JP6284471B2 - インスリン抵抗性のための改善されたペプチドの調合薬 - Google Patents
インスリン抵抗性のための改善されたペプチドの調合薬 Download PDFInfo
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- JP6284471B2 JP6284471B2 JP2014511554A JP2014511554A JP6284471B2 JP 6284471 B2 JP6284471 B2 JP 6284471B2 JP 2014511554 A JP2014511554 A JP 2014511554A JP 2014511554 A JP2014511554 A JP 2014511554A JP 6284471 B2 JP6284471 B2 JP 6284471B2
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Classifications
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- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
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- C07K1/107—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length by chemical modification of precursor peptides
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Landscapes
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Description
本出願は、2011年5月18日に出願された米国仮特許出願第61/487,640号及び2011年10月5日に出願された米国仮特許出願第61/543,716号への優先権を主張するものであり、該仮出願はその全体において引用によって本明細書に組み込まれるものとする。
R1aは、独立的に、各発生時に、単結合、H、置換又は非置換のC1−C30アルキル基、置換又は非置換のアルコキシアリール基、或いは置換又は非置換のアラルキル基であり;
R1b、R1c及びR1dは各々、独立的に、各発生時に、単結合、H、置換又は非置換のC1−C30アルキル基、置換又は非置換のアルコキシアリール基、或いは置換又は非置換のアラルキル基であり;
W1は、独立的に、発生時に、−CH2−、−CH2−O−、−(C=O)、−(C=O)−O−、−(C=O)−NH−、−(C=S)−、−(C=S)−NH−、或いは−CH2−S−であり;
W2は、−O−、−CH2−或いは−S−であり;
R2は各々、独立的に、各発生時に、単結合、H、1置換又は非置換のC1−C30アルキル基、置換又は非置換のアルコキシアリール基、或いは、置換又は非置換のアラルキル基、−NH2、−SH、C2−C4−アルケン、C2−C4−アルキン、−NH(C=O)−CH2−Br、−(CH2)m−マレイミド、或いは−N3であり;
nは1、2或いは3であり;及び
mは1−10であり;
ペプチドは、式IIから選択され:
aa1−aa2−aa3−aa4−aa5−aa6−aa7−aa8−aa9−aa10−aa11−aa12−aa13−aa14−aa15−aa16−aa17−aa18−aa19−aa20−aa21−aa22−aa23−aa24−aa25−aa26−aa27−aa28−aa29−aa30−aa31−aa32−aa33−aa34−aa35−aa36−aa37−Z 式II(配列番号1)
式中:
Zは、OH、又はNH−R3であり、R3は、H、又はC1−C12の置換又は非置換のアルキル、又は10Da未満のPEG鎖であり;
aa1はHis、N−Ac−His、pGlu−His、或いはN−R3−Hisであり;
aa2はSer、Ala、Gly、Aib、Ac4c、又は Ac5cであり;
aa3はGln、又はCitであり;
aa4はGly、又はD−Alaであり;
aa5はThr、又はSerであり;
aa6はPhe、Trp、F2Phe、Me2Phe、又はNal2であり;
aa7はThr、又はSerであり;
aa8はSer、又はAspであり;
aa9はAsp、又はGluであり;
aa10はTyr、Leu、Met、Nal2、Bip、又はBip2EtMeOであり;
aa11はSer、Asn、又はUであり;
aa12はLys、Glu、Ser、Arg、又はUであり;
aa13は存在しない、或いはTyr、Gin、Cit、或いはUであり;
aa14は存在しない、或いはLeu、Met、Nle、或いはUであり;
aa15は存在しない、或いはAsp、Glu、或いはUであり;
aa16は存在しない、或いはSer、Gly、Glu、Aib、Ac5c、Lys、Arg、或いはUであり;
aa17は存在しない、或いはArg、hArg、Gln、Glu、Cit、Aib、Ac4c、Ac5c、或いはUであり;
aa18は存在しない、或いはArg、hArg、Ala、Aib、Ac4c、Ac5cであり、或いはUである;
aa19は存在しない、或いはAla、Val、Aib、Ac4c、Ac5c、或いはUであり;
aa20は存在しない、或いはGln、Lys、Arg、Cit、Glu、Aib、Ac4c、Ac5c、或いはUであり;
aa21は存在しない、或いはAsp、Glu、Leu、Aib、Ac4c、Ac5c、或いはUであり;
aa22は存在しない、或いはPhe、Trp、Nal2、Aib、Ac4c、Ac5c、或いはUであり;
aa23は存在しない、或いはVal、Ile、Aib、Ac4c、Ac5c、或いはUであり;
aa24は存在しない、或いはGln、Ala、Glu、Cit、或いはUであり;
aa25は存在しない、或いはTrp、Nal2、或いはUであり;
aa26は存在しない、或いはLeu、或いはUであり;
aa27は存在しない、或いはMet、Val、Nle、Lys、或いはUであり;
aa28は存在しない、或いはAsn、Lys、或いはUであり;
aa29は存在しない、或いはThr、Gly、Aib、Ac4c、Ac5c、或いはUであり;
aa30は存在しない、或いはLys、Aib、Ac4c、Ac5c、或いはUであり;
aa31は存在しない、或いはArg、Aib、Ac4c、Ac5c、或いはUであり;
aa32は存在しない、或いはAsn、Aib、Ac4c、Ac5c、或いはUであり;
aa33は存在しない、或いはArg、Aib、Ac4c、Ac5c、或いはUであり;
aa34は存在しない、或いはAsn、Aib、Ac4c、Ac5c、或いはUであり;
aa35は存在しない、或いはAsn、Aib、Ac4c、Ac5c、或いはUであり;
aa36は存在しない、或いはIle、Aib、Ac4c、Ac5c、或いはUであり;
aa36は存在しない、或いはAla、Aib、Ac4c、Ac5c、或いはUであり;
aa37は存在しない、或いはUであり;
Uは,界面活性物質Xへの共有結合的な付着のために使用される官能基を含む天然又は非天然アミノ酸であり;
ここで、aa1−aa37のうちのいずれか2つが、ラクタム結合を形成するために、それらの側鎖を介して随意に環化され;及び
ただし、aa11−aa37の1つ、或いは少なくとも1つが、Xに共有結合的に付けられたリンカーアミノ酸Uであることを条件とする。
R1aは、H、保護基、置換又は非置換のC1−C30アルキル基、或いはステロイド核を含有する部分であり;
R1b、R1c及びR1dは各々、独立的に、各発生時に、H、保護基、或いは置換又は非置換のC1−C30アルキル基であり;
W1は、独立的に、各発生時に、−CH2−、−CH2−O−、−(C=O)、−(C=O)−O−、−(C=O)−NH−、−(C=S)−、−(C=S)−NH−、又は−CH2−S−であり;
W2は−O−、−S−であり;
R2は、単結合、C2−C4−アルケン、C2−C4−アルキン、又は(CH2)m−マレイミドであり;
及び、Mは1−10である。
