JP6359972B2 - Glp−1受容体アゴニストペプチドガストリンコンジュゲート - Google Patents
Glp−1受容体アゴニストペプチドガストリンコンジュゲート Download PDFInfo
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- JP6359972B2 JP6359972B2 JP2014539352A JP2014539352A JP6359972B2 JP 6359972 B2 JP6359972 B2 JP 6359972B2 JP 2014539352 A JP2014539352 A JP 2014539352A JP 2014539352 A JP2014539352 A JP 2014539352A JP 6359972 B2 JP6359972 B2 JP 6359972B2
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- LZNWYQJJBLGYLT-UHFFFAOYSA-N tenoxicam Chemical compound OC=1C=2SC=CC=2S(=O)(=O)N(C)C=1C(=O)NC1=CC=CC=N1 LZNWYQJJBLGYLT-UHFFFAOYSA-N 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
- 230000035922 thirst Effects 0.000 description 1
- 229960000984 tocofersolan Drugs 0.000 description 1
- 229960002905 tolfenamic acid Drugs 0.000 description 1
- YEZNLOUZAIOMLT-UHFFFAOYSA-N tolfenamic acid Chemical compound CC1=C(Cl)C=CC=C1NC1=CC=CC=C1C(O)=O YEZNLOUZAIOMLT-UHFFFAOYSA-N 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 229940007428 victoza Drugs 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 210000001835 viscera Anatomy 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 150000003722 vitamin derivatives Chemical class 0.000 description 1
- ZAFYATHCZYHLPB-UHFFFAOYSA-N zolpidem Chemical compound N1=C2C=CC(C)=CN2C(CC(=O)N(C)C)=C1C1=CC=C(C)C=C1 ZAFYATHCZYHLPB-UHFFFAOYSA-N 0.000 description 1
- 229960001475 zolpidem Drugs 0.000 description 1
- 235000004835 α-tocopherol Nutrition 0.000 description 1
- 239000002076 α-tocopherol Substances 0.000 description 1
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Description
本発明は特に、いくつかのペプチドコンジュゲートと、糖尿病(1型及び/又は2型)と糖尿病関連疾患又は障害を含む種々の疾患又は障害の治療及び/又は予防におけるこのコンジュゲートの使用と、に関する。
糖尿病(特に1型及び2型糖尿病)は、2型糖尿病の発症の主要な原因であると考えられている肥満とともに、世界的に大きなかつ増大し続けている健康問題となっている。糖尿病に帰結する疾患又は障害は、心血管疾患と末梢血管疾患、微小血管と巨大血管合併症、卒中、及びおそらくある種の癌を含む。
HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPS−NH2である。
2つの共有的に結合又は連結したペプチド成分を含むいくつかのコンジュゲートが、例えば糖尿病(1型及び/又は2型糖尿病)と種々の他の糖尿病関連疾患又は障害の治療において、問題の2つの個々のペプチドの組合せの治療活性と比較して、予想外に高い治療活性を示すことがあることが、わかっている。
R1−Za−La−Ya−R2 (I)
[式中、
R1は、H、C1-4アルキル、アセチル、ホルミル、ベンゾイル、又はトリフルオロアセチルであり、
R2は、OH又はNH2であり;そして
Zaは、式Ia
His−Gly−Glu−Gly−Thr−Phe−Thr−Ser−Z9−Leu−Ser−Z12−Z13−Z14−Glu−Z16−Glu−Ala−Val−Z20−Leu−Phe−lle−Z24−Z25−Leu−Z27−Z28 (Ia)
(ここで、
Z9は、Asp及びGluから選択され、
Z12は、Lys、Arg、及びOrnから選択され、
Z13は、Gln及びTyrから選択され、
Z14は、Met及びLeuから選択され、
Z16は、Glu、Cys、Arg、Orn、及びLysから選択され、
Z20は、Arg、Lys、及びOrnから選択され、
Z24は、Lys、Arg、Orn、及びGluから選択され、
Z25は、Trp、Lys、Cys、及びPheから選択され、
Z27は、Lys、Arg、及びOrnから選択され、
Z28は、Asn及びAspから選択されるか、又は存在しない)
を有するペプチド配列であり、
Laは、式Ib
L1−L2−L3−L4 (Ib)
(ここで、
L1は、Orn、8Ado、Cys、Lys、及びGlnから選択されるか、又は存在せず、
L2は、Orn、8Ado、Cys、Lys、及びGlnから選択されるか、又は存在せず、
L3は、Orn、8Ado、Cys、Lys、及びGlnから選択されるか、又は存在せず、及び
L4は、Orn、8Ado、Cys、Lys、及びGlnから選択されるか、又は存在しない)
を有するペプチド配列であり、
Yaは、式Ic
Y12−Y13−Y14−Y15−Asp−Y17 (lc)
(ここで、
Y12は、Tyr及びAlaから選択されるか、又は存在せず、
Y13は、Gly及びAlaから選択されるか、又は存在せず、
Y14は、Trp、1Nal及びPheから選択され;
Y15は、Met、Leu、Nle、Thr、及びPheから選択され;及び
Y17は、Phe及び3−(3−ピリジル)−アラニンから選択される)
