JP4585037B2 - アシル化glp−1化合物 - Google Patents
アシル化glp−1化合物 Download PDFInfo
- Publication number
- JP4585037B2 JP4585037B2 JP2010009025A JP2010009025A JP4585037B2 JP 4585037 B2 JP4585037 B2 JP 4585037B2 JP 2010009025 A JP2010009025 A JP 2010009025A JP 2010009025 A JP2010009025 A JP 2010009025A JP 4585037 B2 JP4585037 B2 JP 4585037B2
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- Prior art keywords
- glp
- peptide
- acid
- ethoxy
- xaa
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- 238000001248 thermal gelation Methods 0.000 description 1
- 230000000930 thermomechanical effect Effects 0.000 description 1
- 229960004605 timolol Drugs 0.000 description 1
- 239000008181 tonicity modifier Substances 0.000 description 1
- FGMPLJWBKKVCDB-UHFFFAOYSA-N trans-L-hydroxy-proline Natural products ON1CCCC1C(O)=O FGMPLJWBKKVCDB-UHFFFAOYSA-N 0.000 description 1
- 238000005891 transamination reaction Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- ILWRPSCZWQJDMK-UHFFFAOYSA-N triethylazanium;chloride Chemical compound Cl.CCN(CC)CC ILWRPSCZWQJDMK-UHFFFAOYSA-N 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 229920001664 tyloxapol Polymers 0.000 description 1
- MDYZKJNTKZIUSK-UHFFFAOYSA-N tyloxapol Chemical compound O=C.C1CO1.CC(C)(C)CC(C)(C)C1=CC=C(O)C=C1 MDYZKJNTKZIUSK-UHFFFAOYSA-N 0.000 description 1
- 229960004224 tyloxapol Drugs 0.000 description 1
- 229960001130 urapidil Drugs 0.000 description 1
- 239000000777 urocortin Substances 0.000 description 1
- RUDATBOHQWOJDD-UZVSRGJWSA-N ursodeoxycholic acid Chemical compound C([C@H]1C[C@@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)CC1 RUDATBOHQWOJDD-UZVSRGJWSA-N 0.000 description 1
- GHCZAUBVMUEKKP-UHFFFAOYSA-N ursodeoxycholic acid glycine-conjugate Natural products OC1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(=O)NCC(O)=O)C)C1(C)CC2 GHCZAUBVMUEKKP-UHFFFAOYSA-N 0.000 description 1
- 229960001661 ursodiol Drugs 0.000 description 1
- 210000001215 vagina Anatomy 0.000 description 1
- 239000006213 vaginal ring Substances 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 229960001722 verapamil Drugs 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 239000000811 xylitol Substances 0.000 description 1
- 235000010447 xylitol Nutrition 0.000 description 1
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
- 229960002675 xylitol Drugs 0.000 description 1
- 239000002888 zwitterionic surfactant Substances 0.000 description 1
Classifications
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Description
本明細書で使用される「ポリペプチド」および「ペプチド」の用語は、ペプチド結合により連結される少なくとも5つの構成アミノ酸から構成される化合物を意味する。構成アミノ酸は、遺伝暗号にコードされるアミノ酸のグループに由来してもよいし、遺伝暗号にコードされない天然アミノ酸であってもよいし、合成アミノ酸であってもよい。遺伝暗号にコードされない天然アミノ酸は、たとえば、γ−カルボキシグルタメート、オルニチン、ホスホセリン、D−アラニンおよびD−グルタミンである。合成アミノ酸には、化学合成により製造されるアミノ酸、すなわち、遺伝暗号にコードされるアミノ酸のD−異性体、たとえばD−アラニンおよびD−ロイシン、Aib(α−アミノイソ酪酸)、Abu(α−アミノ酪酸)、Tle(tert−ブチルグリシン)、β−アラニン、3−アミノメチル安息香酸、アントラニル酸が含まれる。
ペプチドの一部(5 nmol)を、100μL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1μLの精製ジペプチジルアミノペプチダーゼIVと37℃で10−180分間インキュベートする。酵素反応は、5μLの10%トリフルオロ酢酸の添加により停止させ、ペプチド分解産物を、HPLC分析を用いて分離、定量する。この分析を行うための一つの方法は、以下のとおりである:混合物を、Vydac C18 widepore (30 nm孔、5μm粒子) 250 x 4.6 mmカラムに添加し、1 ml/minの流速で、0.1%トリフルオロ酢酸中のアセトニトリルの直線的段階勾配 (3分間0%アセトニトリル、17分間0−24%アセトニトリル、1分間24−48%アセトニトリル) を用いて、Siegel et al., Regul. Pept. 1999; 79: 93-102 and Mentlein et al. Eur. J. Biochem. 1993; 214: 829-35に従って溶出した。ペプチドおよびその分解産物は、220 nm (ペプチド結合) または280 nm (芳香族アミノ酸) における吸光度によりモニターすることができ、スタンダードのピーク面積に対するピーク面積の積算(integration)により定量する。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速度は、加水分解されるペプチドが10%未満になるインキュベーション時間で評価する。