R1aは、H、保護基、置換又は非置換のC1−C30アルキル基、又はステロイド核を含有する部分であり;
R1b、R1c及びR1dは各々、独立的に、各発生時に、H、保護基、或いは置換又は非置換のC1−C30アルキル基であり;
W1は−(C=O)−NH−であり;
W2は−O−であり;
R2は単結合である。
R1aは置換又は非置換のC1−C30アルキル基であり;
R1b、R1c及びR1dはHであり;
W1は−(C=O)−NH−であり;
W2は−O−であり;及び
R2は単結合である。
aa1−aa2−aa3−aa4−aa5−aa6−aa7−aa8−aa9−aa10−aa11−aa12−aa13−aa14−aa15−aa16−aa17−aa18−aa19−aa20−aa21−aa22−aa23−aa24−aa25−aa26−aa27−aa28−aa29−Z 式III−A(配列番号2)
式中:
Zは、OH、又はNH−R3であり、ここでR3はH、又はC1−C12の置換又は非置換のアルキル、又は10Da未満のPEG鎖であり;
aa1はHis、N−Ac−His、pGlu−His、或いはN−R3−Hisであり;
aa2はSer、Ala、Gly、Aib、Ac4c、或いはAc5cであり;
aa3はGln、或いはCitであり;
aa4はGly、或いはD−Alaであり;
aa5はThr、或いはSerであり;
aa6はPhe、Trp、F2Phe、Me2Phe、或いはNal2であり;
aa7はThr、或いはSerであり;
aa8はSer、或いはAspであり;
aa9はAsp、或いはGluであり;
aa10はTyr、Leu、Met、Nal2、Bip、或いはBip2EtMeOであり;
aa11はSer、Asn、或いはUであり;
aa12はLys、Glu、Ser、Arg、或いはU(X)であり;
aa13は存在しない、或いはTyr、Gln、Cit、或いはU(X)であり;
aa14は存在しない、或いはLeu、Met、Nle、或いはU(X)であり;
aa15は存在しない、或いはAsp、Glu、或いはU(X)であり;
aa16は存在しない、或いはSer、Gly、Glu、Aib、Ac5c、Lys、Arg、或いはU(X)であり;
aa17は存在しない、Arg、hArg、Gln、Glu、Cit、Aib、Ac4c、Ac5c、或いはU(X)であり;
aa18は存在しない、或いはArg、hArg、Ala、Aib、Ac4c、Ac5c、或いはU(X)であり;
aa19は存在しない、或いはAla、Val、Aib、Ac4c、Ac5c、或いはU(X)であり;
aa20は存在しない、或いはGln、Lys、Arg、Cit、Glu、Aib、Ac4c、Ac5c或いはU(X)であり;
aa21は存在しない、或いはAsp、Glu、Leu、Aib、Ac4c、Ac5c、或いはU(X)であり;
aa22は存在しない、或いはPhe、Trp、Nal2、Aib、Ac4c、Ac5c、或いはU(X)であり;
aa23は存在しない、或いはVal、Ile、Aib、Ac4c、Ac5c、或いはU(X)であり;
aa24は存在しない、或いはGln、Ala、Glu、Cit或いはU(X);
aa25は存在しない、或いはTrp、Nal2、或いはU(X)であり;
aa26は存在しない、或いはLeu、或いはU(X)であり;
aa27は存在しない、或いはMet、Val、Nle、Lys、或いはU(X)であり;
aa28は存在しない、或いはAsn、Lys、或いはU(X)であり;
aa29は存在しない、或いはThr、Gly、Aib、Ac4c、Ac5c、或いはU(X)であり;
ここで、aa1−aa29のうちのいずれか2つが、ラクタム結合を形成するため、それらの側鎖を介して随意に環化され;及び
ただし、aa16、aa17、aa18、aa19、aa20、aa21、aa22、aa23、aa24、aa25、aa26、aa27、aa28又はaa29の1つ、或いは少なくとも1つが、Xに共有結合的に付けられた天然又は非天然のアミノ酸Uであることを条件とする。
His1−aa2−aa3−Gly4−Thr5−aa6−Thr7−Ser8−Asp9−aa10−aa11−aa12−aa13−aa14−aa15−aa16−aa17−aa18−aa19−aa20−aa21−aa22−aa23−Z 式III−B(配列番号3)
式中:
ZはOH、又はNH−R3、ここで、R3はH、又は置換又は非置換のC1−C12アルキル、或いは10Da未満のPEG鎖であり;
aa2はSer、Ala、Gly、Aib、Ac4c、或いはAc5cであり;
aa3はGln、或いはCitであり;
aa6はPhe、Trp、F2Phe、Me2Phe、MePhe、或いはNal2であり;
aa10はTyr、Leu、Met、Nal2、Bip、或いはBip2EtMeOであり;
aa11はSer、Asn、或いはU(X)であり;
aa12はLys、Glu、Ser、或いはU(X)であり;
aa13は存在しない、或いはTyr、Gln、Cit、或いはU(X)であり;
aa14は存在しない、或いはLeu、Met、Nle、或いはU(X)であり;
aa15は存在しない、或いはAsp、Glu、或いはU(X)であり;
aa16は存在しない、或いはSer、Gly、Glu、Aib、Ac4c、Ac5c、Lys、R、或いはU(X)であり;
aa17は存在しない、或いはArg、hArg、Gln、Glu、Cit、Aib、Ac4c、Ac5c、或いはU(X)であり;
aa18は存在しない、或いはArg、hArg、Ala、Aib、Ac4c、Ac5c、或いはU(X)であり;
aa19は存在しない、或いはAla、Val、Aib、Ac4c、Ac5c、或いはU(X)であり;
aa20は存在しない、或いはGln、Lys、Arg、Cit、Glu、Aib、Ac4c、Ac5c、或いはU(X)であり;
aa21は存在しない、或いはAsp、Glu、Leu、Aib、Ac4c、Ac5c、或いはU(X)であり;
aa22は存在しない、或いは、Phe、Aib、Ac4c、Ac5c、或いはU(X)であり;
aa23は存在しない、或いはVal、Ile、Aib、Ac4c、Ac5c、或いはU(X)であり;
ここで、aa1−aa23のうちのいずれか2つが、ラクタム結合を形成するため、それらの側鎖を介して随意に環化され;及び
ただし、aa16、aa17、aa18、aa19、aa20、aa21、aa22、aa23、或いはaa24の1つ、或いは少なくとも1つが、Xに共有結合的に付けられた天然又は非天然アミノ酸Uであることを条件とする。
His1−aa2−Gln3−Gly4−Thr5−Phe6−Thr7−Ser8−Asp9−Tyr10−Ser11−Lys12−Tyr13 −Leu14−Asp15−Aib16−aa17−Lys(N−オメガ−1’−アルキルベータD−グルクロニル)18−aa19−NH2;(配列番号318)式中:
aa2はAib、或いはAc4cであり;
aa17はArg、hArg、或いはGlnであり;
aa19はAib、Ac4c、或いはAc5cであり;
及び、アルキルはC8からC20までの直線状のアルキル鎖である。
His1−aa2−Gln3−Gly4−Thr5−Phe6−Thr7−Ser8 −Asp9−Tyr10−Ser11−Lys12−Tyr13−Leu14−Asp15−Aib16−aa17−Lys(N−オメガ−1’−アルキルベータD−グルクロニル)18−aa19−aa20−NH2;(配列番号319)式中:
aa2はAib、或いは、Ac4cであり、
aa17はArg、hArg、或いは、Glnであり、
aa19とaa20は各々、Aib、Ac4c、或いはAc5cであり;
及び、アルキルはC8からC20までの直線状のアルキル鎖である。
His1−aa2−Gln3−Gly4−Thr5−Phe6−Thr7−Ser8 −Asp9−Tyr10−Ser11−Lys12−Tyr13−Leu14−Asp15−aa16−aa17−Lys(N−オメガ−1’−アルキルベータD−グルクロニル)18−aa19−NH2;(配列番号320)
式中:
aa2はAib、或いは、Ac4cであり;
aa16はAib、或いは、Ac4cであり;
aa17はArg、hArg、或いはGlnであり;
aa19はAib、Ac4c、或いはAc5cであり;及び
アルキルはC8−C20までの直線状のアルキル鎖である。