を有するペプチド配列であり、
ここで、式IaとIb中のLys、Orn、又はCysの少なくとも1つはさらに、親油性及び/又はビオチン性置換基に結合しているか、及び/又はペグ化されている]を有するペプチドコンジュゲートであるか、
又はその医薬的に許容される塩もしくは溶媒和物である。
His−Gly−Glu−Gly−Thr−Phe−Thr−Ser−Z9−Leu−Ser−Lys−Z13−Z14−Glu−Z16−Glu−Ala−Val−Arg−Leu−Phe−lle−Glu−Z25−Leu−Lys−Z28 (lla)
(ここで、
Z9は、Glu及びAspから選択され、
Z13は、Gln及びTyrから選択され、
Z14は、Met及びLeuから選択され、
Z16は、Glu、Cys、及びLysから選択され、
Z25は、Lys、Phe、Cys、及びTrpから選択され、
Z28は、Asn及びAspから選択されるか、又は存在しない)を有するペプチド配列であり、
Laが、上記した式Ibを有するペプチド配列であり、そして
Yaが、式IIc
Tyr−Gly−Trp−Y15−Asp−Phe (lIc)
(ここで、Y15は、Leu及びThrから選択される)を有するペプチド配列であり、
ここで、式IIaのZ16位とZ25位のLys残基の少なくとも1つはさらに、親油性及び/又はビオチン性置換基に結合しているか、及び/又はペグ化されている、式Iのペプチドコンジュゲート、
又はその医薬的に許容される塩もしくは溶媒和物を提供する。
H−HGEGTFTSDLSKQLEEEAVRLFIEWLKN−8Ado−K(ヘキサデカノイル−イソGlu)−8Ado−YGWLDF−NH2(化合物1)、
H−HGEGTFTSDLSKQLEEEAVRLFIE−K(ヘキサデカノイル−イソGlu)−LKN−8Ado−8Ado−YGWLDF−NH2(化合物2)、
H−HGEGTFTSDLSKQLE−K(ヘキサデカノイル−イソGlu)−EAVRLFIEWLKN−8Ado−8Ado−YGWLDF−NH2(化合物3)、
H−HGEGTFTSDLSKQMEEEAVRLFIEWLKN−8Ado−C(ビオチン−Mal)−8Ado−YGWLDF−NH2(化合物4)、
H−HGEGTFTSDLSKQLEEEAVRLFIE−C(ビオチン−Mal)−LKN−8Ado−8Ado−YGWLDF−NH2(化合物5)、
H−HGEGTFTSDLSKQLE−C(ビオチン−Mal)−EAVRLFIEWLKN−8Ado−8Ado−YGWLDF−NH2(化合物6)、
H−HGEGTFTSELSKYLEEEAVRLFIE−K(ヘキサデカノイル−イソGlu)−LK−8Ado−8Ado−YGWLDF−NH2(化合物7)、
H−HGEGTFTSELSKYLEEEAVRLFIE−K(ヘキサデカノイル−イソGlu)−LK−8Ado−QQYGWLDF−NH2(化合物8)、
を有するペプチドコンジュゲート、
又はその医薬的に許容される塩もしくは溶媒和物に関する。
R1−Zb−Lb−Yb−R2 (III)
[式中、
R1は、H、C1-4アルキル、アセチル、ホルミル、ベンゾイル、又はトリフルオロアセチルであり、
R2は、OH又はNH2であり;そして
Zbは、式IIIa
His−Gly−Glu−Gly−Thr−Phe−Thr−Ser−Glu−Leu−Ser−Lys−Tyr−Leu−Glu−Glu−Glu−Ala−Val−Arg−Leu−Phe−lle−Glu−Z25−Leu−Lys−Z28 (IIIa)
(ここで、
Z25は、Phe及びTrpから選択され、そして
Z28は、Asn及びAspから選択されるか、又は存在しない)
を有するペプチド配列であり、
Lbは、式IIIb
L5−L6−L7−L8 (IIIb)
(ここで、
L5は、8Ado、8Aoc、Ala、Gly、及びGlnから選択されるか、又は存在せず、
L6は、8Ado、8Aoc、Ala、Gly、及びGlnから選択されるか、又は存在せず、
L7は、8Ado、8Aoc、Ala、Gly、及びGlnから選択されるか、又は存在せず、
L8は、8Ado、8Aoc、Ala、Gly、及びGlnから選択されるか、又は存在しない)
を有するペプチド配列であり、
Ybは、式IIIc
Y10−Y11−Tyr−Gly−Trp−Y15−Asp−Phe (IIlc)
(ここで、
Y10は、Gluであるか、又は存在せず、
Y11は、Alaであるか、又は存在せず、そして
Y15は、Leu及びThrから選択される)
を有するペプチド配列である]を有するペプチドコンジュゲート、
又はその医薬的に許容される塩もしくは溶媒和物を提供するが、
ただし、式IIIは、
H−HGEGTFTSELSKYLEEEAVRLFIEFLK−8Ado−8Ado−YGWLDF−NH2;
H−HGEGTFTSELSKYLEEEAVRLFIEFLKYGWLDF−NH2;
H−HGEGTFTSELSKYLEEEAVRLFIEFLK−8Ado−YGWLDF−NH2ではない。
Zbが、式IVa
His−Gly−Glu−Gly−Thr−Phe−Thr−Ser−Glu−Leu−Ser−Lys−Tyr−Leu−Glu−Glu−Glu−Ala−Val−Arg−Leu−Phe−lle−Glu−Z25−Leu−Lys−Asn (IVa)
(ここで、Z25は、Lys、Phe、及びTrpから選択される)を有するペプチド配列であり、
Lbが、上記した式IIIbを有するペプチド配列であり、
Ybが、式IVc
Tyr−Gly−Trp−Y15−Asp−Phe (IVc)
(ここで、Y15は、Leu及びThrから選択される)を有するペプチド配列である、式IIIのペプチドコンジュゲート、
又はその医薬的に許容される塩もしくは溶媒和物を提供する。
H−HGEGTFTSELSKYLEEEAVRLFIEFLKQQYGWLDF−NH2 (化合物9)、
H−HGEGTFTSELSKYLEEEAVRLFIEFLKQQEAYGWLDF−NH2 (化合物10)、
H−HGEGTFTSELSKYLEEEAVRLFIEFLK−8Ado−QQYGWLDF−NH2 (化合物11)、
H−HGEGTFTSELSKYLEEEAVRLFIEFLKDYGWLDF−NH2 (化合物12)、
H−HGEGTFTSELSKYLEEEAVRLFIEFLKAAAYGWLDF−NH2 (化合物13)、
H−HGEGTFTSELSKYLEEEAVRLFIEFLKGGGYGWLDF−NH2 (化合物14)、
H−HGEGTFTSELSKYLEEEAVRLFIEFLK−8Aoc−YGWLDF−NH2 (化合物15)、
H−HGEGTFTSELSKYLEEEAVRLFIEFLKNYGWLDF−NH2 (化合物16)、
H−HGEGTFTSELSKYLEEEAVRLFIEFLKAYGWLDF−NH2 (化合物17)、