mは0, 1, 2, 3, 4, 5, または6であり、
nは1, 2または3であり、
sは0, 1, 2, または3であり、
tは0, 1, 2, 3, または4であり、
pは1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, または23であり;
Bは
lは12, 13, 14, 15, 16, 17, 18, 19または20である、GLP-1類似体を提供する。
Xaa7は、L-ヒスチジン、イミダゾプロピオニル、α-ヒドロキシ-ヒスチジン、D-ヒスチジン、デスアミノ-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、Nα-ホルミル-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-ピリジルアラニンまたは4-ピリジルアラニンであり;
Xaa8は、Ala、Gly、Val、Leu、Ile、Thr、Ser、Lys、Aib、(1-アミノシクロプロピル)カルボン酸、(1-アミノシクロブチル)カルボン酸、(1-アミノシクロペンチル)カルボン酸、(1-アミノシクロヘキシル)カルボン酸、(1-アミノシクロヘプチル)カルボン酸、または(1-アミノシクロオクチル)カルボン酸であり;
Xaa16は、ValまたはLeuであり;
Xaa18は、Ser, LysまたはArgであり;
Xaa19は、TyrまたはGlnであり;
Xaa20は、LeuまたはMetであり;
Xaa22は、Gly, GluまたはAibであり;
Xaa23は、Gln, Glu, LysまたはArgであり;
Xaa25は、AlaまたはValであり;
Xaa27は、GluまたはLeuであり;
Xaa30は、Ala, GluまたはArgであり;
Xaa33は、ValまたはLysであり;
Xaa34は、Lys, Glu, AsnまたはArgであり;
Xaa35は、GlyまたはAibであり;
Xaa36は、Arg, GlyまたはLys, または存在せず;
Xaa37は、Gly, Ala, Glu, Pro, Lys, または存在せず;
BおよびU’は、ともにアシル化部分であり、U’は、
mは0, 1, 2, 3, 4, 5, または6であり、
nは1, 2または3であり、
sは0, 1, 2, または3であり、
tは0, 1, 2, 3, または4であり、
pは1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, または23であり;
Bは
lは12, 13, 14, 15, 16, 17, 18, 19または20である。
Xaa7は、L-ヒスチジン、D-ヒスチジン、デスアミノ-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-ピリジルアラニンまたは4-ピリジルアラニンであり;
Xaa8は、Ala、Gly、Val、Leu、Ile、Lys、Aib、(1-アミノシクロプロピル)カルボン酸、(1-アミノシクロブチル)カルボン酸、(1-アミノシクロペンチル)カルボン酸、(1-アミノシクロヘキシル)カルボン酸、(1-アミノシクロヘプチル)カルボン酸、または(1-アミノシクロオクチル)カルボン酸であり;
Xaa16は、ValまたはLeuであり;
Xaa18は、Ser, LysまたはArgであり;
Xaa19は、TyrまたはGlnであり;
Xaa20は、LeuまたはMetであり;
Xaa22は、Gly, GluまたはAibであり;
Xaa23は、Gln, Glu, LysまたはArgであり;
Xaa25は、AlaまたはValであり;
Xaa27は、GluまたはLeuであり;
Xaa30は、Ala, GluまたはArgであり;
Xaa33は、ValまたはLysであり;
Xaa34は、Lys, Glu, AsnまたはArgであり;
Xaa35は、GlyまたはAibであり;
Xaa36は、Arg, GlyまたはLys, または存在せず;
Xaa37は、Gly, Ala, Glu, Pro, Lys, または存在せず;
Xaa38は、Lys, Ser, アミドまたは存在せず;
Uは
nは12, 13, 14, 15, 16, 17または18であり、
lは12, 13, 14, 15, 16, 17または18であり、
mは0, 1, 2, 3, 4, 5, または6であり、
sは0, 1, 2, または3であり、
pは3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, または23であり;
Bは
mは2, 3, 4または5であり、
nは1または2であり、
sは0, 1, または2であり、
tは0, 1, 2, または3であり、
pは1, 2, 3, 4, 7, 11または23である、GLP-1類似体を提供する。
lは14, 15, 16, 17, 18, 19または20であり;
pは1, 2, 3, 4, 7, 8, 9, 10, 11または12であり;
sは0, 1または2であり;
tは0または1である、GLP-1類似体を提供する。
lは14, 15, 16, 17または18であり;
pは1, 2, 3, 4または11であり;
sは0, 1または2であり;
tは0または1である。
lは14, 15, 16, 17, 18, 19または20であり;
pは1, 2, 3, または4であり;
sは0, 1または2であり;
nは0, 1または2である、GLP-1類似体を提供する。
Xaa7は、Hisまたはデスアミノ-ヒスチジンであり;
Xaa8は、Ala, Gly, Val, Leu, Ile, LysまたはAibであり;
Xaa16は、Valであり;
Xaa18は、Serであり;
Xaa19は、Tyrであり;
Xaa20は、Leuであり;
Xaa22は、Gly, GluまたはAibであり;
Xaa23は、GlnまたはGluであり;
Xaa25は、Alaであり;
Xaa27は、Gluであり;
Xaa30は、AlaまたはGluであり;
Xaa33は、Valであり;
Xaa34は、LysまたはArgであり;
Xaa35は、GlyまたはAibであり;
Xaa36は、ArgまたはLysであり;
Xaa37は、Gly, アミドまたは存在しない、GLP-1類似体を提供する。
Xaa7は、Hisであり;
Xaa8は、Gly, またはAibであり;
Xaa16は、Valであり;
Xaa18は、Serであり;
Xaa19は、Tyrであり;
Xaa20は、Leuであり;
Xaa22は、GluまたはAibであり;
Xaa23は、Glnであり;
Xaa25は、Alaであり;
Xaa27は、Gluであり;
Xaa30は、Alaであり;
Xaa33は、Valであり;
Xaa34は、LysまたはArgであり;
Xaa35は、GlyまたはAibであり;
Xaa36は、Argであり;
Xaa37は、Glyである、GLP-1類似体を提供する。
Aib8,Arg34-GLP-1(7-37)
Aib8,22,Arg34-GLP-1(7-37).