His1−aa2−Gln3−Gly4−Thr5−Phe6−Thr7−Ser8−Asp9−Tyr10−Ser11−Lys12−Tyr13−Leu14−Asp15−aa16−aa17―Ala18−Ala19−aa20−Glu21−Phe22−Ile23−Lys(N−オメガ−1’−アルキルベータD−グルクロニル)24−Trp25−Leu26−aa27−Asn28−Thr29−NH2;(配列番号321)
式中:
aa2はAib、或いは、Ac4cであり;
aa16とaa20は各々Lys又はGluのいずれかであり、ラクタム結合を形成するために、それらの側鎖を介して環化され;
aa17はArg、hArg、或いはGlnであり;
aa27はMet、或いはNleであり;及び
アルキルはC8−C20の直線状のアルキル鎖である。
His1−aa2−Gln3−Gly4−Thr5−Phe6−Thr7−Ser8−Asp9−Tyr10−Ser11−Lys12−Tyr13−Leu14−Asp15−環式(Glu16−Gln17−Ala18−Ala19−Lys20)−Glu21−Phe22−Ile23−Lys(N−オメガ−1’−アルキルベータD−グルクロニル)24−Trp25−Leu26−Met27−Asn28−aa29−NH2;(配列番号322)
式中:aa2はAib、或いは、Ac4cであり;aa29はThr、Aib、Ac4c、或いは、Ac5cであり、及び1’−アルキル基は、ドデシル、テトラデシル、ヘキサデシル、或いはオクタデシルから選択され;及び
位置16及び20におけるアミノ酸上の側鎖は側鎖ラクタムを形成するために環化される。
His1−aa2−Gln3−Gly4−Thr5−Phe6−Thr7−Ser8−Asp9−Tyr10−Ser11−aa12−Tyr13−Leu14−Asp15−aa16−aa17−Lys(N−オメガ−1’−アルキルベータD−グルクロニル)18−aa19−aa20−NH2;(配列番号323)
式中:
aa2はAib又はAc4cであり;
aa12とaa16は各々Lys又はGluのいずれかであり、ラクタム結合を形成するためにそれらの側鎖を介して環化され;
aa17はArg、hArgであり;
aa19とaa20は各々Aib、Ac4c、又はAc5cのいずれかであり;及び
アルキルはC8−C20の直線状のアルキル鎖である。
His1−Ac4c2−Gln3−Gly4−Thr5−Phe6−Thr7−Ser8−Asp9−Tyr10−Ser11−環式(Glu12−Tyr13−Leu14−Asp15− Lys16)−aa17−Lys(N−オメガ−1’−アルキルベータD−グルクロニル)18−Aib19−Aib20−NH2;(配列番号324)
式中:
aa12とaa16はラクタム結合を形成するために、それらの側鎖を介して環化され;
aa17はArg、或いはhArgであり;及び
アルキルは、C12、C14、C16、或いはC18の直線状のアルキル鎖である。
His1−aa2−Gln3−Gly4−Thr5−Phe6−Thr7−Ser8−Asp9−Tyr10−Ser11−aa12−Tyr13−Leu14−Asp15−aa16−aa17−Lys(N−オメガ−1’−アルキルベータD−グルクロニル)18−aa19−aa20−NH2;(配列番号325)
式中:
aa12とaa16は各々Lys又はGluのいずれかであり、aa12及びaa16はラクタム結合を形成するためにそれらの側鎖を介して環化され;
aa17はArg、或いはhArgであり;
aa19とaa20は各々Aib、Ac4c、或いはAc5cのいずれかであり;及び
1’−アルキル基はドデシル、テトラデシル、ヘキサデシル、或いはオクタデシルから選択される。
His1−aa2−Gln3−Gly4−Thr5−aa6−Thr7−Ser8−Asp9−Tyr10−Ser11−Lys12−Tyr13−Leu14−Asp15−Ser16−Aib17−Lys(N−オメガ−1’−ドデシルベータD−グルクロニル)18−aa19−NH2;(配列番号326)
式中:aa2はAib、或いはAc4cであり;aa6はMe2Phe、MePhe、或いはPheであり;或いは、aa19はAib、Ac4c、或いはAc5cである。
His1−aa2−Gln3−Gly4−Thr5−aa6−Thr7−Ser8−Asp9−Tyr10−Ser11−Lys12−Tyr13−Leu14−Asp15−Ser16−aa17−Lys(N−オメガ−1’−ドデシルベータD−グルクロニル)18−aa19−aa20−NH2;(配列番号327)
式中:aa2はAib、或いはAc4cであり、aa6はMe2Phe、MePhe、或いはPheであり;aa17はArg、或いはhArgであり、及び、aa19又はaa20はAib、Ac4c、或いはAc5cである。
His1−Aib2−Gln3−Gly4−Thr5−Phe6−Thr7−Ser8−Asp9−Tyr10−Ser11−Lys12−Tyr13−Leu14−Asp15−環式(Glu16−Arg17−Ala18−Ala19−Lys20)−Lys(N−オメガ−1’−アルキルベータD−グルクロニル)21−Phe22−aa23−NH2;(配列番号328)
式中:aa23はAib、Ac4C、或いはAc5cであり、及び、1’−アルキル基はドデシル、テトラデシル、ヘキサデシル、或いはオクタデシルから選択される。
His1−aa2−Gln3−Gly4−Thr5−aa6−Thr7−Ser8−Asp9−Tyr10−Ser11−aa12−Tyr13−Leu14−Asp15−aa16−aa17−aa18−Ala19−aa20−Lys(N−オメガ−1’−アルキルベータD−グルクロニル)21−Phe22−aa23−NH2;(配列番号329)
式中:
aa2はAib、或いはAc4cであり:
aa6はMe2Phe、MePhe或いはPheであり;
aa12とaa16も各々Lys或いはGluのいずれかであり;及び
aa16とaa20はラクタム結合を形成するためにそれらの側鎖を介して環化され;
aa17はArg、hArg或いはGlnであり;
aa18はAib又はAlaであり;
aa23はAib、Ac4c或いはAc5cであり、及び、1’−アルキル基はドデシル、テトラデシル、ヘキサデシル或いはオクタデシルから選択される。
His1−aa2−Gln3−Gly4−Thr5−aa6−Thr7−Ser8−Asp9−Tyr10−Ser11−aa12−Tyr13−Leu14−Asp15−aa16−aa17−Lys(N−オメガ−1’−アルキルベータD−グルクロニル)18−aa19−aa20−NH2;(配列番号330)
式中:
aa2はAib又はAc4cであり;
aa6はPheであり;
aa12とaa16は各々Lys又はGluのいずれかであり;及び、aa12とaa16はラクタム結合を形成するために、それらの側鎖を介して環化され;
aa17はArg又はhArgであり;
aa19はAib、Ac4c或いはAc5cであり;
aa20はAib、Ac4c或いはAc5cであり;及び、1’−アルキル基はドデシル、テトラデシル、ヘキサデシル或いはオクタデシルから選択される。
(a)中間体(すなわち式IVの化合物)とペプチドを連結させる工程:
R1aは、独立的に、各発生時に、単結合、H、脱離基、保護基、天然又は非天然のアミノ酸、置換又は非置換のC1−C30アルキル基、置換又は非置換のアルコキシアリール基、或いは置換又は非置換のアラルキル基であり;
R1b、R1c及びR1dは各々、独立的に、各発生時に、単結合、H、脱離基、保護基、可逆的に保護された天然又は非天然のアミノ酸、置換又は非置換のC1−C30アルキル基、置換又は非置換のアルコキシアリール基、或いは、置換又は非置換のアラルキル基であり;
W1は、独立的に、各発生時に、−CH2−、−CH2−O−、−(C=O)、−(C=O)−O−、−(C=O)−NH−、−(C=S)−、−(C=S)−NH−、或いは−CH2−S−であり;
W2は−O−、−CH2−、或いは−S−であり;
R2は、独立的に、各発生時に、単結合、H、脱離基、保護基、可逆的に保護された天然又は非天然のアミノ酸、置換又は非置換のC1−C30アルキル基、置換又は非置換のアルコキシアリール基、或いは置換又は非置換のアラルキル基、−NH2、−SH、C2−C4−アルケン、C2−C4−アルキン、−NH(C=O)−CH2−Br、−(CH2)m−マレイミド、或いは−N3であり;