H−HGEGTFTSELSKYLEEEAVRLFIEFLKN−8Ado−8Ado−YGWLDF−NH2 (化合物18)、
H−HGEGTFTSELSKYLEEEAVRLFIEFLKD−8Ado−8Ado−YGWLDF−NH2 (化合物19)、
H−HGEGTFTSELSKYLEEEAVRLFIEFLKNYGWTDF−NH2 (化合物20)、
H−HGEGTFTSELSKYLEEEAVRLFIEFLKDYGWTDF−NH2 (化合物21)、
H−HGEGTFTSELSKYLEEEAVRLFIEWLKNYGWLDF−NH2 (化合物22)、
H−HGEGTFTSELSKYLEEEAVRLFIEWLKDYGWLDF−NH2 (化合物23)、
を有するペプチドコンジュゲート、
又はその医薬的に許容される塩もしくは溶媒和物に関する。
(a)標準的固相法又は液相法で、段階的にもしくは断片の組み立てにより、ペプチドコンジュゲートを合成し、最終的にペプチドコンジュゲート生成物を単離し精製する工程、
(b)ペプチドコンジュゲートをコードする核酸構築体を宿主細胞中で発現させ、発現生成物を宿主細胞培養物から回収する工程、又は
(c)ペプチドコンジュゲートをコードする核酸構築体の無細胞インビトロ発現を行い、抽出生成物を回収する工程、を含む方法、
又は(a)、(b)、もしくは(c)の方法の任意の組合せにより、ペプチドコンジュゲートの断片を得て、次にこれらの断片をペプチドコンジュゲートに結合させ、ペプチドコンジュゲートを回収する方法、を含む多くの方法により合成することができる。
上記したように、本発明の1つの形態は以下の式を有するペプチドコンジュゲートに関する:
H−HGEGTFTSDLSKQLEEEAVRLFIEWLKN−8Ado−K(ヘキサデカノイル−イソGlu)−8Ado−YGWLDF−NH2(化合物1)、
H−HGEGTFTSDLSKQLEEEAVRLFIE−K(ヘキサデカノイル−イソGlu)−LKN−8Ado−8Ado−YGWLDF−NH2(化合物2)、
H−HGEGTFTSDLSKQLE−K(ヘキサデカノイル−イソGlu)−EAVRLFIEWLKN−8Ado−8Ado−YGWLDF−NH2(化合物3)、
H−HGEGTFTSDLSKQMEEEAVRLFIEWLKN−8Ado−C(ビオチン−Mal)−8Ado−YGWLDF−NH2(化合物4)、
H−HGEGTFTSDLSKQLEEEAVRLFIE−C(ビオチン−Mal)−LKN−8Ado−8Ado−YGWLDF−NH2(化合物5)、
H−HGEGTFTSDLSKQLE−C(ビオチン−Mal)−EAVRLFIEWLKN−8Ado−8Ado−YGWLDF−NH2(化合物6)、
H−HGEGTFTSELSKYLEEEAVRLFIE−K(ヘキサデカノイル−イソGlu)−LK−8Ado−8Ado−YGWLDF−NH2(化合物7)、
H−HGEGTFTSELSKYLEEEAVRLFIE−K(ヘキサデカノイル−イソGlu)−LK−8Ado−QQYGWLDF−NH2(化合物8)。
H−HGEGTFTSELSKYLEEEAVRLFIEFLKQQYGWLDF−NH2 (化合物9)、
H−HGEGTFTSELSKYLEEEAVRLFIEFLKQQEAYGWLDF−NH2 (化合物10)、
H−HGEGTFTSELSKYLEEEAVRLFIEFLK−8Ado−QQYGWLDF−NH2 (化合物11)、
H−HGEGTFTSELSKYLEEEAVRLFIEFLKDYGWLDF−NH2 (化合物12)、
H−HGEGTFTSELSKYLEEEAVRLFIEFLKAAAYGWLDF−NH2 (化合物13)、
H−HGEGTFTSELSKYLEEEAVRLFIEFLKGGGYGWLDF−NH2 (化合物14)、
H−HGEGTFTSELSKYLEEEAVRLFIEFLK−8Aoc−YGWLDF−NH2 (化合物15)、
H−HGEGTFTSELSKYLEEEAVRLFIEFLKNYGWLDF−NH2 (化合物16)、
H−HGEGTFTSELSKYLEEEAVRLFIEFLKAYGWLDF−NH2 (化合物17)、
H−HGEGTFTSELSKYLEEEAVRLFIEFLKN−8Ado−8Ado−YGWLDF−NH2 (化合物18)、
H−HGEGTFTSELSKYLEEEAVRLFIEFLKD−8Ado−8Ado−YGWLDF−NH2 (化合物19)、
H−HGEGTFTSELSKYLEEEAVRLFIEFLKNYGWTDF−NH2 (化合物20)、
H−HGEGTFTSELSKYLEEEAVRLFIEFLKDYGWTDF−NH2 (化合物21)、
H−HGEGTFTSELSKYLEEEAVRLFIEWLKNYGWLDF−NH2 (化合物22)、
H−HGEGTFTSELSKYLEEEAVRLFIEWLKDYGWLDF−NH2 (化合物23)、
H−HGEGTFTSELSKYLEEEAVRLFIEFLKEAYGWLDF−NH2 (化合物24)。
H−HGEGTFTSELSKYLEEEAVRLFIEFLKN−K(ヘキサデカノイル−イソGlu)−YGWLDF−NH2(化合物25)、
H−HGEGTFTSELSKYLEEEAVRLFIEFLKN−K(ヘキサデカノイル−イソGlu)−WLDF−NH2(化合物26)、
H−HGEGTFTSELSKYLE−(ヘキサデカノイル−イソGlu)−EAVRLFIEFLNYGWLDF−NH2(化合物27)、
H−HGEGTFTSELSKYLE−K(ヘキサデカノイル−イソGlu)−EAVRLFIEFLKNWLDF−NH2(化合物28)、
H−HGEGTFTSELSKYLEEEAVRLFIEFLK−K(ヘキサデカノイル−イソGlu)−YGWLDF−NH2(化合物29)、
H−HGEGTFTSELSKYLEEEAVRLFIEFLK−K(ヘキサデカノイル−イソGlu)−WLDF−NH2(化合物30)、
H−HGEGTFTSELSKYLE−K(ヘキサデカノイル−イソGlu)−EAVRLFIEFLKYGWLDF−NH2(化合物31)、
H−HGEGTFTSELSKYLE−K(ヘキサデカノイル−イソGlu)−EAVRLFIEFLKWLDF−NH2(化合物32)、
H−HGEGTFTSELSKYLEEEAVRLFIE−K(ヘキサデカノイル−イソGlu)−LK−8Ado−YGWLDF−NH2(化合物33)、
H−HGEGTFTSELSKYLEEEAVRLFIE−K(ヘキサデカノイル−イソGlu)−LKQQYGWLDF−NH2(化合物34)、
H−HGEGTFTSELSKYLEEEAVRLFIE−K(ヘキサデカノイル−イソGlu)−LK−Orn−Orn−YGWLDF−NH2(化合物35)、
H−HGEGTFTSELSKYLEEEAVRLFIE−K(ヘキサデカノイル−イソGlu)−LKNYGWLDF−NH2(化合物36)、
