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JP2013533227A5
JP2013533227A5 JP2013513645A JP2013513645A JP2013533227A5 JP 2013533227 A5 JP2013533227 A5 JP 2013533227A5 JP 2013513645 A JP2013513645 A JP 2013513645A JP 2013513645 A JP2013513645 A JP 2013513645A JP 2013533227 A5 JP2013533227 A5 JP 2013533227A5
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ethoxy
fgf21
acetylamino
des181
conh
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JP2013533227A (en
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Priority claimed from PCT/EP2010/057986 external-priority patent/WO2010142665A1/en
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Priority claimed from PCT/EP2011/059273 external-priority patent/WO2011154349A2/en
Publication of JP2013533227A publication Critical patent/JP2013533227A/en
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Claims (15)

[-1A, L166F, M168L, G174V, Y179F] FGF21、
以下のアミノ酸置換(交換):71C、121Q、173Aおよび/もしくはdes181の1つもしくは複数を含んでいてもよく、4個以下のさらなる変異を有していてもよく、ならびに/または179および/もしくは180番目のアミノ酸が存在しなくてもよい、[-1A, L166F, M168L, G174V, Y179F] FGF21の類似体、または
71番目にシステイン残基を含み、71番目のシステイン残基に存在するメルカプト基の硫黄原子に一般式HOOC-(CH2)n-CONH-CH(COOH)-CH2-CH2-CONH-(CH2CH2O)m-CH2-CONH-(CH2CH2O)p-CH2-CONH-(CH2)q-NHCO-CH2-(修飾部分)(式中、nは10〜20の範囲の整数であり、mは1〜3の範囲の整数であり、pは1〜3の範囲の整数であり、qは2〜4の範囲の整数である)の基が共有結合している前記類似体の誘導体。 [-1A, L166F, M168L, G174V, Y179F] FGF21,
May include one or more of the following amino acid substitutions (exchanges): 71C, 121Q, 173A and / or des181, may have 4 or fewer additional mutations, and / or 179 and / or The 180th amino acid may not be present, [-1A, L166F, M168L, G174V, Y179F] FGF21 analogues, or
The 71st cysteine residue contains a cysteine residue, and the sulfur atom of the mercapto group present in the 71st cysteine residue has the general formula HOOC- (CH 2 ) n -CONH-CH (COOH) -CH 2 -CH 2 -CONH- ( CH 2 CH 2 O) m -CH 2 -CONH- (CH 2 CH 2 O) p -CH 2 -CONH- (CH 2 ) q -NHCO-CH 2- (Modifying moiety) (wherein n is 10 to An integer in the range of 20, m is an integer in the range of 1 to 3, p is an integer in the range of 1 to 3, and q is an integer in the range of 2 to 4). Derivatives of said analogues. [-1A, 71C, L166F, M168L, G174V, Y179F] FGF21、
以下のアミノ酸置換(交換):121Q、173Aおよび/もしくはdes181の1つもしくは複数を含んでいてもよく、4個以下のさらなる変異を有していてもよく、ならびに/または179および/もしくは180番目のアミノ酸が存在しなくてもよい、[-1A, 71C, L166F, M168L, G174V, Y179F] FGF21の類似体、または
71番目にシステイン残基を含み、71番目のシステイン残基に存在するメルカプト基の硫黄原子に一般式HOOC-(CH2)n-CONH-CH(COOH)-CH2-CH2-CONH-(CH2CH2O)m-CH2-CONH-(CH2CH2O)p-CH2-CONH-(CH2)q-NHCO-CH2-(修飾部分)(式中、nは10〜20の範囲の整数であり、mは1〜3の範囲の整数であり、pは1〜3の範囲の整数であり、qは2〜4の範囲の整数である)の基が共有結合している前記類似体の誘導体。 [ -1A, 71C, L166F, M168L, G174V, Y179F] FGF21,
The following amino acid substitutions (exchanges): may include one or more of 121Q, 173A and / or des181, may have no more than 4 further mutations, and / or 179 and / or 180th [-1A, 71C, L166F, M168L, G174V, Y179F] FGF21 analogs, or