Arg34-GLP-1(7-37).
[3-(4-イミダゾリル)プロピオニル7,Arg34]GLP-1-(7-37)ペプチド
Gly8,Arg34-GLP-1(7-37)
Aib8,Arg34,Pro37-GLP-1(7-37)
Aib8,22,27,30,35,Arg34,Pro37-GLP-1(7-37)アミド
であり、これらのすべてが、位置26においてB−U’により置換されている、GLP-1類似体を提供する。
lは14, 15または16であり;
nは15, 16, 17または18であり;
pは3, 7, 11または24である。
r.t: 室温
DIPEA: ジイソプロピルエチルアミン
H2O: 水
CH3CN: アセトニトリル
DMF: NN ジメチルホルムアミド
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
Fmoc: 9 H-フルオレン-9-イルメトキシカルボニル
Boc: tert ブチルオキシカルボニル
OtBu: tert ブチルエステル
tBu: tert 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
ivDde: 1-(4,4-ジメチル-2,6-ジオキソシクロヘキシリデン)-3-メチルブチル
Mtt: 4-メチルトリチル
Mmt: 4-メトキシトリチル
DCM: ジクロロメタン
TIS: トリイソプロピルシラン
TFA: トリフルオロ酢酸
Et2O: ジエチルエーテル
NMP: 1-メチル-ピロリジン-2-オン
DIPEA: ジイソプロピルエチルアミン
HOAt: 1-ヒドロキシ-7-アザベンゾトリアゾール
HOBt: 1-ヒドロキシベンゾトリアゾール
DIC: ジイソピロピルカルボジイミド。
保護されたぺプチジル樹脂を、Fmocストラテジーに従って、Applied Biosystems 433ペプチド合成機で、0.25 mmolまたは1.0 mmolスケールにおいて、NMP (N-メチルピロリドン)中の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)またはHATU (O-(7-アザ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)介在カップリングを採用する製造メーカー提供FastMoc UVプロトコールを用いて、Fmoc保護基の脱保護のUVモニタリングをして、合成した。GLP-1ペプチドアミドの合成のために使用した出発樹脂は、Rink-Amide樹脂であり、Wangまたはクロロトリチル樹脂の何れかを、カルボキシC-末端を有するGLP-1ペプチドのために使用した。使用され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) などの非天然アミノ酸を除いて、ABI433A合成機に適した予め重量測定されたカートリッジ内に提供される (たとえばAnaspecまたはNovabiochemから提供される) 標準的なFmoc-アミノ酸であった。N末端アミノ酸は、アルファーアミノ基においてBoc保護された (たとえば、N-末端にHisを有するペプチドのためにBoc-His(Boc)OHを使用した)。位置26におけるリジンのイプシロンアミノ基は、アルブミン結合部分およびスペーサーの付着ルートに依存して、Mtt、Mmt、Dde、ivDde、またはBocの何れかで保護された。ペプチドの合成は、幾つかのケースでは、酸性条件下で切断可能な基(たとえば2-Fmoc-オキシ-4-メトキシベンジルまたは2,4,6-トリメトキシベンジルであるがこれらに限定されない)によりジペプチドのアミド結合上で保護されたジペプチドを使用して改良されてもよい。セリンまたはトレオニンがペプチドに存在する場合、シュードプロリンジペプチドの使用が採用されてもよい (たとえば、Novobiochem 2002/2003もしくは新しいバージョンのカタログ、またはW.R. Sampson (1999), J. Pep. Sci. 5, 403が参照される)。
樹脂 (0.25 mmol) を、手動の振盪機/濾過装置に置き、N-メチルピロリドン中の2%ヒドラジンで処理して (20 ml, 2x12分)、DdeまたはivDde基を除去し、N-メチルピロリドン (4x20 ml) で洗浄した。
樹脂 (0.25 mmol) を、手動の振盪機/濾過装置に置き、DCM中の2% TFAおよび2-3% TISで処理して (20 ml、5-10分、6-12回繰り返す)、MttまたはMmt基を除去し、DCM (2x20 ml)、DCM中の10% MeOHおよび5% DIPEA (2x20ml)、およびN-メチルピロリドン (4x20 ml) で洗浄した。
アルブミン結合残基 (式IのB-U-側鎖) は、標準的なアシル化試薬(たとえばDIC、HOBt/DIC、HOAt/DIC、またはHBTUでありこれらに限定されない)を用いて、樹脂結合ペプチドに対するアシル化または未保護のペプチドに対する溶液中でのアシル化の何れかにより、GLP-1ペプチドに付着させることができる。
ルートI