H−HGEGTFTSELSKYLEEEAVRLFIE−K(ヘキサデカノイル−イソGlu)−LKDYGWLDF−NH2(化合物37)。
H−HGEGTFTSDLSKQLEEEAVRLFIEC(PEG5K)LKN−8Ado−8Ado−YGWLDF−NH2(化合物38)、
H−HGEGTFTSELSKYLEEEAVRLFIEC(PEG10K)LK−8Ado−8Ado−YGWLDF−NH2(化合物39)、
H−HGEGTFTSELSKYLEEEAVRLFIEC(PEG20K)LK−8Ado−8Ado−YGWLDF−NH2(化合物40)、
H−HGEGTFTSELSKYLEEEAVRLFIEC(PEG40K)LK−8Ado−8Ado−YGWLDF−NH2(化合物41)、
H−HGEGTFTSDLSKQMEEEAVRLFIEWLKNYGWTDF−OH(化合物42)、
H−HGEGTFTSELSKYLEEEAVRLFIEFLKN−8Ado−8Ado−YGWTDF−NH2(化合物43)、
又はその医薬的に許容される塩もしくは溶媒和物に関する。
8Ado(又はPeg3):−NH−CH2−CH2−O−CH2−CH2−O−CH2−C(O)−(8−アミノ−3,6−ジオキサオクタン酸から誘導される);
8Aoc:−NH−CH2−CH2−CH2−CH2−CH2−CH2−CH2−C(O)−(8−アミノオクタン酸から誘導される);
ヘキサデカノイル:CH3−(CH2)14−C(O)−;
イソGlu:−NH−CH(COOH)−CH2−CH2−C(O)−;
Orn:オルニチン;及び
ビオチン−Mal:ビオチン−マレイミド。
−NH−CH2−CH2−O−CH2−CH2−O−CH2−C(O)−NH−CH2−CH2−O−CH2−CH2−O−CH2−C(O)−
を示し、問題のリンカー成分の末端の−NH−・・・成分は、問題のペプチドコンジュゲートのGLP−1アゴニスト(例えばエキセンジン−4由来)成分に共有結合しており、問題のリンカー成分の右にある・・・−C(O)−成分は、問題のペプチドコンジュゲートのガストリン由来成分に結合している。
また同様に、コンジュゲート中の[Leu15]ガストリン17成分は、ヒトガストリンから合成的に得られる。
ある態様において本発明のポリペプチドの1つ又はそれ以上のシステインは、他の残基(例えばセリン)で置換されてもよい。
1型糖尿病、2型糖尿病、糖尿病前症、インスリン抵抗性症候群、耐糖能障害(IGT)、高血中グルコースレベルに関連する疾患状態、高血糖、高血圧、アテローム発生性脂質異常症、動脈硬化症(例えば、アテローム性動脈硬化症)、大血管疾患、冠状動脈性心臓疾患、末梢動脈疾患、脳卒中、微小血管疾患、胃疾患、メタボリック症候群、癌(例えば結腸癌)、炎症性腸疾患(IBD)、過敏性腸症候群(IBS)、糖尿病性神経障害、糖尿病性網膜症、糖尿病性腎症、及び腎不全、
を治療又は予防するための方法における、その使用に関する。
いくつかの態様において、本発明の医薬は、その必要がある対象者の治療に使用するための医薬である。
さらなる形態において、本発明の医薬は、その必要がある対象者において、膵島中のβ−細胞の生存(例えば、膵島におけるβ−細胞の損失を防止するための)を誘導するための医薬である。
さらなる態様において、本発明の医薬は、その必要がある対象者において、上記のプロセス(すなわち膵島新生、膵島におけるβ−細胞の生存、及び/又は膵島中のβ−細胞の増殖)の任意の組合せを誘導するための医薬である。
その必要がある対象者において膵島の新生を誘導するための医薬の製造、
その必要がある対象者において膵島中のβ−細胞のアポトーシスを防止するための医薬の製造、
その必要がある対象者において膵島中のβ−細胞の生存を誘導するのに使用するための医薬の製造、
その必要がある対象者において膵臓のβ−細胞増殖を誘導するための医薬の製造、
その必要がある対象者の血中のヘモグロビンb1Ac(グリコシル化ヘモグロビン;HbA1c)レベルを低下させるための医薬の製造、
及び/又はこれらの任意の組合せ、において、さらに使用し得る。
本発明のペプチドコンジュゲート又はその医薬的に許容される塩もしくは溶媒和物の治療的有効量をその対象者に投与することを含む方法に関する。
その必要がある対象者において、高血中グルコースレベルに関連する疾患状態の治療法、
その必要がある対象者において、血中グルコースレベルを低下させる方法、
その必要がある対象者において、インスリン放出を刺激する方法、
その必要がある対象者において、胃内容排出を調節する方法、及び
その必要がある対象者において、血漿脂質レベルを低下させる方法、
その必要がある対象者において、血圧を低下させる方法、
その必要がある対象者において、体重を低下させる方法。
本発明のペプチドコンジュゲートは、標準的合成法により、組換え発現系の使用により、又は他の任意の適切な方法により、製造することができる。すなわち、このコンジュゲートは、例えば
(a)標準的な固相法又は液相法により、段階的に又は断片の組み立てにより、ペプチドコンジュゲートを合成し、最終ペプチドコンジュゲート生成物を単離し精製する方法、
(b)ペプチドコンジュゲートをコードする核酸構築体を宿主細胞中で発現させ、宿主細胞培養物から発現生成物を回収する方法、又は
(c)ペプチドコンジュゲートをコードする核酸構築体の無細胞インビトロ発現を行い、発現生成物を回収する方法、
を含む方法、
又は、(a)、(b)、又は(c)の方法の任意の組合せによりペプチドコンジュゲートの断片を得て、次にこれらの断片を連結してペプチドコンジュゲートを得て、ペプチドコンジュゲートを回収する方法、を含む多くの方法により合成することができる。
本発明のペプチドコンジュゲートは、エキセンジン−4の1つ又はそれ以上の生物活性とガストリンの1つ又はそれ以上の生物活性とを有する。
好適な態様において、本発明のポリペプチドは、CCKB−Rについて100nM未満のEC50値を有してもよい。
好適な態様において、本発明のポリペプチドは、CCKB−Rについて50nM未満のEC50値を有してもよい。
EC50値は、実施例4に記載するように測定すべきである。
本発明のペプチドコンジュゲートの使用はまた、その医薬的に許容される塩もしくは溶媒和物の使用を包含する。
2型糖尿病は、糖尿病症例の90〜95%を占め、代謝性疾患の複雑な組合せの結果である。2型糖尿病は、内因性インスリン産生及び/又は全身のインスリン感受性の結果であり、血漿グルコースレベルを診断閾値以下に維持するには不十分となる。
妊娠糖尿病は、妊娠中に特定される耐糖能異常のすべての程度を指す。
以下において、本発明のペプチドコンジュゲートの1つ又はそれ以上を医薬組成物に含めることはまた、本発明のペプチドコンジュゲートの医薬的に許容される塩もしくは溶媒和物を含めることを包含する。