nは1、2或いは3であり;
mは1−10であり;及び
(b)工程(a)のカップリングペプチドを随意に脱保護する工程。
nは1であり;
W1は、−(C=O)−であり;
R1aは、置換又は非置換のC1−C30アルキル基、置換又は非置換のアルコキシアリール基、或いは置換又は非置換のアラルキル基であり、
R2は、D−或いはL−配置の可逆的に保護されたリジンである。
nは1であり;
W1は−(C=O)−であり;
R1aは、置換又は非置換のC8−C30アルキル基、置換又は非置換のアルコキシアリール基、或いは置換又は非置換のアラルキル基であり;
R2はD−或いはL−配置の可逆的に保護されたリジンである。
nは1であり;
W1は−(C=O)−NH−或いは(C=O)−O−であり;
R2は、置換又は非置換のC1−C30アルキル疎水基、置換又は非置換のアルコキシアリール基、或いは置換又は非置換のアラルキル基であり;
R1aはD−、L−配置の可逆的に保護されたセリン又はトレオニンである。
nは1であり;
mは1−6であり;
W1は−CH2−であり;
R1aは、置換又は非置換のC1−C30アルキル疎水基、置換又は非置換の−アルコキシアリール基、或いは置換又は非置換の−アラルキル基であり、
R2は−N3、NH2、−C2−アルキン、−(CH2)m−マレイミド、NH−(C=O)−CH2−Br、或いはNH−(C=O)−CH2−Iである。
nは1であり;
W1は−(C=O)−O−であり;
R2はHであり、
R1aは置換又は非置換のC1−C30アルキル疎水基である。
長引く高血糖症に関連するリスクは、微小血管の合併症、感覚ニューロパチー、心筋梗塞、脳卒中、大血管性の死亡率及び総死亡率の増加のリスクを含む。2型糖尿病はまた、肥満症が原因であると常に関連付けられ、さらなる世界的な流行病である。2007年に、世界中の糖尿病の処置及び予防には、少なくとも2320億ドルが費やされ、その4分の3が、微小血管と大血管性の合併症の予防に努める等、長期的合併症の処置及び一般看護のために、工業先進国で費やされる。2007年に、米国の経済に対する糖尿病(障害、生産性の損失、及び糖尿病による若死)のおよその間接費用は、580億ドルであった。
「インクレチン効果」は、経口送達されるグルコース負荷が、経静脈投与される同じグルコース負荷よりも、はるかに多いインスリン分泌を提供する現象を記載するために使用される。この効果は、腸のL細胞によって分泌される少なくとも2つのインクレチンホルモンによって媒介される。グルコース依存性インスリン分泌刺激ポリペプチド(GIP)及びグルカゴン様ペプチド1(GLP−1)は、インクレチン等として識別され、また、健康な個体はインクレチン効果から、食事のインスリン分泌反応を70%まで引き出すことができると考えられる。
上記の満腹感と代謝グルカゴン前駆体タンパク質の生成物の複合体及び相互に作用する行動を考慮して、多数の団体の研究員は、GLP−1及びグルカゴン構造上の構造活性関係を研究してきた。配列の全体にわたる残基は、交替を許容すると示された。例えば、Alaによる交換は、GLP−1のN‐末端領域、特に2、3、5、8、11及び12において、十分に許容される(Adelhost,K.,et al.(1994)J Biol Chem 269:6275−6278)。
1つの態様において、共有結合的に修飾され、且つ、本明細書に記載の方法に適しているペプチドは、以下のものを含むがこれらに限定されない、グルカゴンの切断型アナログ(truncated analogs)及び/又は関連ホルモンGLP−1である:
グルカゴン:
His1−Ser2−Gln3−Gly4−Thr5 Phe6−Thr7−Ser8−Asp9−Tyr10−Ser11−Lys12−Tyr13−Leu14−Asp15−Ser16−Arg17−Arg18−Ala19−Gln20−Asp21−Phe22−Val23−Gln24−Trp25−Leu26−Met27−Asn28−Thr29(配列番号331)
オキシントモジュリン:
His1−Ser2−Gln3−Gly4−Thr5 Phe6−Thr7−Ser8−Asp9−Tyr10−Ser11−Lys12−Tyr13−Leu14−Asp15−Ser16−Arg17−Arg18−Ala19−Gln20−Asp21−Phe22−Val23−Gln24−Trp25−Leu26−Met27−Asn28−Thr29−Lys30−Arg31−Asn32−Arg33−Asn34−Asn35−Ile36−Ala37(配列番号332)
GLP−1(グルカゴンのナンバリングを使用):
His1−Ala2−Glu3−Gly4−Thr5 Phe6−Thr7−Ser8−Asp9−Val10−Ser11−Ser12−Tyr13−Leu14−Glu15−Gly16−Gln17−Ala18−Ala19−Lys20−Glu21−Phe22−Ile23−Ala24−Trp25−Leu26−Val27−Lys28−Gly29−Arg30(配列番号333)
aa1−aa2−aa3−aa4−aa5−aa6−aa7−aa8−aa9−aa10−aa11−aa12−aa13−aa14−aa15−aa16−aa17−aa18−aa19−aa20−aa21−aa22−aa23−aa24−aa25−aa26−aa27−aa28−aa29−aa30−aa31−aa32−aa33−aa34−aa35−aa36−aa37−Z 式5(配列番号334)
式中:
Uは結合アミノ酸(linking amino acid)であり;
Xは、Uの側鎖に結合した界面活性物質であり;
Zは、OH、又は−NH−R3であり、ここで、R3は、H、又はC1−C12の置換又は非置換のアルキルであり;
aa1は、His、N−Ac−His、pGlu−His、又はN−R3−Hisであり;
aa2は、Ser、Ala、Gly、Aib、Ac4c、又はAc5cであり;
aa3は、Gln、又はCitであり;
aa4は、Gly、又はD−Alaであり;
aa5は、Thr、又はSerであり、
aa6は、Phe、Trp、F2Phe、Me2Phe、又はNal(2)であり;
aa7は、Thr、又はSerであり;
aa8は、Ser、又はAspであり;
aa9は、Asp、又はGluであり;
aa10は、Tyr、Leu、Met、Nal(2)、Bip、又はBip2EtMeOであり;
aa11は、Ser、Asn、又はU(X)であり;
aa12は、Lys、Glu、Ser、Arg、又はU(X)であり;
aa13は、存在しない、Tyr、Glu、Cit、又はU(X)であり;
aa14は、存在しない、Leu、Met、Nle、又はU(X)であり;
aa15は、存在しない、Asp、Glu、又はU(X)であり;
aa16は、存在しない、Ser、Gly、Glu、Aib、Ac5c、Lys、Arg、又はU(X)であり;
aa17は、存在しない、Arg、hArg、Gln、Glu、Cit、Aib、Ac4c、Ac5c、又はU(X)であり;
aa18は、存在しない、Arg、hArg、Ala、Aib、Ac4c、Ac5c、又はU(X)であり;
aa19は、存在しない、Ala、Val、Aib、Ac4c、Ac5c、又はU(X)であり;
aa20は、存在しない、Gln、Lys、Arg、Cit、Glu、Aib、Ac4c、Ac5c、又はU(X)であり;
aa21は、存在しない、Asp、Glu、Leu、Aib、Ac4c、Ac5c、又はU(X)であり;
aa22は、存在しない、Phe、Trp、Nal(2)、Aib、Ac4c、Ac5c、又はU(X)であり;
aa23は、存在しない、Val,Ile、Aib、Ac4c、Ac5c、又はU(X)であり;
aa24は、存在しない、Gln、Ala、Glu、Cit、又はU(X)であり;
aa25は、存在しない、Trp、Nal(2)、又はU(X)であり;
aa26は、存在しない、Leu、U(X)であり;
aa27は、存在しない、Met、Val、Nle、Lys、又はU(X)であり;
aa28は、存在しない、Asn、Lys、又はU(X)であり;
aa29は、存在しない、Thr、Gly、Aib、Ac4c、Ac5c、又はU(X)であり;
aa30は、存在しない、Lys、Aib、Ac4c、Ac5c、又はU(X)であり;