活性化された (活性エステルまたは対称無水物) アルブミン結合残基 (式IのB-U-側鎖)、たとえばオクタデカン二酸モノ-(2,5-ジオキソ-ピロリジン-1-イル)エステル (Ebashi et al. EP511600, 樹脂結合ペプチドに対して4モル当量) を、NMP (25 mL) 中に溶解し、樹脂に添加し、室温で一晩振盪させた。反応混合液を濾過し、樹脂をNMP、ジクロロメタン、2-プロパノール、メタノールおよびジエチルエーテルで十分に洗浄した。
アルブミン結合残基 (式IのB-U-側鎖) を、N-メチルピロリドン/メチレンクロライド (1:1, 10 ml) 中に溶解した。活性化試薬、たとえばヒドロキシベンゾトリアゾール (HOBt) (樹脂に対して4モル当量) およびジイソプロピルカルボジイミド (樹脂に対して4モル当量) を添加し、溶液を15分間撹拌した。溶液を樹脂に添加し、ジイソプロピルエチルアミン (樹脂に対して4モル当量) を添加した。樹脂を室温で2〜24時間振盪させた。樹脂をN-メチルピロリドン (2x20 ml)、N-メチルピロリドン/メチレンクロライド (1:1) (2x20ml) およびメチレンクロライド (2x20 ml) で洗浄した。
活性化された (活性エステルまたは対称無水物) アルブミン結合残基 (式IのB-U-側鎖)、たとえばオクタデカン二酸モノ-(2,5-ジオキソ-ピロリジン-1-イル)エステル (Ebashi et al. EP511600, GLP-1ペプチドに対して1-1.5モル当量) を、有機溶媒、たとえばアセトニトリル、THF、DMF、DMSO、または水/有機溶媒の混合液 (1-2 ml) 中に溶解し、10モル当量のDIPEAとともに、ペプチドの水溶液 (10-20ml) に添加した。アルブミン結合残基、たとえばtert.-ブチル上の保護基の場合、反応混合液を凍結乾燥させO/N、その後、単離されたクルードなペプチドを脱保護した。tert-ブチル基の場合、ペプチドをトリフルオロ酢酸、水およびトリイソプロピルシラン (90:5:5) の混合液中に溶解した。30分後、混合液を真空中で蒸発させ、最終ペプチドをプレパレイティブHPLCにより精製した。
樹脂 (0.25 mmol) を、手動の振盪装置のフィルターフラスコに置き、N-メチルピロリドン/メチレンクロライド (1:1) (2x20 ml)で処理し、N-メチルピロリドン (1x20 ml)、N-メチルピロリドン中の20%ピペリジンの溶液 (3x20 ml, それぞれ10分) で処理した。樹脂をN-メチルピロリドン (2x20 ml)、N-メチルピロリドン/メチレンクロライド (1:1) (2x20ml) およびメチレンクロライド (2x20 ml) で洗浄した。
トリフルオロ酢酸、水およびトリイソプロピルシラン (95:2.5:2.5〜92:4:4) の混合液を用いて室温で180分間撹拌することにより、ペプチドを樹脂から切断した。切断混合液を濾過し、濾液を窒素流により油状物に濃縮した。クルードなペプチドを、この油状物から45 mlジエチルエーテルを用いて沈殿させ、45 mlジエチルエーテルで1〜3回洗浄した。
クルードなペプチドを、セミセパレイティブHPLCにより、5μまたは7μ C-18シリカを充填した20 mm x 250 mmカラムで精製した。ペプチドに応じて、一または二の精製システムを使用した。
A1: 濃H2SO4でpH 2.5に調整された0.1M (NH4)2SO4からなる緩衝液によるカラムの平衡化、および同緩衝液中0%−60% CH3CNの勾配による50分にわたる溶出。
LCMSは、Sciex API 100シングル四重極質量分析計、Perkin Elmerシリーズ200クオードポンプ、Perkin Elmerシリーズ200オートサンプラー、Applied Biosystems 785A UV検出器、Sedex 75 蒸発光散乱検出器からなるセットアップで行った。
A: 水中の0.05% トリフルオロ酢酸
B: アセトニトリル中の0.05% トリフルオロ酢酸
を含有する二つの溶離液リザーバに連結される。
勾配 : 7.5分にわたって、1.5 ml/分で、5%−90 % アセトニトリル直線的
検出 : 210 nm (DADからアナログ出力)
ELS (ELSからアナログ出力)、40℃
MSイオン化モードAPI-ES。
A: 水中の10mM NH4OH
B: 90% アセトニトリル中の10mM NH4OH
を含有する二つの溶離液リザーバに連結される。
勾配 : 6.5分にわたって、1.5 ml/分で、5%−100 % アセトニトリル直線的
検出 : 210 nm (DADからアナログ出力)
ELS (ELSからアナログ出力)
MSイオン化モードAPI-ES。スキャン100-1000 amu step 0.1 amu。
