平衡化し、5% アセトニトリル / 0.1% トリフルオロ酢酸 / H2Oで1.0 min、そして90% アセトニトリル / 0.1% トリフルオロ酢酸 / H2Oまでのリニアグラジエントで7 min溶出した。検出を、UV検出器で214nm及び蒸発光散乱で行った。カラム溶出液のフラクションを、PE-Sciex API 100 質量分析計のイオンスプレー インターフェースに導入した。質量範囲300〜2000 amuを、試験の間2秒毎にスキャンした。
アミノ酸配列を、Applied Biosystem モデル494タンパク質シークエンサーを用いた自動化エドマン分解で、基本的に製造者によって記載されたとおりに決定した。通常、50pmolのペプチドを、分析に使用した。PEG化(PEGylated)または脂肪酸誘導体化(fatty-acid derivatized)アミノ酸残基は、ブランクのエドマン サイクルを提示する。
タンパク質濃度を、UV分光光度計を用いて280nmでの吸収を測定することで見積もった。16170 M÷1 cm÷1 のモル吸光係数を使用した。量を、ボリューム(volumes)および濃度から計算した。
ペプチドマッピングを、還元された又はアルキル化されたタンパク質のAsp-N消化を用いて行った。最初に、タンパク質を標準の手順にしたがいDTT(ジチオスレイトール)およびヨードアセトアミドで処理した。アルキル化された産物を、HPLCを用いて精製した。引き続いて、アルキル化された精製産物を、酵素:基質の比率を1:100でエンドプロテアーゼ Asp-N(Boehringer)で一晩消化した。消化物を、C-18カラムおよび標準のトリフルオロ酢酸/アセトニトリル緩衝系を用いて、HPLC分離した。結果的に生じたペプチドマップを、未誘導体化hGHのものと比較した。そして、異なる保持時間を有するフラクションを、収集し、Maldi-tof 質量分析を用いてさらに分析した。
SDS ポリアクリルアミドゲル電気泳動を、NuPAGE 4%-12%Bis-Trisゲル(インビトロゲン NP0321BOX)を用いて実施した。ゲルを、銀染色(インビトロゲン LC6100)またはクーマシー染色(インビトロゲン LC6065)した。そして妥当な場合には、M. M. Kurfurst(Anal.Biochem. 200(2):244-248, 1992)による記載のとおりにPEGに関してヨウ化バリウムで染色した。
II. Nε141-(2-ヒドロキシ-3-アミノ-プロピル)hGH
III. Nε141-(2-オキソ-エチル)hGH
IV. Nε141-[2-(4-(4-(mPEGyl)ブタノイル)-アミノ-ブチルオキシイミノ)-エチル]hGH
V. Nε141-[2-(1-(ヘキサデカノイル)ピペリジン-4-イル)エチルオキシイミノ)-エチル]hGH。
hGH (I.)(200 mg)を、リン酸緩衝液(50 mM, pH 8.0, 14 ml)に溶解した。
例1で生成した溶液を、緩衝液A(50 mM tris, pH 8.5)で前平衡化したMonoQ 10/100 GLカラム(Amersham Biosciences cat.No.17-5167-01)に適用した。それを次に2 ml/minの流速で緩衝液B(50 mM tris, 2 M NaCl, pH 8.5)の3%から6%のグラジエントで溶出した。フラクションを280 nmでのUV吸収に基づいて収集した。そして、Maldi-Tof分析を選択したフラクションで行った。Maldi-Tof質量分析法による予想mwを提示している最大ピークに対応するフラクションをプールした。
例2で収集されたプールのペプチドマッピングは次の事項を提示した。その事項とは、Asp-N断片AA130-146が、グルタミン残基の側鎖中にアミノアルコールの付加に対応する73 amuの質量増加を提示したことである。これは本来のhGHのものと比較した際に、HPLCマップ中で保持時間が変化した唯一のペプチドであった。この断片は、2つのグルタミン残基を含有する。前記ペプチドをエドマンシークエンシングに供試した。そしてGln-137は予測された産物で発見されたが、Gln-141はブランクのエドマン サイクルを提示した。誘導体化はGln-141で選択的に発生したと結論された。
工程1: 2-(4-(tert-ブトキシカルボニルアミノキシ)ブチル)イソインドール-1,3-ジオン