皮下又は経皮型の投与は、本発明のペプチドコンジュゲートに特に適している。
本発明の文脈において使用される本発明のペプチドコンジュゲートの典型的な用量は、約0.0001〜約100mg/kg体重/日、例えば約0.0005〜約50mg/kg体重/日、約0.001〜約10mg/kg/日、約0.005〜約5mg/kg/日、約0.01〜約1mg/kg/日、約0.015〜約0.1mg/kg/日の範囲が、1回又は複数回、例えば1〜3回投与されてよい。既にある程度上記したように、用いられる正確な用量は、特に、治療すべき疾患又は障害の性質及び重症度;治療すべき対象者の性別、年齢、体重、全身状態;治療を受けているか又は受ける予定の他の可能性のある付随する疾患又は障害;並びに、当該分野の医師に知られているであろう他の要因などに依存するであろう。
すなわちペプチドコンジュゲートは、各休薬期で区切られた2回以上の投与期を含む投与処方を介して送達してもよい。
上記したように、本発明のペプチドコンジュゲートへの以下の言及はまた、その医薬的に許容される塩もしくは溶媒和物、並びに2つ以上の異なる本発明のペプチドコンジュゲートを含む組成物も包含することは、理解されるであろう。
ステロイド及びコルチコステロイド、例えばベクロメタゾン、メチルプレドニゾロン、ベタメタゾン、プレドニゾン、デキサメタゾン、及びヒドロコルチゾン;
非ステロイド性抗炎症薬(NSAID)、例えばプロピオン酸誘導体(例えばアルミノプロフェン、ベノキサプロフェン、ブクロキシ酸、カルプロフェン、フェンブフェン、フェノプロフェン、フルプロフェン、フルルビプロフェン、イブプロフェン、インドプロフェン、ケトプロフェン、ミプロフェン、ナプロキセン、オキサプロジン、ピルプロフェン、プラノプロフェン、スプロフェン、チアプロフェン酸、及びチオキサプロフェン);酢酸誘導体(例えばインドメタシン、アセメタシン、アルクロフェナック、クリダナク、ジクロフェナク、フェンクロフェナク、フェンクロジン酸、フェンチアザク、フロフェナク、イブフェナク、イソキセパク、オキスピナク、スリンダク、チオピナク、トルメチン、ジドメタシン、及びゾメピラック);フェナム酸誘導体(例えばフルフェナム酸、メクロフェナム酸、メフェナム酸、ニフルム酸、及びトルフェナム酸);ビフェニルカルボン酸誘導体(例えばジフルニサル及びフルフェニサル);オキシカム(例えばイソキシカム、ピロキシカム、スドキシカム、及びテノキシカム);サリチル酸塩(例えばアセチルサリチル酸及びスルファサラジン);及びピラゾロン(例えばアパゾン、ベズピペリロン、フェプラゾン、モフェブタゾン、オキシフェンブタゾン、及びフェニルブタゾン);
COXII阻害剤、例えばロフェコキシブ及びセレコキシブ;インターフェロンベータの調製物(例えば、インターフェロンベータ−1a又はインターフェロンベータ−1b);
及び、いくつかの他の化合物、例えば5−アミノサリチル酸、及び、これらののプロドラッグと薬学的に許容される塩]とともに使用することができる。
NMP:N−メチルピロリドン
DCM:ジクロロメタン
DMF:N、N−ジメチルホルムアミド
HATU:2−(7−アザ−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
DIPEA:ジイソプロピルエチルアミン
EtOH:エタノール
Et2O:ジエチルエーテル
8Ado:8−アミノ−3,6−ジオキサオクタノイル
8Aoc:8−アミノオクタノイル
TFA:トリフルオロ酢酸
MeCN:アセトニトリル
HPLC:高速液体クロマトグラフィー
MS:質量分析法
IBMX:3−イソブチル−1−メチルキサンチン
BSA:ウシ血清アルブミン
cAMP:環状アデノシン一リン酸
DMEM:ダルベッコ改変イーグル培地
FCS:ウシ胎児血清
HEPES:N−2−ヒドロキシエチルピペラジン−N’−2−エタンスルホン酸
P−ERK:リン酸化細胞外制御キナーゼ
PBS:リン酸緩衝化生理食塩水
BOC:t−ブトキシカルボニル
NEP:N−エチルピロリドン
リラグルチド:[Arg34,Lys26(ヘキサデカノイル−イソGlu)]GLP−1(7〜37)
材料と方法
特に明記しない場合は、以下で使用される試薬と溶媒は、標準的な実験用試薬又は分析グレードで市販されており、さらに精製することなく使用された。
標準的Fmoc化学を使用して、固相ペプチド合成をCEM Liberty Peptide Synthesizer上で行った。使用の前に、TentaGel(登録商標)S Ram 樹脂(1g;0.25mmol/g)をNEP(10ml)中で膨潤させ、DCM及びNEPを使用してチューブと反応槽との間を移動させた。ペプチド合成中の凝集を最小にするために使用されるジペプチドであるシュードプロリン、例えばFmoc−Phe−Thr(ψ−Me,Me−Pro)−OH及びFmoc−Asp−Ser(ψ−Me,Me−Pro)−OHを適宜使用し、非天然のアミノ酸(すなわち、Fmoc−8Ado−OH)を、一般的操作に変更を加えることなく使用した。
NEP/DMF/DCM(1:1:1;0.2M;5ml)中のFmoc−アミノ酸をCEM Discover マイクロ波装置中の樹脂に、HATU/DMF(0.5M;2ml)及びDIPEA/NEP(2.0M;1ml)と共に添加した。混合物を通して窒素を泡立てせながら、カップリング混合物を75°Cまで5分間加熱した。続いて樹脂をNEPで洗浄した(4x10ml)。
最初の脱保護のためにピペリジン/NEP(1/4(4部のNEPに対する1部のピペリジンを示す);10ml)を樹脂に添加し、混合物をマイクロ波加熱した(40℃;30秒)。反応容器を排出し、ピペリジン/NEP(1/4;10ml)の2回目の量を添加し、再度加熱した(75℃;3分)。続いて樹脂をNEPで洗浄した(6x10ml)。
樹脂をエタノール(3x10ml)及びEジエチルエーテル(3x10ml)で洗浄し、一定の重量まで室温で(r.t.)乾燥した。TFA/TIS/水(95/5/5;40ml、2h;r.t.)を用いる処置によって、未精製のペプチドを樹脂から切断した。TFAの大半を減圧で除去し、未精製のペプチドを沈殿させ、ジエチルエーテルで3回洗浄し、室温で一定の重量まで乾燥した。
適切なカラムとフラクションコレクターを備えたPerSeptive Biosystems VISION Workstationを使用して、未精製のペプチドを分取用逆相HPLCによって90%超の純度まで精製し、緩衝液A(0.1%TFA、aq.)及び緩衝液B(0.1%TFA、90%MeCN、aq.)との勾配で実行した。分析用HPLC及びMSによって画分を分析し、関連画分をプールし凍結乾燥した。最終生成物をHPLC及びMSによって性状解析した。