結合アッセイは、ヒトGLP-1レセプターを含有する精製された原形質膜を用いて行った。レセプターを含有する原形質膜は、安定に発現するBHK tk-ts 13細胞から精製した。膜は、アッセイ緩衝液 (50 mM HEPES、5 mM EGTA、5 mM MgCl2、0.005% Tween 20、pH=7.4) で、0.2 mg/ml タンパク質の最終濃度に希釈し、0.3 % PEIでプレコーティングされた96ウェルマイクロタイタープレートに分配した。膜は、0.05 nM [125I]GLP-1、増大する濃度の非標識リガンド、および異なるHSA濃度 (0.005%、0.05%、および2%) の存在下において、30℃で2 hrインキュベートした。インキュベーション後、未結合のリガンドは、真空マニホルドを通した濾過により、結合リガンドから分離し、次いで、氷冷アッセイ緩衝液で2 X 100μlの洗浄を行った。フィルターはRTで一晩乾燥させ、パンチで打ち抜いて、γ-カウンターで定量した。
樹脂 (Fmoc-Gly-NovaSyn TGT、0.22 mmol/g Novabiochem 0.25 mmole) を使用して、製造メーカーのガイドラインに従ってABI433Aマシンで一次配列を作成した。すべての保護基は酸に不安定であり、ただし位置26で使用した残基 (FmocLys(ivDde)-OH, Novabiochem) は例外であり、任意の他のリジンよりもこのリジンの特異的な脱保護を可能にする。
樹脂 (0.09 mmole) を、手動の振盪機/濾過装置に置き、N-メチルピロリドン中で4% ヒドラジンにより処理して (4x10分、4x4 ml)、ivDde基を除去した。樹脂を、N-メチルピロリドンで洗浄した (3x4 ml)。オクタデカン二酸モノ-(2,5-ジオキソ-ピロリドン-1-イル)エステル) (樹脂に対して4モル当量) をDMF (4 ml) 中に溶解した。その溶液を樹脂に添加し、ジイソプロピルエチルアミン (樹脂に対して8モル当量) を添加した。樹脂を室温で24時間振盪させた。樹脂をN-メチルピロリドン (4x4 ml) およびDCM (4x4 ml) で洗浄した。トリフルオロ酢酸、水およびトリイソプロピルシラン (92.5:5.0:2.5 4 ml) の混合液を用いて室温で180分間撹拌することにより、ペプチドを樹脂から切断した。切断混合液を濾過し、クルードなペプチドを、40 mlジエチルエーテルから沈殿させ、45 mlジエチルエーテルで3回洗浄した。クルードなペプチドを、プレパレイティブHPLCにより、7μ C-18シリカを充填した20 mm x 250 mm columnで精製した。クルードなペプチドを、5 ml 50% 酢酸水に溶解し、H2Oで20 mlに希釈し、カラムに注入し、その後、25−65 % (0.1% TFAを含む水中のCH3CN) の勾配を用いて、RTにおいて40分にわたり20 ml/分で溶出した。ペプチドを含有するフラクションを回収した。溶出液を水で希釈した後、精製されたペプチドを凍結乾燥させた。
LCMS: m/z = 1232 (MH3 3+) Calculated for (MH3 3+) = 1232。
例1のとおり「合成方法」に従って調製した。
LCMS: m/z = 1242 (MH3 3+), Calculated for (MH3 3+) = 1242。
THF (1 ml) 中の4-(N-(2-(tert-ブトキシカルボニル)エチル)-N-(15-(tert-ブトキシカルボニル)ペンタデカノイル)アミノメチル)安息香酸 (36 mg, 60μmol) の溶液に、DIPEA (7μl) および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 (TSTU, 17 mg, 56μl) を添加した。混合液を、室温で1時間撹拌した後、THF (1 ml) で希釈し、得られた溶液の1 mlを、[Arg34]GLP-1-(7-37)ペプチド (約100 mg) およびDIPEA (103μl) の水溶液 (5 ml) に添加した。0.5時間後、追加のアシル化剤のTHF-溶液 (0.4 ml) を添加した。反応混合液を、室温でトータル1.5時間撹拌した後、濾過し、プレパレイティブHPLC (35−55% MeCN/55−35% 水/10% 1% TFAを含む水による勾配溶出) に適用した。所望の生成物を含有するフラクションを一つに合わせ、凍結乾燥させた。その後、生成物を、TFAと水の混合液 (95/5 vol) 25 mlにより室温で15分間処理し、濃縮し、HPLCによりもう一回精製した。15.4 mgの標題化合物を得た。
LCMS: m/z = 1287 (MH3 3+). Calculated for (MH3 3+): 1287。
N-ε26-[2-(2-[2-(2-[2-(2-[4-(17-カルボキシヘプタデカノイルアミノ)-4(S)-カルボキシブチリルアミノ]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][Aib8,Arg34]GLP-1-(7-37)ペプチド
LCMS: m/z = 1372 (MH3 3+). Calculated for (MH3 3+): 1372。
ペプチドは、以下のとおり調製した: 「A.樹脂結合ペプチドの合成」を、Fmoc-Gly-Wang樹脂 (0.66 mmol/g Novabiochem) 上で0.25 mMolスケールで使用して、製造メーカーのガイドラインに従ってABI433Aマシンで一次配列を作成した。すべての保護基は酸に不安定であり、ただし位置26で使用した残基 (FmocLys(Mtt)-OH, Novabiochem) は例外であり、これは超酸に不安定であり、任意の他のリジンよりもこのリジンの特異的な脱保護を可能にする。