48.7mgの(II.)を含有している例2からのプールしたフラクションの緩衝液を、アミコンウルトラ-15限外濾過装置(ミリポア)を用いて、15 mMトリエタノールアミン pH8.5(1N塩酸で調整した)緩衝液に対して4回交換した。最終的に溶液は、2mlまで濃縮された。これに2 mllの100mMメチオニン溶液(15 mM トリエタノールアミン緩衝液pH 8.5中に存在)が添加された。最終的に、0.4 mlの25 mM過ヨウ素酸ナトリウム(水溶液)を添加し、そして混合物を30 min室温でインキュベーションした。次にそれを氷上で冷却し、1.6 mlの氷冷したN, N-ジメチルホルムアミドを添加した。
380 mgのN-(4-アミノオキシ-ブチル)-4-mPEGyl-ブチルアミド(butyramide)を、4mlの水に溶解し、pHを1N塩酸で6.0に調整した。例5から結果的に生じた混合物を、次に穏やかに撹拌しながらゆっくりと添加し、反応を室温で72h進行させた。
例6で結果的に得られた溶液を、緩衝液A(50 mM tris, pH 8.5)で前平衡化したMonoQ 10/100 GL カラム(Amersham Biosciences cat. No. 17-5167-01)に適用した。次にそれを緩衝液Aにおいて0%から7%の緩衝液B(50 mM tris, 2 M NaCl, pH 8.5)のグラジエントで流速0.5 ml/minで1120 min以上溶出した。フラクションを280 nmでのUV吸収に基づいて収集し、Maldi-Tof分析を選択したフラクションで行った。Maldi-Tof 質量分析によって予想されたmwを提示している最大ピークに対応するフラクションをプールした。Maldi-Tof分析は、mPEGの多分散特性と一致して43130 Da付近を中心とするブロードなピークを呈した。SDS pageは、60kDaの見かけの分子量を有する単一バンドを示した。前記バンドは銀およびヨウ化バリウムの双方で染色されたので、PEG誘導化タンパク質であることが確認された。これらの分析的結果によって、分離された産物化合物がhGHのモノペグ化誘導体(mono pegylated derivative)であることが確認された。
1H-NMR (DMSO-d6):δ 1.30 (m, 2 H); 1.65 (m, 2 H); 1.90 (m, 3 H); 2.90 (q, 2 H); 3.30 (d, 2 H); 4.20 (t, 2 H); 7.90 (s, 4 H); 8.30 (br, 1 H); 8.65 (br, 1 H)。
1H-NMR (DMSO-d6):δ 0.90 (t, 3 H); 1.10 (m, 2 H); 1.25 (m, 26 H); 1.45 (m, 2 H); 1.65 (m, 1 H); 1.80 (m, 2 H); 2.30 (t, 2 H); 2.95 (t, 1 H); 3.85 (m, 3 H); 4.20 (t, 2 H); 4.40 (d, 1 H); 7.90 (s, 4 H)。
ヒドラジン水和物(0.14 ml, 20 mmol)を、エタノール(30 ml)中の2-[2-(1-(ヘキサデカノイル)ピペリジン-4-イル)エトキシ]イソインドール-1, 3-ジオン(1.52 g, 2.96 mmol)の溶液に添加した。反応混合物を熱して75 min還流(reflux)し、室温に冷却した。形成された沈殿を、濾過で除去した。濾過物の溶媒を、減圧下で除去した。粗製品を、ジクロロメタン/メタノール/25%アンモニア水(100:10:1)の混合物を溶出液として用いて、シリカ(30 g)上でフラッシュ・クロマトグラフィーで精製し、800 mgの1-[4-(2-(アミノオキシ)エチル)ピペリジン-1-イル]ヘキサデカン-1-オンを生成した。
1H-NMR (CDCl3):δ 0.80 (t, 3 H); 1.25 (m, 2 H); 1.60 (m, 26 H); 1.70 (m, 4 H); 1.65 (m, 3 H); 2.70 8t, 2 H); 2.60 (t, 1 H); 3.05 (t, 1 H); 3.80 (m, 3 H); 4.60 (d, 1 H)。
5 mgのNε141-(2-ヒドロキシ-3-アミノ-プロピル)hGH(II.)を、0.5 mlの15 mMトリエタノールアミン緩衝剤pH 8.5(1N塩酸で調整した)に溶解した。これに0.13 mlの173 mMメチオニン溶液(水に溶解)を添加した。最終的に、0.06 mlの24 mM過ヨウ素酸ナトリウム(水溶液)を添加し、そして混合物を10 min、0゜Cでインキュベーションした。