aa31は、存在しない、Arg、Aib、Ac4c、Ac5c、又はU(X)であり;
aa32は、存在しない、Asn、Aib、Ac4c、Ac5c、又はU(X)であり;
aa33は、存在しない、Arg、Aib、Ac5c、又はU(X)であり;
aa34は、存在しない、Asn、Aib、Ac4c、Ac5c、又はU(X)であり;
aa35は、存在しない、Asn、Aib、Ac4c、Ac5c、又はU(X)であり;
aa36は、存在しない、Ile、Aib、Ac4c、Ac5C、又はU(X)であり;
aa36は、存在しない、Ala、Aib、Ac4c、Ac5C、又はU(X)であり;
aa37は、存在しない、又はU(X)であり;
ただし、aa11−aa37の1つ、又は少なくとも1つがU(X)であることを条件とする。
His1−aa2−aa3−Gly4−Thr5−aa6−Thr7−Ser8−Asp9−aa10−aa11−aa12−aa13−aa14−aa15−aa16−aa17−aa18−aa19−aa20−aa21−aa22−aa23−Z 式III−B(配列番号3)
式中:
Zは、OH、又は−NH−R3であり、ここで、R3は、H、或いは置換又は非置換のC1−C12アルキル;又は10Da未満のPEG鎖であり;
aa2は、Ser、Ala、Gly、Aib、Ac4c、又はAc5cであり;
aa3は、Gln、又はCitであり;
aa6は、Phe、Trp、F2Phe、Me2Phe、MePhe、又はNal2であり;
aa10は、Tyr、Leu、Met、Nal2、Bip、又はBip2EtMeOであり;
aa11は、Ser、Asn、又はUであり;
aa12は、Lys、Glu、Ser、又はU(X)であり;
aa13は、存在しない或いはTyr、Gln、Cit、又はU(X)であり;
aa14は、存在しない或いはLeu、Met、Nle、又はU(X)であり;
aa15は、存在しない或いはAsp、Glu、又はU(X)であり;
aa16は、存在しない或いはSer、Gly、Glu、Aib、Ac4c、Ac5c、Lys、R、又はU(X)であり;
aa17は、存在しない或いはArg、hArg、Gln、Glu、Cit、Aib、Ac4c、Ac5c、又はU(X)であり;
aa18は、存在しない或いはArg、hArg、Ala、Aib、Ac4c、Ac5c、又はU(X)であり;
aa19は、存在しない或いはAla、Val、Aib、Ac4c、Ac5c、又はU(X)であり;
aa20は、存在しない或いはGlu、Lys、Arg、Cit、Glu、Aib、Ac4c、Ac5c又はU(X);
aa21は、存在しない或いはAsp、Glu、Leu、Aib、Ac4c、Ac5c、又はU(X)であり;
aa22は、存在しない或いはPhe、Aib、Ac4c、Ac5c、又はU(X)であり;
aa23は、存在しない或いはVal、Ile、Aib、Ac4c、Ac5c、又はU(X)であり;
ここで、aa1−aa23の何れか2つは、ラクタム結合を形成するため、それらの側鎖によって随意に環化され;及び
ただし、aa16、aa17、aa18、aa19、aa20、aa21、aa22、aa23、又はaa24の1つ、又は少なくとも1つが、Xに共有結合的に付けられる、天然又は非天然のアミノ酸Uであることを条件とする。
R1aは、置換又は非置換のC1−C30アルキル基であり;
R1b、R1c、及びR1dは、Hであり;
W1は、−(C=O)−NH−であり;
W2は、−O−であり;及び
R2は、単結合である。
R1aは、独立的に、各発生時に、単結合、H、置換又は非置換のC1−C30アルキル基、置換又は非置換のアルコキシアリール基、置換又は非置換のアラルキル基、或いはステロイド核を含有する部分であり;
R1b、R1c、及びR1dは各々、独立的に、各発生時に、単結合、H、置換又は非置換のC1−C30アルキル基、置換又は非置換のアルコキシアリール基、或いは置換又は非置換のアラルキル基であり;
W1は、独立的に、各発生時に、−CH2−、−CH2−O−、−(C=O)、−(C=O)−O−、−(C=O)−NH−、−(C=S)−、−(C=S)−NH−、或いは−CH2−S−であり;
W2は、−O−、−CH2−、又は−S−であり;
R2は、独立的に、各発生時に、Uに対する単結合、H、置換又は非置換のC1−C30アルキル基、置換又は非置換のアルコキシアリール基、或いは置換又は非置換のアラルキル基、−NH2、−SH、C2−C4−アルケン、C2−C4−アルキン、−NH(C=O)−CH2−Br、−(CH2)m−マレイミド、又は−N3であり;
nは、1、2、又は3であり;及び
mは1−10である。
R1aは、置換又は非置換のC1−C30アルキル基であり;
R1b、R1c、及びR1dは、Hであり;
W1は、−(C=O)−NH−であり;
W2は、−O−であり;及び
R2は、単結合である。
R1aは、独立的に、各発生時に、単結合、H、置換又は非置換のC1−C30アルキル基、置換又は非置換のアルコキシアリール基、置換又は非置換のアラルキル基、或いはステロイド核を含有する部分であり;
R1b、R1c、及びR1dは各々、独立的に、各発生時に、単結合、H、置換又は非置換のC1−C30アルキル基、置換又は非置換のアルコキシアリール基、或いは置換又は非置換のアラルキル基であり;
W1は、独立的に、各発生時に、−CH2−、−CH2−O−、−(C=O)、−(C=O)−O、−(C=O)−NH−、−(C=S)−、−(C=S)−NH−、或いは−CH2−S−であり;
W2は、−O−、−CH2−、又は−S−であり;
R2は、独立的に、各発生時に、Uに対する単結合、H、置換又は非置換のC1−C30アルキル基、置換又は非置換のアルコキシアリール基、或いは置換又は非置換のアラルキル基、−NH2、−SH、C2−C4−アルケン、C2−C4−アルキン、−NH(C=O)−CH2−Br、−(CH2)m−マレイミド、又は−N3であり;
nは、1、2、又は3であり;及び
mは1−10である。
R1aは、置換又は非置換のC1−C30アルキル基であり;
R1b、R1c、及びR1dは、Hであり;
W1は、−(C=O)−NH−であり;
W2は、−O−であり;及び
R2は、単結合である。
本明細書中で使用されるように、「a」又は「an」は、1以上を意味する。請求項(複数)において使用されるように、単語「comprising」と共に使用すると、単語「a」又は「an」は、1以上を意味する。本明細書中で使用されるように、「another」は、少なくとも2つ以上を意味する。
本明細書には、幾つかの実施形態において、インスリン感受性の減少に関連した疾病の予防及び/又は処置のための方法が提供され、該方法は、本明細書に記載の、界面活性物質により修飾されたペプチド及び/又はタンパク質の生成物(例えば、式I−A、III−A、III−B、又は式Vのペプチド生成物)の治療上効果的な量を、それを必要とする個体に投与する工程を含む。幾つかの実施形態において、インスリン感受性の減少を特徴とする疾病は、限定されないが、メタボリック症候群、インスリン抵抗性に関連する肥満症、高血圧、高いC反応タンパク質に関連した全身性の炎症、糖尿病などを含む。
ここで、前記治療薬は、糖尿病薬剤、抗肥満剤、満腹剤(satiety agent)、抗炎症薬、抗昇圧薬、抗アテローム性動脈硬化薬剤、及び脂質低下薬剤から選択される。
上記の方法の幾つかの実施形態において、界面活性物質により修飾されたペプチド及び/又はタンパク質(例えば、式I−A、III−A、III−B、又は式Vのペプチド生成物)は、糖尿病薬剤、抗肥満剤、抗昇圧薬、抗アテローム性動脈硬化薬剤、及び脂質低下薬剤を含む群から選択された、メタボリック症候群の処置の他の方法と組み合わせて投与される。一例として、本明細書に記載の界面活性物質により修飾されたペプチド及び/又はタンパク質の生成物と組み合わせた投与に適切な、有効な糖尿病薬剤は、ビグアニド、スルホニル尿素、αグルコシダーゼ阻害剤、PPARγアゴニスト、PPARα/γの2重アゴニスト、aP2阻害剤、DPP4阻害剤、インスリン抵抗性改善薬、GLP−1アナログ、インスリン、及びメグリチニドを含む。追加の例は、メトホルミン、グリブライド、グリメピリド、グリピリド、グリピジド、クロルプロパミド、グリクラジド、アカルボース、ミグリトール、ピオグリタゾン、トログリタゾン、ロシグリタゾン、ムラグリタザール(muraglitazar)、インスリン、Gl−262570、イサグリタゾン、JTT−501、NN−2344、L895 645、YM−440、R−119702、A19677、レパグリニド、ナテグリニド、KAD、AR−HO 39242 1129、GW−40 I 5 44、KRP2 I 7、AC2993、LY3 I 5902、NVP−DPP−728A、及びサクサグリプチンを含む。