LCMS: m/z = 1381.8 (MH3 3+). Calculated for (M+H+): 4142.7。
例5のとおり、「合成方法」に従って調製した。
LCMS: m/z = 1362.3 (MH3 3+). Calculated for (M+H+): 4085.6。
例5のとおり、「合成方法」に従って調製した。
LCMS: m/z = 1367.3 (MH3 3+). Calculated for (M+H+): 4100.6。
例5のとおり、「合成方法」に従って調製した。
LCMS: m/z = 1379.8 (MH3 3+). Calculated for (M+H+): 4136.7。
150 mg 2-クロロトリチルクロライド樹脂 (1.4 mmol/g) から始まる[Gly8,Arg34]GLP-1(7-37)ペプチドを、Fmoc-固相ペプチド合成により、Advanced ChemtechのApex396を用いて調製した。位置26におけるLys残基は、Lys(ivDde) として保護し、一方、他のアミノ酸の官能性側鎖は、酸に不安定な標準的な保護基で保護した。Lys残基は、NMP中の3% ヒドラジン/3% ピペリジンを用いて1時間かけて脱保護した。その後、2ユニットの8-アミノ-3,6-ジオキサオクタン酸、γ-グルタミン酸およびオクタデカン二酸を、DIC/HOAtを用いて、樹脂付着ペプチドにカップリングさせた。ペプチドは、最後に脱保護し、TFA/TIS/H2O/チオアニソール (90/5/3/2) を用いて樹脂から切断した。ペプチドは、LC-MSにより単離した。
MALDI: 4087 (MH+)。
200 mg Tentagel RAM S樹脂 (0.26 mmol/g) から始まる[Aib8,34]GLP-1(7-37)アミドを、Fmoc-固相ペプチド合成により、Advanced ChemtechのApex396を用いて調製した。位置26におけるLys残基は、Lys(ivDde) として保護し、一方、他のアミノ酸の官能性側鎖は、酸に不安定な標準的な保護基で保護した。Lys残基は、NMP中の3% ヒドラジン/3% ピペリジンを用いて1時間かけて脱保護した。その後、2ユニットの8-アミノ-3,6-ジオキサオクタン酸、γ-グルタミン酸およびオクタデカン二酸を、DIC/HOAtを用いて、樹脂付着ペプチドにカップリングさせた。ペプチドは、最後に脱保護し、TFA/TIS/H2O/チオアニソール (90/5/3/2) を用いて樹脂から切断した。ペプチドは、LC-MSにより単離した。
MALDI: 4114 (MH+)。
ペプチドは、Rinkアミド樹脂 (0.70 mmol/g Novabiochem) 上で調製し、それ以外は、例5のとおり、「合成方法」に従って調製した。
LCMS: m/z = 1385.3 (MH3 3+). Calculated for (M+H+): 4153.8。
HPLC (method B6): RT= 30.41 min
LCMS: m/z = 1362.9 (MH3 3+) Calculated for (M+) = 4085.61。
150 mg 2-クロロトリチルクロライド樹脂 (1.4 mmol/g) から始まる[Aib8,Arg34]GLP-1(7-37)ペプチドを、Fmoc-固相ペプチド合成により、Advanced ChemtechのApex396を用いて調製した。位置26におけるLys残基は、Lys(ivDde) として保護し、一方、他のアミノ酸の官能性側鎖は、酸に不安定な標準的な保護基で保護した。Lys残基は、NMP中の3% ヒドラジン/3% ピペリジンを用いて1時間かけて脱保護した。2ユニットの8-アミノ-3,6-ジオキサオクタン酸および4{[(2-tert-ブトキシカルボニル-エチル)-(17-tert-ブトキシカルボニル-ヘプタデカノイル)-アミノ]-メチル}-安息香酸を、DIC/HOAtを用いて、樹脂付着ペプチドにカップリングさせた。ペプチドは、最後に脱保護し、TFA/TIS/H2O/チオアニソール (90/5/3/2) を用いて樹脂から切断した。ペプチドは、プレパレイティブLC-MSにより単離した。
MALDI: 4191 (MH+)。
HPLC (method B6): RT= 32,6 min
LCMS: m/z = 1377.3 (MH3 3+) Calculated for (M+) = 4128.0。
150 mg Fmoc-Gly-Wang樹脂 (0.66 mmol/g) から始まる[Aib8,Glu22,Arg34]GLP-1(7-37)ペプチドを、Fmoc-固相ペプチド合成により、Advanced ChemtechのApex396を用いて調製した。位置26におけるLys残基は、Lys(Mtt) として保護し、一方、他のアミノ酸の官能性側鎖は、酸に不安定な標準的な保護基で保護した。Lys残基は、DCM中の2% TFA/2% TISを用いて4 x 5分かけて脱保護した。2ユニットの8-アミノ-3,6-ジオキサオクタン酸、γ-グルタミン酸およびオクタデカン酸tert-ブチルエステルを、DIC/HOAtを用いて、樹脂付着ペプチドにカップリングさせた。ペプチドは、最後に脱保護し、TFA/TIS/H2O/チオアニソール (90/5/3/2) を用いて樹脂から切断した。ペプチドは、LC-MSにより単離した。