2 mgの1-[4-(2-(アミノオキシ)エチル)ピペリジン-1-イル]ヘキサデカン-1-オンを、3 mlのN, N-ジメチルホルムアミドに溶解し、溶液を氷上で冷却した。例12からの0.14 mlの反応混合物を添加し、混合物を0゜Cで一晩反応させた。
例13からの粗製の反応混合物のアリコートを、RP-HPLCにより分析用スケール(analytical scale)で分画し、Maldi-TOF質量分析を前記フラクションで行った。産物の構造から予想される予想分子量を呈している前記フラクションを、ペプチドマッピングに供した。前記マップは次の事項を示した。その事項とは、Asp-N断片AA130-146が、グルタミン残基の側鎖中に2-(1-(ヘキサデカノイル)ピペリジン-4-イル)エチルオキシイミノ)-エチルの付加に対応する407 amuの質量増加を提示したことである。これは本来のhGHのものと比較した際に、HPLCマップ中で保持時間が変化した唯一のペプチドであった。この断片は、2つのグルタミン残基を含有する。前記ペプチドをエドマン シークエンシングに供試した。そしてGln-137は予測された産物で発見されたが、Gln-141はブランクのエドマン サイクルを提示した。誘導体化はGln-141で選択的に発生したことが結論づけられた。
Claims (10)
- 以下の式で表される化合物、並びに、その薬学的に許容される塩および溶媒和物:
Dは、結合または酸素を表し;
Rは、リンカーまたは結合を表し;
Eは、リンカーまたは結合を表し;
Aは、オキシム, ヒドラゾン, フェニルヒドラゾン, セミカルバゾン, トリアゾールまたはイソオキサゾリジン成分を表し;および
Zは、PEGまたはmPEGラジカル及びそのアミノ誘導体(直鎖状および分枝状のPEGおよびmPEGラジカルを含む);直鎖状、分枝状および/または環状のC1-22 アルキル, C2-22 アルケニル, C2-22 アルキニル, C1-22 ヘテロアルキル, C2-22 ヘテロアルケニル, C2-22 ヘテロアルキニル(ここで1以上の単素環式芳香族化合物ビラジカルまたは複素環式化合物ビラジカルが挿入されてもよく、ここで前記C1-C22 または C2-C22 ラジカルはヒドロキシル, ハロゲン, カルボキシル, ヘテロアリールおよびアリールから選択される1以上の置換基で任意に置換されてもよく、ここで前記アリールまたはヘテロアリールはヒドロキシル, ハロゲン, およびカルボキシルから選択される1以上の置換基で任意にさらに置換されてもよい);ステロイドラジカル; 脂質ラジカル; ポリサッカライドラジカル; デキストラン; ポリアミドラジカル; ポリアミノ酸ラジカル; PVPラジカル; PVAラジカル; ポリ(1-3-ジオキサラン(dioxalane)); ポリ(1,3,6-トリオキサン); エチレン/無水マレイン酸ポリマー; シバクロン染料; またはシバクロンブルー3GA(商標)のなかから選択される。 - 前記成長ホルモンが成長ホルモン化合物である、請求項1に記載の化合物。
- 前記成長ホルモンがヒト成長ホルモンである、請求項1に記載の化合物。
- 請求項1〜3の何れか1項に記載の化合物であって、前記化合物がヒト成長ホルモン中のポジション141に対応するポジションで結合される化合物。
- 請求項3に記載の化合物であって、前記化合物がヒト成長ホルモン中のポジション141に対応するポジションで結合される化合物。
- Nε141-[2-(4-(4-(mPEG(20k)イルブタノイル)-アミノ-ブチルオキシイミノ)-エチル]hGH,
Nε141-[2-(1-(ヘキサデカノイル)ピペリジン-4-イル)エチルオキシイミノ)-エチル]hGH,
Nε141(2-(4-(4-(1,3-ビス(mPEG(20k)イルアミノカルボニルオキシ)プロパ-2-イルオキシ)ブチリルアミノ)ブチルオキシイミノ)エチル)hGH,
Nε141(2-(4-(2,6-ビス(mPEG(20k)イルオキシカルボニルアミノ)ヘキサノイルアミノ)ブチルオキシイミノ)エチル)hGH,
Nε141(2-(4-(4-(mPEG(30k)イルオキシ)ブチリルアミノ)ブチルオキシイミノ)エチル)hGH,