化合物2[Leu14,Lys25(ヘキサデカノイル−イソGLu)]エキセンジン−4(1〜28)−8Ado−8Ado−[Leu4]ガストリン6の合成
CEM Liberty Peptide Synthesizer上で上記したTentaGel S Ram 樹脂(1.13g;0.24mmol/g)とFmoc化学を使用して、[Leu14]エキセンジン−4(1〜28)−8Ado−8Ado−[Leu4]ガストリン6を合成した。Fmoc−8−アミノ−3,6−ジオキサオクタン酸(Fmoc−8Ado−OH)並びにFmoc−Lys(Dde)−OHを、アシル化のために結合点で使用した。
化合物6[Cys16(ビオチン−Mal),Leu14]エキセンジン−4(1〜28)−8Ado−8Ado−[Leu4]ガストリン6の合成
CEM Liberty Peptide Synthesizer上で上記した2部のTentaGel S Ram 樹脂(1.12g;0.25mmol/g)とFmoc化学を使用して、Fmoc−Phe−Thr(ψ−Me,Me−Pro)−OH及びFmoc−8−アミノ−3,6−ジオキサオクタン酸(Fmoc−8Ado−OH)を使用して、[Cys16,Leu14]エキセンジン−4(1〜28)−8Ado−8Ado−[Leu4]ガストリン6を合成した。このペプチドを上記したように樹脂から切断した(部分1)。
化合物9[Glu9,Leu14,Phe25,Tyr13]エキセンジン−4(1〜27)−QQ−[Leu4]ガストリン6の合成
このペプチドは、上記したようにCEM Liberty Peptide Synthesizer上でTentaGel S Ram 樹脂(1.10g;0.25mmol/g)とFmoc化学を使用して、Fmoc−Phe−Thr(ψ−Me,Me−Pro)−OHを使用して合成した。未精製ペプチドをGemini-NXカラム(5×25cm;10μm;C18)上で、緩衝液A(0.1%TFA;aq.)及び緩衝液B(0.1%TFA、90%MeCN;aq.)の混合物の35ml/分流量で精製した。生成物を20%〜50%の緩衝液Bで47分間直線勾配で溶出し、フラクションコレクターによって画分(9ml)を採取した。関連画分を分析用HPLCとMSによって分析し、プールし、白色粉末(137mg)となるまで凍結乾燥し、これを、分析用HPLCによって78%純度として分析した。質量はMSにより測定すると、4208.11Daであった(計算値4208.09Da)。
本発明のペプチドコンジュゲートによるGLP−1受容体とガストリンCCK−B受容体のインビトロ活性化(EC 50 )
材料と方法
ヒトGLP−1受容体(GLP−1 R)有効性アッセイ:
本発明のペプチドコンジュゲートのインビトロ作用を、Perkin-ElmerからのFlashPlate(登録商標)cAMPキットを使用して、GLP−1(7〜36)、エキセンジン−4(1〜39)、又は本発明のコンジュゲートによる受容体の刺激後、cAMPの誘導を測定することにより、評価した。簡単に説明すると、ヒトGLP−1 R(GLP−1 RのcDNAのトランスフェクションと安定なクローンの選択により作成された安定な細胞株)を発現するHEK293細胞を、0.01%ポリリジンで被覆した96ウェルマイクロタイタープレートに40,000細胞/ウェルで接種し、100μlの増殖培地[DMEM、10%FCS、ペニシリン(100IU/ml)、ストレプトマイシン(100μg/ml)]中で一晩培養して増殖させた。分析の日に、増殖培地を取り出し、細胞を200μlのタイロード緩衝液[タイロード塩(0.6g/l)、10mMヘペス、pH7.4]で1回洗浄した。細胞を、上昇する濃度の試験化合物、100μMのIBMX、及び0.1%のBSAを含有する100μlのタイロード緩衝液中で、37℃で15分インキュベートした。25μlの0.5M HClの添加により反応を停止させ、氷上で60分インキュベートした。方法のさらなる詳細については、WO2008/152403を参照されたい。
本発明のペプチドコンジュゲートと対照のガストリン17類似体[Leu15]ガストリン17のインビトロ作用を、ヒトCCK−B R(高親和性ガストリン受容体;CCK−B RのcDNAのトランスフェクションと安定なクローンの選択により作成された安定な細胞株)を安定に発現するHEK293細胞中でp−ERKを測定して(AlphaScreen(登録商標)SureFire p-ERKアッセイを使用して)推定した。ガストリン受容体有効性アッセイ(AlphaScreen(登録商標)SureFire p-ERKアッセイ)は、以下のように行った:1日目に、CCK−B Rを発現する細胞を、ポリ−D−リジンで被覆した96ウェルプレートウェル中の100μlの増殖培地[DMEM、10%FCS、ペニシリン(100IU/ml)、ストレプトマイシン(100μg/ml)]中で20,000細胞/ウェルで接種した。細胞をインキュベーター(37℃、5%CO2)中で2日間インキュベートした。次に増殖培地を、ウェル当たり80μlの無血清培地[DMEM、ペニシリン(100IU/ml)、ストレプトマイシン(100μg/ml)]に添加し、細胞のインキュベーションをインキュベーター中で一晩続けた。分析の日に、上昇する濃度で化合物を20μlの無血清培地に加え、細胞を室温で5分インキュベートした。プレートを素早く上下にひっくり返して刺激培地を捨て、60μlの1×溶解緩衝液(SureFireアッセイキットから)をウェルに加えた。さらなる詳細については、WO2011/134471を参照されたい。
ヒトGLP−1受容体(hGLP−1 R)活性化アッセイ中の陽性対照としてエキセンジン−4(1〜39)を使用し、ヒトCCK−B受容体(hCCK−B R)活性化アッセイの陽性対照としてh[Leu15]ガストリン17を使用した。
上記表1に要約した結果は、本発明のペプチドコンジュゲートが、問題の2つの受容体の強力なアゴニストであること、及びこれらが非常によく似たレベルの活性を示すことを、示す。
マウス中の選択された化合物の薬物動態(PK)
方法
C57BlL/6Jマウスに、試験すべき各ペプチドの100nmol/kgを単回皮下投与した。5分後及び30分後、そして1、2、4、6、16、及び24時間後に、血液試料を採取した。各時点で、2匹のマウスから試料を取った。採血後直ちに、マウスを頸椎脱臼により安楽死させた。固相抽出(SPE)後、血漿試料を液体クロマトグラフィー質量スペクトル法(MC−MS/MS)により分析した。
3週間のインビボdb/dbマウス試験