MALDI: 4187 (MH+)。
方法および分析
例3のとおり、「合成方法」に従って調製した。
LCMS: m/z = 1450 (MH3 3+). Calculated for (MH3 3+): 1450。
150 mg Fmoc-Gly-Wang樹脂 (0.66 mmol/g) から始まる[Aib8,Arg34]GLP-1(7-37)ペプチドを、Fmoc-固相ペプチド合成により、Advanced ChemtechのApex396を用いて調製した。位置26におけるLys残基は、Lys(Mtt) として保護し、一方、他のアミノ酸の官能性側鎖は、酸に不安定な標準的な保護基で保護した。Lys残基は、DCM中の2% TFA/2% TISを用いて4 x 5分かけて脱保護した。2ユニットの8-アミノ-3,6-ジオキサオクタン酸、γ-グルタミン酸および4{[(2-tert-ブトキシカルボニル-エチル)-(17-tert-ブトキシカルボニル-ヘプタデカノイル)-アミノ]-メチル}-安息香酸を、DIC/HOAtを用いて、樹脂付着ペプチドにカップリングさせた。ペプチドは、最後に脱保護し、TFA/TIS/H2O/チオアニソール (90/5/3/2) を用いて樹脂から切断した。ペプチドは、プレパレイティブHPLCにより単離した。
MALDI: 4320 (MH+)。
ペプチドは、Fmoc化学を用いて、Liberty Microwave Peptide Synthesizer (CEM Corporation) で合成した。合成は、Gly-Wang樹脂 (Novabiochem) 上で、0.66 mmol/gのローディングで、4倍過剰のアミノ酸およびカップリングのためのDIC/HOAtを用いて行った。N-末端のヒスチジンは、Boc-保護し、修飾されるリジンは、Mtt-保護した。ペプチド骨格を合成した後、Mtt基をDCM中の3% TFAで除去し、側鎖を、Libertyで、標準的なペプチド合成プロトコールを用いて作成した。最後の工程で、脂肪二酸(fatty diacid)を、モノ-t-ブチル-エステルとして付加した。
MALDI: 4239 (MH+)。
方法および分析
例4のとおり「合成方法」に従って調製した。
LCMS: m/z: = 1276 (MH3 3+), Calculated for (MH3 3+) 1276。
LCMS*: m/z: = 1417 (MH3 3+), Calculated for (MH3 3+) 1417
*HPLC (0.5 mL/分で、42℃において、5---->80% アセトニトリル、85---->10% 水、および10%の1.0% トリフルオロ酢酸溶液の直線的勾配により、50分にわたって溶出。Symmetry300, 5um, 3.9 mm x 150 mm C-18 シリカカラムで214においてUV検出) method B4): Rt = 32.09 min (95 %)。
HPLC (method B6): RT= 35.0 min
LCMS: m/z = 1394.0 (MH3 3+) Calculated for (M+) = 4180.0。
例19と同じ方法を用いて調製した。
MALDI: 4025 (MH+)。
本発明の一つの側面において、GLP-1アゴニストは、db/dbマウスに30 nmol/kg投薬した後、少なくとも24時間の作用持続期間を有する。
適切な週1回の候補物質を同定するためのGLP-1類似体の薬物動態学的スクリーニングは、糖尿病マウスモデル (db/dbマウス) でのグルコース低下能についてプロジェクトスクリーニングプランにより十分効果があることが示され、かつその後db/dbマウスモデルにおいて48時間以上の持続期間を有していた候補物質について行った。
薬物動態学的スクリーニングの第一のパートは、8-12 kgの体重の3匹のミニブタに2 nmol/kgを単回投薬で皮下投与することから構成された。血液サンプルは、投薬前、0.5、1、2、4、6、8、12、24、48、72、96および120時間の注入後に、各動物から採取した。すべての血液サンプルは、GLP-1類似体の酵素的分解を防ぐために、EDTA (二ナトリウム) 0.18 M、Aprotenin 15000 KIE/ml、Val-Pyr 0.30 mM、7.4に調整されたpHから成る特別な安定化緩衝液を用いて安定化した。血漿は、安定化された血液サンプルのそれぞれから、遠心分離 (4℃、10分、1270 G (4000 rpm) により回収し、ELISAアッセイによりGLP-1類似体の含量について分析した。血漿の分析に関して、3つの異なるELISAアッセイを使用した: 35 pMの検出限界 (LOD) および35-30000 pMのダイナミック分析レンジで、N-末端がインタクトな7-37GLP-1分子およびN-末端が酵素的に分解された9-37GLP分子の両方を検出する抗体コンビネーションF1/Ra2135を使用する「トータルアッセイ」。抗体コンビネーションF1/Mab26.1を使用する「インタクトなアッセイ」。このアッセイは、N-末端がインタクトな7-37GLP-1分子のみを検出した。LODは35 pMであり、ダイナミック分析レンジは35-30000 pMであった。抗体コンビネーションF1/GLP162-3F15を使用する「Aib-インタクトなアッセイ」。このアッセイは、GLP-1分子のAib安定化N-末端を検出し、安定化されたGLP-1類似体の検出を可能にした。LODは45 pMであり、ダイナミック分析レンジは45-30000 pMであった。