1つの実施形態において、本明細書では、天然又は非天然のアミノ酸上で反応性官能基との結合を形成することが可能な、界面活性剤部分及び反応性官能基を含む、中間体及び/又は試薬が提供される。これらの中間体及び/又は試薬は、ヒト及び動物の疾患において使用されるペプチド及び/又はタンパク質のバイオアベイラビリティと薬学的、薬物動態学的及び/又は薬力学的な動きにおける改善を可能にする。アミノ酸の側鎖上の官能基を介する、例えば、Lysのイプシロン−アミノ官能基、Cysのスルフィドリル上での、又はペプチド及び/又はタンパク質標的のアミノ又はカルボキシの末端での、そのような中間体及び/又は試薬の共有結合的な付着は、本明細書に記載のペプチド生成物の合成を可能にする。特定の実施形態において、非イオン性の界面活性物質部分は、O−アルキルグリコシドの置換を備えた、単糖類又は二糖類であり、前記グリコシド結合は、アルファ又はベータ構造である。特定の実施形態において、O−アルキル鎖は、C1−C20又はC6−C16のアルキル鎖に由来する。
用語「界面活性物質(surfactant)」は、句「界面活性物質(surface active agent)」を短くしたものに由来する。製薬の適用において、界面活性物質は、それらが乳化剤、可溶化剤、及び加湿薬として作用して、多くの目的に役立つ、液体の医薬製剤に有用である。乳化剤は、親油性の又は部分的に親油性の物質の水溶液を安定させる。可溶化剤は、達成され得る濃度を増加させる医薬組成物の成分の溶解度を増加させる。加湿薬は、適用される表面上で容易に広がるためにそれを含む、液体の表面張力を縮小する化学添加物であり、故に、流体により表面の「湿り」までも引き起こす。加湿薬は、医薬製剤が接触する粘膜又は他の表面積との密接な接触を液体製剤が達成するための手段を提供する。故に、界面活性物質は、ペプチド自体の特性の修飾と同様、本明細書に記載のペプチド生成物の製剤の安定化のための、有用な添加物であり得る。
幾つかの実施形態において、本明細書に記載の界面活性物質により修飾されたペプチド生成物は、1以上のPEG部分を組み込むように更に修飾される(Veronese, F.M. and Mero, A. (2008) BioDrugs 22: 315−329)。幾つかの例において、大きなPEG鎖の組み込みは、そこに生ずる薄い尿の中への、腎臓中の糸球体におけるペプチドの濾過を防ぐ(Nestor, J.J., Jr. (2009) Current Medicinal Chemistry 16: 4399 − 4418, Caliceti, P. and Veronese, F.M. (2003) Adv Drug Deliv Rev 55: 1261−1277)。幾つかの実施形態において、任意のPEG親水性の鎖は、より長鎖のアルキルグリコシド部分の組み込みにより疎水性を与えられる、ペプチド又はタンパク質の溶解度及び物理的性質の平衡を保つことを可能にする。
1つの実施形態において、本明細書に記載されるように共有結合的に修飾されたペプチド又はタンパク質は、組成物におけるペプチド及び/又はタンパク質の会合(association)又は凝集を更に縮小、防ぐ、又は減少させる(例えば、ペプチド及び/又はタンパク質の自己会合又は自己凝集を縮小する)、又は、被験体への投与時に他のペプチド又はタンパク質との会合又は凝集を縮小する製剤において、提供される。
本明細書に記載の共有結合的に修飾したペプチド及び/又はタンパク質は、多くの疾患状態における有益な治療効果を与えるために、任意の量で投与され得る。幾つかの実施形態において、共有結合的に修飾したペプチド及び/又はタンパク質は、炎症の処置に有用である。1つの実施形態において、本明細書で提示される化合物は、手術後又は慢性的疼痛の調節において有益な活性を与える。1つの実施形態において、ペプチドは、疼痛を調節する処置の他の形態の濃度よりも高い又は低い濃度で患者に投与される。また別の実施形態において、ペプチドは、相乗的な治療効果を生むために他の化合物と共に投与される。
オーブン乾燥した250mLのエルレンマイヤーフラスコに、1−オクチルβ−D−グルクロン酸(Carbosynth Ltd.、3.06g、10mmol)、50mLの無水のDMF、及び無水の1−ヒドロキシベンゾトリアゾール(1.62g、12mmol)を入れる。50mLのDMF中のN,N’−ジシクロヘキシルカルボジイミドの冷却した(4℃)溶液を加えて攪拌し、反応を5分間進めることを可能にする。N,N’−ジシクロヘキシル尿素の豊富な白降汞を、フリットガラス漏斗上で濾過し、濾液を25mlの無水のDMF中のN−α−Fmoc−L−リジン(3.68g、10mmol)の溶液に加える。反応を、室温にまで温めることにより、又はニンヒドリン色が非常に弱くなるまで、25分間進めることを可能にする。反応混合物を濾過し、取り除いて乾燥して、MeOH中の希釈及びEt2Oによる曇り点までの遅い希釈、その後の冷凍によって、MeOH/Et2Oから結晶化する。更なる精製は、EtOAcからEtOAc/EtOH/AcOHまでの溶媒勾配を使用するシリカゲルクロマトグラフィーによって達成することができる。
一般に、ペプチド合成方法は、増殖するペプチド鎖への保護されたアミノ酸の連続した追加に関与する。通常、第1のアミノ酸及び任意の反応的な側鎖の基であるアミノ基又はカルボキシル基の何れかを、保護する。この保護したアミノ酸をその後、不活性な固体支持体に付着、又は溶液中で利用し、及び適切に保護された配列における次のアミノ酸を、アミド結合の形成に受け入れられる条件下で加える。全ての所望のアミノ酸を適切な配列において結合した後、保護基及び任意の固体支持体を除去し、未精製のペプチドを得る。ペプチドを脱塩し、クロマトグラフィーにより精製する。
HOBtを脱保護溶液に加え、アスパルトイミド形成を縮小する。その後、次のアミノ酸のカップリングは、5分、75℃の最大二重カップリングサイクルを備えたHBTU:DIEA(1:2)を使用して、5倍のモル過剰を利用する。
20mLのアセトニトリル及び20mLのDI水における1−ドデシルβ−D−グルコピラノシドの溶液(Carbosynth)[2.0g、5.74mmol]に、(ジアセトキシヨード)ベンゼン(Fluka)[4.4g、13.7mmol]とTEMPO(SigmaAldrich)[0.180g、1.15mmol]を加えた。結果として生じる混合物を、室温で20時間攪拌した。反応混合物を水で希釈し、凍結乾燥して、白色粉末として、1.52gの未精製の生成物(未精製の収率73.1%)、1−ドデシルβ−D−グルクロン酸を得て、それを更に精製することなく、固相合成法に直接使用した。この生成物を、本明細書に記載されるように、酸化体としてNaOClを使用する代替のプロセスによって調製し、また、より長いアルキル基に使用した。同様の方法において、所望のアルキル糖類ウロン酸を調整し、それを使用して、本明細書に記載の生成物及び試薬を作る。
Fmoc−His−Aib−Gln−Gly−Thr−Phe−Thr−Ser−Asp−Bip−Ser−Lys−Tyr−Leu−Glu−Ser−Lys(Alloc)−Rinkアミドレジンのサンプルを、実施例1に記載されるように、N−アルファ−Fmocにより保護したアミノ酸の連続追加によって調製し、室温で暗所の中で一晩、DMF/CH2Cl2(1:1)中のPd(PPh3)4(0.5 eq)及びDMBA(20 eq)によるインキュベーションにより、Lys−N−イプシロン位置上で脱保護した。DMF/CH2Cl2によって洗浄した後、Lys側鎖を、DIC/HOBtの使用を通じて、DMF/CH2Cl2の中の1’−ドデシル−β−D−グルクロン酸によりアシル化した。カップリングの完了を、ニンヒドリンによって確認し、生成物をCH2Cl2により広範囲に洗浄した。