Nε141(2-(4-(4-(mPEG(20k)イルオキシ)ブチリルアミノ)ブチルオキシイミノ)エチル)hGH, および
Nε141(2-(4-(3-(mPEG(30k)イルオキシ)プロパノイルアミノ)ブチルオキシイミノ)エチル)hGH;並びに、その薬学的に許容される塩および溶媒和物から選択される請求項1に記載の化合物であって、
上記のmPEG(20k)イルおよびmPEG(30k)イルが、それぞれ1.06未満の多分散性指標を有するmPEG(20k)イルおよびmPEG(30k)イルを指すことを意図する、化合物。 - 請求項1〜6の何れか1項に記載の化合物を含む薬学的組成物。
- 治療で使用するための、請求項1〜6の何れか1項に記載の化合物。
- 以下の治療で使用するための、請求項1〜6の何れか1項に記載の化合物:
成長ホルモン分泌不全症(GHD); ターナー症候群; プラーダーヴィリ症候群(PWS); ヌーナン症候群; ダウン症候群; 慢性腎臓病、若年性関節リウマチ; 嚢胞性線維症、HAART治療を受けている小児におけるHIV感染症(HIV/HALS小児); 在胎齢が短く誕生した小さい小児(SGA); SGAを除く極低出生体重(VLBW)で誕生した小児における低身長; 骨格形成異常; 低軟骨形成症; 軟骨形成不全症; 特発性低身長(ISS); 成人におけるGHD; 脛骨, 腓骨, 大腿骨, 上腕骨, 橈骨, 尺骨, 鎖骨, 中手骨, 中足骨, および指などの長骨における、又は、それらの骨折; 頭蓋骨, 手の基部, および足の基部などの海綿状骨における、又は、それらの骨折; 手, 膝, または肩部などにおける腱または靭帯の手術後の患者; 伸延骨形成を有している又は経験している患者; 臀部または円板の置換, メニスカスの修復, 脊椎固定または膝, 臀部, 肩部, 肘, 手関節または下顎などのプロテーゼ固定の後の患者; 釘、スクリューおよびプレートなどの骨接合材料が固定された患者; 癒着不能または変形癒合の骨折を有する患者; 脛骨または第一足指からなどのオステアトミア(osteatomia)後の患者; 移植物の移植後の患者; 外傷または関節炎が原因の膝の関節軟骨変性; ターナー症候群の患者のオステオポローシス; 男性のオステオポローシス; 慢性透析の成人患者(APCD); APCDにおける栄養不良関連性心臓血管疾患; APCDにおけるカヘキシーの反転; APCDにおけるガン; APCDにおける慢性閉塞性(abstractive)肺疾患; APCDにおけるHIV; APCDを伴う高齢者; APCDにおける慢性肝疾患, APCDにおける疲労症候群; クローン病; 肝機能の障害; HIV感染症を伴う男性; 短小腸症候群; 中心性肥満; HIV関連性リポジストロフィ症候群 (HALS); 男性の不妊症; 主要な待機手術後の患者, アルコール/薬の解毒または神経学的な外傷; 加齢; 虚弱な高齢者; 骨関節炎; 外傷性に傷害された軟骨; 勃起不全; 線維筋痛; 記憶障害; うつ病; 外傷性の脳傷害; くも膜下出血; 非常に低い出生時体重; 代謝症候群; 糖質コルチコイドミオパシー;または小児の糖質コルチコイド治療による低身長;筋肉組織, 神経組織または傷のヒーリングの促進のため;損傷を受けた組織の血流の促進または改善のため;或いは損傷を受けた組織における感染率の減少のため。 - 請求項1〜6の何れか1項に記載の化合物の、以下の治療に使用される医薬の製造における使用:
成長ホルモン分泌不全症(GHD); ターナー症候群; プラーダーヴィリ症候群(PWS); ヌーナン症候群; ダウン症候群; 慢性腎臓病、若年性関節リウマチ; 嚢胞性線維症、HAART治療を受けている小児におけるHIV感染症(HIV/HALS小児); 在胎齢が短く誕生した小さい小児(SGA); SGAを除く極低出生体重(VLBW)で誕生した小児における低身長; 骨格形成異常; 低軟骨形成症; 軟骨形成不全症; 特発性低身長(ISS); 成人におけるGHD; 脛骨, 腓骨, 大腿, 上腕骨, 橈骨, 尺骨, 鎖骨, 中手骨, 中足骨, および指などの長骨における、又は、それらの骨折; 頭蓋骨, 手の基部, および足の基部などの海綿状骨における、又は、それらの骨折; 手, 膝, または肩部などにおける腱または靭帯の手術後の患者; 伸延骨形成を有している又は経験している患者; 臀部または円板の置換, メニスカスの修復, 脊椎固定または膝, 臀部, 