薬物動態学的スクリーニングの第二のパートは、60-70時間以上の初期のターミナル半減期を有する化合物について行った。このスクリーニングは、各ルートの投与に対して、6匹のミニブタに2 nmol/kgを単回投薬で静脈内投与および皮下投与することから構成された。血液サンプリングのスケジュールは、静脈内投与後および皮下投与後、それぞれ、0-120時間から0-432時間および0-504時間に延長した。これは、薬物動態学的パラメータ推定値、とりわけターミナル半減期、AUC、および導き出されるパラメータ、クリアランスおよび分布体積の精度および正確性を増大させるため、および皮下投与後のバイオアベイラビリティを評価するために行った。
アッセイは、検体とキャッチャーおよびディテクター抗体との同時インキュベーションを伴う二部位アッセイ(two-site assay)であった。使用可能な状態の化学発光基質を、シグナルを最大化するために使用した。アッセイは、内在性GLP-1 (7-37) またはDPPIV切断GLP-1 (9-37) のいずれも認識しない。
0-血漿は、絶食動物から、バリンピロリジドおよびアプロチニンなしで、プールEDTA血漿から調製した。プールEDTA血漿は、微量のGLP-1を除去するために37℃で4時間インキュベートし、インキュベーション後、バリンピロリジドおよびアプロチニンを添加した。
コーティング緩衝液
コーティング緩衝液としてPBSを使用した: 10mM リン酸ナトリウムおよび145mM 塩化ナトリウム、pH 7.4に調整
洗浄緩衝液
0.05% (v/v) Tween 20を含むPBS
アッセイ緩衝液
0.05% (v/v) Tween 20、10g/L BSAおよび10mg/L anti-TNPを含むPBS
ストレプトアビジン緩衝液
追加の0.5M NaClを含む洗浄緩衝液
基質
使用可能な状態の基質SuperSignal ELISA Femto (Pierce, cat.no. 37075)
スタンダード
スタンダードは、25μMストック溶液の0113-0000-0217から調製した。ペプチドをリファレンス血漿に連続希釈して、最終濃度30000-10000-3333-1111-370-123-41および0 pMのスタンダードを作成した。スタンダードは、Micronicチューブに100μLずつ入れて-20℃で保存した。
Crystal 2000 Microplates (black) を、モノクローナル抗体GLPb1-7F1、PBS中5μg/mLの100μLにより、4℃で一晩コーティングした。
アッセイは、検体とキャッチャーおよびディテクター抗体との同時インキュベーションを伴う二部位アッセイ(two-site assay)であった。アッセイは、N-末端で切断されたGLP-1をGLP-1(12-37)まで認識する。
コーティング緩衝液
コーティング緩衝液としてPBSを使用した: 10mM リン酸ナトリウムおよび145mM 塩化ナトリウム、pH 7.4に調整
洗浄緩衝液
0.05% (v/v) Tween 20を含むPBS
アッセイ緩衝液
0.05% (v/v) Tween 20、10g/L BSAおよび10mg/L anti-TNPを含むPBS
ストレプトアビジン緩衝液
追加の0.5M NaClを含む洗浄緩衝液
基質
使用可能な状態の基質TMB (KemEnTec code 4380A)
停止緩衝液
4 M H3PO4
スタンダード
スタンダードは、25μMストック溶液の0113-0000-0217から調製した。ペプチドをリファレンス血漿に連続希釈して、最終濃度30000-10000-3333-1111-370-123-41および0 pMのスタンダードを作成した。スタンダードは、Micronicチューブに100μLずつ入れて-20℃で保存した。
Maxisorpマイクロタイタープレート (NUNC) を、モノクローナル抗体GLPb1-7F1、PBS中5μg/mLの100μLにより、4℃で一晩コーティングした。
本発明の化合物は、以下のとおり調合され得る:
例4の化合物 6,25 mg/ml
プロピレングリコール 14,0 mg/ml
フェノール 5.5 mg/ml
リン酸緩衝液 pH 8.15
必要に応じて、化合物は、PCT/ EP2005/055946に記載されるとおり、調合前に熱および/または塩基で処理する。
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