[a]30分にわたり35乃至65%のCH3CN。
[b]20分にわたり30乃至60%のCH3CN。
[c]20分にわたり35乃至65%のCH3CN。
[d]20分にわたり25乃至55%のCH3CN。
[e]20分にわたり40乃至70%のCH3CN。
Phenomenex Luna C18 5micron 250x4.6 mm上のHPLC。
化合物を、およそ1mgの量で正確に重さを量り、標準の細胞アッセイ(Cerep SA)において分析した。読み出し情報は、アゴニスト又はアンタゴニストのモードの何れかにおいて、試験化合物により処置される細胞において生成されるcAMPの量である。使用される分析は、グルカゴン及びGLP−1細胞アッセイにおけるcAMPレベルの刺激であった。分析は、「Chicchi, G.G., et al. (1997) J Biol Chem 272: 7765−7769 and Runge, S., et al. (2003) Br J Pharmacol 138: 787−794」に記載される。
60(60)の食事により誘発した肥満のC57BL/6Jのオスのマウスは、生後14週でJAX研究所から得られる。識別のため、マウスの耳に傷をつけ、1つのケージ当たり1匹のマウスの密度でのHEPA除菌空気を備えた、個々に及び積極的に換気したポリカーボネートケージに収容する。動物ルームを、制御した12hの光/暗闇のサイクルにより、人工の蛍光照明で完全に照らす。動物ルーム内の標準温度及び相対湿度の範囲は、それぞれ22±4℃及び50±15%である。水道水を濾過し、2.8乃至3.1のpHに酸性化し、及び高脂肪食(60kcal%)を適宜提供する。
本明細書に記載の共有結合的に修飾したペプチド及び/又はタンパク質は、肥満症に関連する様々な疾患、メタボリック症候群、心疾患、及び糖尿病の予防及び処置に有用である。適切に標識化した、界面活性物質により修飾したペプチドは、診断プローブとして使用され得る。
インスリン又はメタボリック症候群の証拠を備えるヒト患者を、0.5乃至10mg/mLの医薬品を含み、且つ、ベンジルアルコールなどの標準賦形剤を含む、生理食塩水の中の医薬品の溶液の当該技術分野において使用される標準アトマイザーからの鼻腔内投与(200μl)によって、EU−A596により処置する。肥満症、高血糖などの症状の緩和に必要であるため、処置を繰り返す。同様の方法において、ヒドロフルオロアルカンなどを含む蒸発する溶媒における、EU−A596の溶液、及び選択された賦形剤を、インスリン抵抗性を縮小するために必要とされるものとして、定量噴霧式吸入器(MDI)によって鼻腔内投与する。処置効果を、血糖レベル、体容量指数、及び/又は体重の測定及び/又は腰と臀部の比率の測定を含む、標準試験を使用して測定する。
本明細書は、配列番号1乃至3及び配列番号318乃至343についての配列を提供する。加えて、図1の表1は、図1の表1に示されるように、それぞれ配列番号4乃至129を有する化合物EU−A300乃至EU−A425についての配列番号を提供する。図1の表1の化合物、及び図1の表1に示されるそれら各々の配列番号は、出願された通りの本明細書に組み込まれる。加えて、図2の表2は、図2の表2に示されるように、それぞれ配列番号130乃至317を有する化合物EU−A426乃至EU−599についての配列番号を提供する。図2の表2の化合物、及び図2の表2に示されるそれら各々の配列番号は、出願された通りの本明細書に組み込まれる。
Claims (16)
- ペプチドに共有結合的に付けられる界面活性物質Xを含むペプチド生成物であって、前記ペプチドは、リンカーアミノ酸U及び少なくとも1つの他のアミノ酸を含み、 前記ペプチド生成物は前記ペプチドに共有結合的に付けられた前記界面活性物質Xを含み前記ペプチドの生物活性を発揮し得るものであり、:
R1aは、独立的に各発生時に、結合、H、又は置換若しくは非置換のC6−C20アルキル基であり、少なくとも1つのR1aは発生時に疎水性のC6−C20アルキル基であって、置換又は非置換のC6−C20アルキル基であり;
R1b、R1c及びR1dは、各々独立的に各発生時に、単結合、又はHであり;
W1は、独立的に発生時に−CH2−、−CH2−O−、−(C=O)、−(C=O)−NH−、又は−CH2−S−であり;
W2は−O−、−CH2−又はS−であり;
R2は各々、独立的に、各発生時に、結合、Uへの結合、又はHであり;且つ
nは1又は2であり;
前記ペプチドは、式IIから選択され:
aa1−aa2−aa3−aa4−aa5−aa6−aa7−aa8−aa9−aa10−aa11−aa12−aa13−aa14−aa15−aa16−aa17−aa18−aa19−aa20−aa21−aa22−aa23−aa24−aa25−aa26−aa27−aa28−aa29−aa30−aa31−aa32−aa33−aa34−aa35−aa36−aa37−Z 式II(配列番号1)
式中:
ZはOH、又はNH−R3であり、R3はH、置換若しくは非置換のC1−C12のアルキル、又は10Da未満のPEG鎖であり;
aa1はHis、N−Ac−His、pGlu−His、又はN−R3−Hisであり;
aa2はSer、Ala、Gly、Aib、Ac4c、又はAc5cであり;
aa3はGln、又はCitであり;
aa4はGly、又はD−Alaであり;
aa5はThr、又はSerであり;
aa6はPhe、Trp、又は3−(2−ナフチル)アラニンであり;
aa7はThr、又はSerであり;
aa8はSer、又はAspであり;
aa9はAsp、又はGluであり;
aa10はTyr、Leu、Met、3−(2−ナフチル)アラニン、3−ビフェニル−L−アラニン、又は3−(2’−エチル−4’−メトキシビフェニル)−L−アラニンであり;
aa11はSer、Asn、又はUであり;
aa12はLys、Glu、Ser、Arg、又はUであり;
aa13は存在しない、又はTyr、Gln、Cit、若しくはUであり;
aa14は存在しない、又はLeu、Met、Nle、若しくはUであり;
aa15は存在しない、又はAsp、Glu、若しくはUであり;
aa16は存在しない、又はSer、Gly、Glu、Aib、Ac5c、Lys、Arg、若しくはUであり;
aa17は存在しない、又はArg、ホモアルギニン、Gln、Glu、Cit、Aib、Ac4c、Ac5c、若しくはUであり;
aa18は存在しない、又はArg、ホモアルギニン、Ala、Aib、Ac4c、Ac5c、若しくはUであり;
aa19は存在しない、又はAla、Val、Aib、Ac4c、Ac5c、若しくはUであり;
aa20は存在しない、又はGln、Lys、Arg、Cit、Glu、Aib、Ac4c、Ac5c、若しくはUであり;
aa21は存在しない、又はAsp、Glu、Leu、Aib、Ac4c、Ac5c、若しくはUであり;
aa22は存在しない、又はPhe、Trp、3−(2−ナフチル)アラニン、Aib、Ac4c、Ac5c、若しくはUであり;
aa23は存在しない、又はVal、Ile、Aib、Ac4c、Ac5c、若しくはUであり;
aa24は存在しない、又はGln、Ala、Glu、Cit、若しくはUであり;
aa25は存在しない、又はTrp、3−(2−ナフチル)アラニン、若しくはUであり;
aa26は存在しない、又はLeu、若しくはUであり;
aa27は存在しない、又はMet、Val、Nle、Lys、若しくはUであり;
aa28は存在しない、又はAsn、Lys、若しくはUであり;
aa29は存在しない、又はThr、Gly、Aib、Ac4c、Ac5c、若しくはUであり;
aa30は存在しない、又はLys、Aib、Ac4c、Ac5c、若しくはUであり;
aa31は存在しない、又はArg、Aib、Ac4c、Ac5c、若しくはUであり;
aa32は存在しない、又はAsn、Aib、Ac4c、Ac5c、若しくはUであり;
aa33は存在しない、又はArg、Aib、Ac4c、Ac5c、若しくはUであり;
aa34は存在しない、又はAsn、Aib、Ac4c、Ac5c、若しくはUであり;
aa35は存在しない、又はAsn、Aib、Ac4c、Ac5c、若しくはUであり;
aa36は存在しない、又はAla、Ile、Aib、Ac4c、Ac5c、若しくはUであり;且つ