db/dbマウスは、可能性のある治療候補のβ−細胞保存作用を評価するために、すでに使用されている[Rolin, B. et al., Am. J. Physiol. Endocrinol. Metab. 283: E745-E752 (2002)]。いくつかの試験が、膵臓インスリン含量とβ−細胞質量との相関を証明している[Rolin, B. et al. (前出); Suarez-Pinzon, W.L. et al., Diabetes 54: 2596-2601 (2005); Suarez-Pinzon W.L. et al., Diabetes 57: 3281-3288 (2008)]。
db/dbマウスを、HbA1cレベルに従って種々の処置群に群分けした。マウスは、全部で21日間の皮下(SC)注射で毎日1回処理した。注射容量は5ml/kgであった。試験中、体重(BW)を毎日記録し、ペプチドの体重補正用量を投与するために使用した。
16日目に、経口耐糖能試験を動物に行った。グルコース投与の前(t=0で、ベースライン)と投与後2時間まで、血中グルコースを測定した。
終了時に、血中グルコースを測定し、血液試料をHbA1cレベルについて分析した。
全血グルコース濃度(mM)を、固定化グルコースオキシダーゼ法により測定した(Elite Autoanalyser, Bayer, Denmark)。血液試料は、Cobas c111 analyzer (Roche Diagnostics, Mannheim, Germany) を使用してHbA1cについて分析した。
エキセンジン−ガストリン2重アゴニスト化合物18と化合物23は両方とも、16日間の処置後、空腹時血中グルコースレベルを低下させた。化合物18は、空腹時血中グルコースレベルを化合物23より大きく低下させた。両方の化合物とも、3週間の処置後HbA1cの血漿レベルを低下させたが、化合物間に有意差はなかった(対応の無い両側t−検定)。
デルタHbA1c:db/dbマウスの21日間の処置後の、ビヒクル、化合物18(100nmol/kg)及び化合物23(100nmol/kg)のSC投与のデルタHbA1c(%)レベルに対する作用(試験の開始時のHbA1cのレベルから試験の終了時のHbA1cのレベルを引く)。データは、平均とSEMで示される(n=11/群)。(−)は、デルタHbA1cレベルが0.5%を超えることを示し、(+)はデルタHbA1cレベルが0.25%〜0.5%であることを示し、(++)は、デルタHbA1cレベルが0%〜0.25%であることを示し、(+++)は、デルタHbA1cレベルが0%未満であることを示す。
インビボdb/dbマウス試験:4週間の処置後に2週間の休薬
処置
db/dbマウスを、HbA1cレベルに従って種々の処置群に群分けした。マウスは、全部で4週間の皮下(SC)注射で毎日1回処理し、次にビヒクルを2週間投与した。注射容量は5ml/kgであった。試験中、体重(BW)を毎日記録し、ペプチドの体重補正用量を投与するために使用した。
3週間と5週間後に、経口耐糖能試験を動物に行った。グルコース投与の前(t=0で、ベースライン)と投与後2時間まで、血中グルコースを測定した。
全血グルコース濃度(mM)は、固定化グルコースオキシダーゼ法により測定した(Elite Autoanalyser, Bayer, Denmark)。
エキセンジン−ガストリン2重アゴニスト化合物18は、3週間の処置後、ビヒクルと比較して空腹時血中グルコースレベルを低下させた。化合物18は、空腹時血中グルコースレベルを等モル用量のリラグルチドより大きく低下させた(図1を参照)。4週間の処置後に1週間の休薬(ビヒクル投与)をすると、化合物18は、ビヒクルと比較して空腹時血中グルコースレベルを有意に低下させた。化合物18は、等モル用量のリラグルチドより、空腹時血中グルコースレベルを大きく低下させた(図2を参照)。
インビボZDFラット試験:6週間の処置
処置
ZDFラットを、HbA1cレベルに従って種々の処置群に群分けした。ラットは、全部で6週間の皮下(SC)注射で毎日2回処理し、注射容量は5ml/kgであった。試験中、体重(BW)を毎日記録し、ペプチドの体重補正用量を投与するために使用した。
5週間後に、経口耐糖能試験を動物に行った。グルコース投与の前(t=0で、ベースライン)と投与後2時間まで、血中グルコースを測定した。
終了時に、血液試料をHbA1cレベルについて分析した。
全血グルコース濃度(mM)は、固定化グルコースオキシダーゼ法により測定した(Elite Autoanalyser, Bayer, Denmark)。
血液試料は、Cobas c111 analyzer (Roche Diagnostics, Mannheim, Germany) を使用してHbA1cについて分析した。
エキセンジン−ガストリン2重アゴニスト化合物18は、5週間の処置後、ビヒクルと比較して空腹時血中グルコースレベルを低下させた。化合物18は、空腹時血中グルコースレベルを等モル用量のリラグルチドより大きく低下させた(図6を参照)。
Claims (15)
- 式:
H−HGEGTFTSELSKYLEEEAVRLFIEFLKN−8Ado−8Ado−YGWLDF−NH 2 、又はH−HGEGTFTSELSKYLEEEAVRLFIEWLKDYGWLDF−NH2
を有するペプチドコンジュゲート、又はその医薬的に許容される塩もしくは溶媒和物。 - 請求項1に記載のペプチドコンジュゲート又はその医薬的に許容される塩もしくは溶媒和物と、医薬的に許容される担体、賦形剤又はビヒクルとを含む、医薬組成物。
- (i)1型糖尿病、2型糖尿病、糖尿病前症、インスリン抵抗性症候群、耐糖能障害(IGT)、高血中グルコースレベルに関連する疾患状態、高血糖、高血圧、アテローム発生性脂質異常症、動脈硬化症、冠状動脈性心臓疾患、末梢動脈疾患、脳卒中、微小血管疾患、胃疾患、メタボリック症候群、癌、炎症性腸疾患(IBD)、過敏性腸症候群(IBS)、糖尿病性神経障害、糖尿病性網膜症、糖尿病性腎症、及び腎不全から選択される疾患又は障害の治療;
(ii)β−細胞及び/又はその壊死の誘導;
(iii)膵島β−細胞の生存の誘導;
(iv)膵島でのβ−細胞アポトーシス及び/又はその壊死の抑制;
(v)膵島でのβ−細胞増殖の誘導;
(vi)体重増加の抑制又は体重減少の促進;
(vii)循環グルコースレベル、耐糖能、及び/又は循環コレステロールレベルの改善、循環LDLレベルの低下、及び/又はHDL/LDL比の上昇;又は
(viii)過剰な体重により引き起こされるか又はこれを特徴とする症状の治療又は予防
のための、請求項2に記載の医薬組成物。 - ヒト対象に使用するための、請求項3に記載の医薬組成物。
- 過剰な体重により引き起こされるか又はこれを特徴とする症状が、肥満、病的肥満、肥満関連炎症、肥満関連胆嚢疾患、及び肥満誘発性睡眠時無呼吸、メタボリック症候群、及び糖尿病前症から選択される、請求項3に記載の医薬組成物。