肩部, 肘, 手関節または下顎などのプロテーゼ固定の後の患者; 釘、スクリューおよびプレートなどの骨接合材料が固定された患者; 癒着不能または変形癒合の骨折を有する患者; 脛骨または第一足指からなどのオステアトミア(osteatomia)後の患者; 移植物の移植後の患者; 外傷または関節炎が原因の膝の関節軟骨変性; ターナー症候群の患者のオステオポローシス; 男性のオステオポローシス; 慢性透析の成人患者(APCD); APCDにおける栄養不良関連性心臓血管疾患; APCDにおけるカヘキシーの反転; APCDにおけるガン; APCDにおける慢性閉塞性(abstractive)肺疾患; APCDにおけるHIV; APCDを伴う高齢者; APCDにおける慢性肝疾患, APCDにおける疲労症候群; クローン病; 肝機能の障害; HIV感染症を伴う男性; 短小腸症候群; 中心性肥満; HIV関連性リポジストロフィ症候群 (HALS); 男性の不妊症; 主要な待機手術後の患者, アルコール/薬の解毒または神経学的な外傷; 加齢; 虚弱な高齢者; 骨関節炎; 外傷性に傷害された軟骨; 勃起不全; 線維筋痛; 記憶障害; うつ病; 外傷性の脳傷害; くも膜下出血; 非常に低い出生時体重; 代謝症候群; 糖質コルチコイドミオパシー;または小児の糖質コルチコイド治療による低身長;筋肉組織、神経組織または傷のヒーリングの促進のため;損傷を受けた組織の血流の促進または改善のため;或いは損傷を受けた組織における感染率の減少のため。
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JP (2) | JP4874811B2 (ja) |
CN (2) | CN103215328B (ja) |
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BR (1) | BRPI0506864A (ja) |
CA (1) | CA2552043A1 (ja) |
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ES (2) | ES2642214T3 (ja) |
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EP1708755B1 (en) | 2012-03-21 |
EP2842576B1 (en) | 2017-06-28 |
EP2842576A1 (en) | 2015-03-04 |
ES2397241T3 (es) | 2013-03-05 |
JP2011219480A (ja) | 2011-11-04 |
CN1909930B (zh) | 2015-12-16 |
DK2842576T3 (en) | 2017-10-16 |
CN103215328A (zh) | 2013-07-24 |
RU2385879C2 (ru) | 2010-04-10 |
EP2033662A1 (en) | 2009-03-11 |
EP1708755A2 (en) | 2006-10-11 |
WO2005070468A3 (en) | 2006-03-16 |
JP2007518747A (ja) | 2007-07-12 |
RU2006126331A (ru) | 2008-02-27 |
EP2368579A1 (en) | 2011-09-28 |
AU2005205867A1 (en) | 2005-08-04 |
ATE550041T1 (de) | 2012-04-15 |
EP2033662B1 (en) | 2012-10-17 |
ES2642214T3 (es) | 2017-11-15 |
JP4874811B2 (ja) | 2012-02-15 |
MXPA06008209A (es) | 2006-08-31 |
CA2552043A1 (en) | 2005-08-04 |
WO2005070468A2 (en) | 2005-08-04 |
CN1909930A (zh) | 2007-02-07 |
CN103215328B (zh) | 2016-08-03 |
BRPI0506864A (pt) | 2007-05-29 |
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