aa37は存在しない、又はUであり;
Uは、前記界面活性物質Xへの共有結合的な付着のために使用される官能基を含む天然又は非天然アミノ酸であり;
ここで、aa1−aa37のうちの何れか2つが、ラクタム結合を形成するために、それらの側鎖を介して随意に環化され;且つ
ただし、aa11−aa37の少なくとも1つが、Xに共有結合的に付けられる前記リンカーアミノ酸Uであることを条件とすることを特徴とする、ペプチド生成物。 - nが1であることを特徴とする、請求項1のペプチド生成物。
- Xは1−アルキルグリコシドのクラスの界面活性物質であることを特徴とする、請求項1に記載のペプチド生成物。
- Xは、1−アイコシルベータ−D−グルクロン酸、1−オクタデシルベータ−D−グルクロン酸、1−ヘキサデシルベータ−D−グルクロン酸、1−テトラデシルベータD−グルクロン酸、1−ドデシルベータD−グルクロン酸、1−デシルベータ−D−グルクロン酸、1−オクチルベータ−D−グルクロン酸、1−アイコシルベータ−D−ジグルクロン酸、1−オクタデシルベータ−D−ジグルクロン酸、1−ヘキサデシルベータ−D−ジグルクロン酸、1−テトラデシルベータ−D−ジグルクロン酸、1−ドデシルベータ−D−ジグルクロン酸、1−デシルベータ−D−ジグルクロン酸、1−オクチルベータ−D−ジグルクロン酸、又は官能化した1−アイコシルベータ−D−グルコース、1−オクタデシルベータ−D−グルコース、1−ヘキサデシルベータ−D−グルコース、1−テトラデシルベータ−D−グルコース、1−ドデシルベータ−D−グルコース、1−デシルベータ−D−グルコース、1−オクチルベータ−D−グルコース、1−アイコシルベータ−D−マルトシド、1−オクタデシルベータ−D−マルトシド、1−ヘキサデシルベータ−D−マルトシド、1−ドデシルベータ−D−マルトシド、1−デシルベータ−D−マルトシド、又は1−オクチルベータ−D−マルトシドから構成されることを特徴とする、請求項1に記載のペプチド生成物。
- Uは、Lys、Cys、Orn、又は界面活性物質Xへの共有結合的な付着のために使用された官能基を含む非天然のアミノ酸から選択されることを特徴とする、請求項1乃至3の何れか1つに記載のペプチド生成物。
- 式III−Aの構造を有し:
aa1−aa2−aa3−aa4−aa5−aa6−aa7−aa8−aa9−aa10−aa11−aa12−aa13−aa14−aa15−aa16−aa17−aa18−aa19−aa20−aa21−aa22−aa23−aa24−aa25−aa26−aa27−aa28−aa29−Z 式III−A(配列番号2)
式中:
ZはOH、又はNH−R3であり、ここでR3はH、置換若しくは非置換のC1−C12のアルキル、又は10Da未満のPEG鎖であり;
aa1はHis、N−Ac−His、pGlu−His、又はN−R3−Hisであり;
aa2はSer、Ala、Gly、Aib、Ac4c、又はAc5cであり;
aa3はGln、又はCitであり;
aa4はGly、又はD−Alaであり;
aa5はThr、又はSerであり;
aa6はPhe、Trp、又は3−(2−ナフチル)アラニンであり;
aa7はThr、又はSerであり;
aa8はSer、又はAspであり;
aa9はAsp、又はGluであり;
aa10はTyr、Leu、Met、3−(2−ナフチル)アラニン、3−ビフェニル−L−アラニン、又は3−(2’−エチル−4’−メトキシビフェニル)−L−アラニンであり;
aa11はSer、Asn、又はU(X)であり;
aa12はLys、Glu、Ser、Arg、又はU(X)であり;
aa13は存在しない、又はTyr、Gln、Cit、若しくはU(X)であり;
aa14は存在しない、又はLeu、Met、Nle、若しくはU(X)であり;
aa15は存在しない、又はAsp、Glu、若しくはU(X)であり;
aa16は存在しない、又はSer、Gly、Glu、Aib、Ac5c、Lys、Arg、若しくはU(X)であり;
aa17は存在しない、又はArg、ホモアルギニン、Gln、Glu、Cit、Aib、Ac4c、Ac5c、若しくはU(X)であり;
aa18は存在しない、又はArg、ホモアルギニン、Ala、Aib、Ac4c、Ac5c、若しくはU(X)であり;
aa19は存在しない、又はAla、Val、Aib、Ac4c、Ac5c、若しくはU(X)であり;
aa20は存在しない、又はGln、Lys、Arg、Cit、Glu、Aib、Ac4c、Ac5c若しくはU(X)であり;
aa21は存在しない、又はAsp、Glu、Leu、Aib、Ac4c、Ac5c、若しくはU(X)であり;
aa22は存在しない、又はPhe、Trp、3−(2−ナフチル)アラニン、Aib、Ac4c、Ac5c、若しくはU(X)であり;
aa23は存在しない、又はVal、Ile、Aib、Ac4c、Ac5c、若しくはU(X)であり;
aa24は存在しない、又はGln、Ala、Glu、Cit若しくはU(X)であり;
aa25は存在しない、又はTrp、3−(2−ナフチル)アラニン、若しくはU(X)であり;
aa26は存在しない、又はLeu、若しくはU(X)であり;
aa27は存在しない、又はMet、Val、Nle、Lys、若しくはU(X)であり;
aa28は存在しない、又はAsn、Lys、若しくはU(X)であり;且つ
aa29は存在しない、又はThr、Gly、Aib、Ac4c、Ac5c、若しくはU(X)であり;
ここで、aa1−aa29のうちの何れか2つが、ラクタム結合を形成するため、それらの側鎖を介して随意に環化され;及び
ただし、aa16、aa17、aa18、aa19、aa20、aa21、aa22、aa23、aa24、aa25、aa26、aa27、aa28及びaa29の1つ、又は少なくとも1つがXに共有結合的に付けられた前記天然又は非天然のアミノ酸Uであることを条件とすることを特徴とする、請求項1に記載のペプチド生成物。 - aa18はXに付けられるリジン残基であることを特徴とする、請求項1又は6に記載のペプチド生成物。
- aa2はAib又はAc4cの残基であることを特徴とする、請求項1又は6に記載のペプチド生成物。
- ペプチドは1つ以上のAib残基を含むことを特徴とする、請求項1又は6に記載のペプチド生成物。
- aa16とaa20はラクタム結合を形成するために環化され、又は随意に、aa12とaa16はラクタム結合を形成するために環化されることを特徴とする、請求項1又は6に記載のペプチド生成物。
- 以下の構造を有し:
His1−aa2−Gln3−Gly4−Thr5−Phe6−Thr7−Ser8−Asp9−Tyr10−Ser11−Lys12−Tyr13−Leu14−Asp15−aa16−aa17−Ala18−Ala19−aa20−Glu21−Phe22−Ile23−Lys(N−オメガ−1’−アルキルベータ−D−グルクロニル)24−Trp25−Leu26−aa27−Asn28−Thr29−NH2;(配列番号321)
式中:
aa2はAib、又は、Ac4cであり;
aa16とaa20は各々、Lys又はGluの何れかであり、ラクタム結合を形成するために、それらの側鎖を介して環化され;
aa17はArg、ホモアルギニン、又はGlnであり;
aa27はMet、又はNleであり;及び
アルキルはC8−C20の直線状のアルキル鎖であることを特徴とする、請求項1又は6に記載のペプチド生成物。 - Xはドデシルアルキル鎖を含むことを特徴とする、請求項1又は2に記載のペプチド生成物。
- 請求項1乃至12の何れか1つに記載の治療上効果的な量のペプチド生成物、又はその薬学的に許容可能な塩、及び少なくとも1つの薬学的に許容可能な担体又は賦形剤を含む、医薬組成物。
- 必要とする個体のインスリン抵抗性に関連する疾病を処置するための薬の製造のための、請求項1乃至12の何れか1つに記載のペプチド生成物の使用。
- 必要とする個体の心血管疾患を処置するための薬の製造のための、請求項1乃至12の何れか1つに記載のペプチド生成物の使用。
- 必要とする個体の糖尿病を処置するための薬の製造のための、請求項1乃至12の何れか1つに記載のペプチド生成物の使用。
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