- 該ペプチドコンジュゲート又はその医薬的に許容される塩もしくは溶媒和物が、プロトンポンプ阻害剤との、又は糖尿病、肥満、脂質異常症、もしくは高血圧を治療するための物質との、併用療法の一部として投与される、請求項3〜5のいずれか1項に記載の医薬組成物。
- (i)糖尿病を治療又は予防するための該物質が、メトホルミン、スルホニル尿素、グリニド、DPP−IV阻害剤、グリタゾン、インスリン、又はインスリン類似体であり;
(ii)肥満を治療又は予防するための該物質が、グルカゴン様ペプチド−1アゴニスト、ペプチドYYもしくはその類似体、ニューロペプチドY(NPY)もしくはその類似体、カンナビノイド受容体1アンタゴニスト、リパーゼ阻害剤、メラノコルチン受容体4アゴニスト、又はメラニン濃縮ホルモン受容体1アンタゴニストであり;
(iii)高血圧を治療又は予防するための該物質が、アンギオテンシン変換酵素阻害剤、アンギオテンシンII受容体遮断薬、利尿剤、ベータ遮断薬、又はカルシウムチャネル遮断薬であり;
(iv)脂質異常症を治療又は予防するための該物質が、スタチン、フィブラート、ナイアシン、及び/又はコレステロール吸収阻害であり;
(v)プロトンポンプ阻害剤が、ベンズイミダゾリル誘導体型又はイミダゾピリジン誘導体型の物質である、請求項6に記載の医薬組成物。 - 請求項1に記載のペプチドコンジュゲート又はその医薬的に許容される塩もしくは溶媒和物を合成法で製造する方法。
- 対象者に、請求項1に記載のペプチドコンジュゲート又はその医薬的に許容される塩もしくは溶媒和物、又は請求項2に記載の医薬組成物を送達するための、少なくとも1つの該ペプチドコンジュゲート又はその医薬的に許容される塩もしくは溶媒和物、又は該医薬組成物を含む、装置。
- 請求項1に記載の少なくとも1つのペプチドコンジュゲート又はその医薬的に許容される塩もしくは溶媒和物、又は請求項2に記載の医薬組成物と、包装材又は使用説明書とを含む、キット。
- (i)1型糖尿病、2型糖尿病、糖尿病前症、インスリン抵抗性症候群、耐糖能障害(IGT)、高血中グルコースレベルに関連する疾患状態、高血糖、高血圧、アテローム発生性脂質異常症、動脈硬化症、冠状動脈性心臓疾患、末梢動脈疾患、脳卒中、微小血管疾患、胃疾患、メタボリック症候群、癌、炎症性腸疾患(IBD)、過敏性腸症候群(IBS)、糖尿病性神経障害、糖尿病性網膜症、糖尿病性腎症、及び腎不全、から選択される疾患又は障害の治療;
(ii)β−細胞及び/又はその壊死の誘導;
(iii)膵島β−細胞の生存の誘導;
(iv)膵島でのβ−細胞アポトーシス及び/又はその壊死の抑制;
(v)膵島でのβ−細胞増殖の誘導;
(vi)体重増加の抑制又は体重減少の促進;
(vii)循環グルコースレベル、耐糖能、及び/又は循環コレステロールレベルの改善、循環LDLレベルの低下、及び/又はHDL/LDL比の上昇;又は
(viii)過剰な体重により引き起こされるか又はこれを特徴とする症状の治療又は予防、
のための医薬の製造のための、請求項1に記載の少なくとも1つのペプチドコンジュゲート又はその医薬的に許容される塩もしくは溶媒和物の使用。 - ヒト対象で使用するための、請求項11に記載の使用。
- 過剰な体重により引き起こされるか又はこれを特徴とする症状が、肥満、病的肥満、肥満関連炎症、肥満関連胆嚢疾患、及び肥満誘発性睡眠時無呼吸、メタボリック症候群、及び糖尿病前症から選択される、請求項11に記載の使用。
- 該ペプチドコンジュゲート又はその医薬的に許容される塩もしくは溶媒和物が、プロトンポンプ阻害剤との、又は糖尿病、肥満、脂質異常症、もしくは高血圧を治療するための物質との、併用療法の一部として投与される、請求項11〜13のいずれか1項に記載の使用。
- (i)糖尿病を治療又は予防するための該物質が、メトホルミン、スルホニル尿素、グリニド、DPP−IV阻害剤、グリタゾン、インスリン、又はインスリン類似体であり;
(ii)肥満を治療又は予防するための該物質が、グルカゴン様ペプチド−1、ペプチドYYもしくはその類似体、ニューロペプチドY(NPY)もしくはその類似体、カンナビノイド受容体1アンタゴニスト、リパーゼ阻害剤、メラノコルチン受容体4アゴニスト、又はメラニン濃縮ホルモン受容体1アンタゴニストであり;
(iii)高血圧を治療又は予防するための該物質が、アンギオテンシン変換酵素阻害剤、アンギオテンシンII受容体遮断薬、利尿剤、ベータ遮断薬、又はカルシウムチャネル遮断薬であり;
(iv)脂質異常症を治療又は予防するための該物質が、スタチン、フィブラート、ナイアシン、及び/又はコレステロール吸収阻害であり;
(v)プロトンポンプ阻害剤が、ベンズイミダゾリル誘導体型又はイミダゾピリジン誘導体型の物質である、請求項14に記載の使用。
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- 2012-11-02 KR KR1020147015223A patent/KR20140100947A/ko not_active Application Discontinuation
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CN104144704A (zh) | 2014-11-12 |
JP2015502918A (ja) | 2015-01-29 |
KR20140100947A (ko) | 2014-08-18 |
AU2012331053A1 (en) | 2014-05-29 |
TW201326194A (zh) | 2013-07-01 |
BR112014010780A2 (pt) | 2017-04-25 |
CN104144704B (zh) | 2018-03-23 |
US9259477B2 (en) | 2016-02-16 |
AR088636A1 (es) | 2014-06-25 |
US9861706B2 (en) | 2018-01-09 |
WO2013064669A1 (en) | 2013-05-10 |
CA2853884A1 (en) | 2013-05-10 |
US20160082118A1 (en) | 2016-03-24 |
US20140336107A1 (en) | 2014-11-13 |
EA201490790A1 (ru) | 2014-10-30 |
EP2773377B1 (en) | 2020-07-08 |
EA028951B9 (ru) | 2018-05-31 |
MX2014005351A (es) | 2014-05-28 |
EP2773377A1 (en) | 2014-09-10 |
EA028951B1 (ru) | 2018-01-31 |
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