The mercapto group present in the 71st cysteine residue contains a cysteine residue at the 71st position, and the general formula HOOC- (CH 2 ) n -CONH-CH (COOH) -CH 2 -CH 2 -CONH- ( CH 2 CH 2 O) m -CH 2 -CONH- (CH 2 CH 2 O) p -CH 2 -CONH- (CH 2 ) q -NHCO-CH 2- (Modifying moiety) (wherein n is 10 to An integer in the range of 20, m is an integer in the range of 1 to 3, p is an integer in the range of 1 to 3, and q is an integer in the range of 2 to 4). Derivatives of said analogues. [-1A, L166F, S167G, M168L, G174V, Y179F, A180E] FGF21、[-1A, L166F, S167G, M168L, G174V, Y179F, A180E] FGF21,
以下のアミノ酸置換(交換):71C、121Q、171L、172E、173Aおよび/もしくはdes181の1つもしくは複数をさらに含み、ならびに/または179および/もしくは180番目のアミノ酸が存在しなくてもよい、[-1A, L166F, S167G, M168L, G174V, Y179F, A180E] FGF21の類似体、またはThe following amino acid substitutions (exchanges): further comprising one or more of 71C, 121Q, 171L, 172E, 173A and / or des181, and / or the 179th and / or 180th amino acid may be absent, [ -1A, L166F, S167G, M168L, G174V, Y179F, A180E] FGF21 analogues, or
71番目にシステイン残基を含み、71番目のシステイン残基に存在するメルカプト基の硫黄原子に一般式HOOC-(CHThe mercapto group containing a cysteine residue at the 71st and present at the 71st cysteine residue has a general formula HOOC- (CH 22 )) nn -CONH-CH(COOH)-CH-CONH-CH (COOH) -CH 22 -CH-CH 22 -CONH-(CH-CONH- (CH 22 CHCH 22 O)O) mm -CH-CH 22 -CONH-(CH-CONH- (CH 22 CHCH 22 O)O) pp -CH-CH 22 -CONH-(CH-CONH- (CH 22 )) qq -NHCO-CH-NHCO-CH 22 -(修飾部分)(式中、nは10〜20の範囲の整数であり、mは1〜3の範囲の整数であり、pは1〜3の範囲の整数であり、qは2〜4の範囲の整数である)の基が共有結合している前記類似体の誘導体。-(Modifying moiety) (wherein n is an integer in the range of 10-20, m is an integer in the range of 1-3, p is an integer in the range of 1-3, q is 2-4 A derivative of said analogue, which is a covalent bond. [-1A, S71C, L166F, S167G, M168L, G174V, Y179F, A180E] FGF21、[-1A, S71C, L166F, S167G, M168L, G174V, Y179F, A180E] FGF21,
以下のアミノ酸置換(交換)：121Q、171L、172E、173Aおよび/もしくはdes181の1つもしくは複数をさらに含む[-1A, S71C, L166F, S167G, M168L, G174V, Y179F, A180E] FGF21の類似体、またはThe following amino acid substitutions (exchanges): further comprising one or more of 121Q, 171L, 172E, 173A and / or des181 [-1A, S71C, L166F, S167G, M168L, G174V, Y179F, A180E] analogs of FGF21, Or
71番目にシステイン残基を含み、71番目のシステイン残基に存在するメルカプト基の硫黄原子に一般式HOOC-(CHThe mercapto group containing a cysteine residue at the 71st and present at the 71st cysteine residue has a general formula HOOC- (CH 22 )) nn -CONH-CH(COOH)-CH-CONH-CH (COOH) -CH 22 -CH-CH 22 -CONH-(CH-CONH- (CH 22 CHCH 22 O)O) mm -CH-CH 22 -CONH-(CH-CONH- (CH 22 CHCH 22 O)O) pp -CH-CH 22 -CONH-(CH-CONH- (CH 22 )) qq -NHCO-CH-NHCO-CH 22 -(修飾部分)(式中、nは10〜20の範囲の整数であり、mは1〜3の範囲の整数であり、pは1〜3の範囲の整数であり、qは2〜4の範囲の整数である) の基が共有結合している前記類似体の誘導体。-(Modifying moiety) (wherein n is an integer in the range of 10-20, m is an integer in the range of 1-3, p is an integer in the range of 1-3, q is 2-4 A derivative of said analogue which is a covalent bond. 以下のアミノ酸交換：121番目にGln(Q)、171番目にLeu(L)、172番目にGlu(E)、173番目にAla(A)または181番目にアミノ酸なしのうちの１つのみ、2つ、3つまたは4つを含む、請求項1から4のいずれか一項に記載の類似体または誘導体。The following amino acid exchanges: Gln (Q) at 121st, Leu (L) at 171st, Glu (E) at 172th, Ala (A) at 173th, or only one of 181th without amino acid, 2 5. An analogue or derivative according to any one of claims 1 to 4, comprising one, three or four. [-1A,S71C,L166F,S167G,M168L,G174V,Y179F,A180E,des181]FGF-21;[-1A,S71C,L166F,S167G,M168L,G174V,Y179F,A180E]FGF-21;[-1A,S71C,L166F,S167G,M168L,P171L,S172E,Q173A,G174V,Y179F,A180E,des181]FGF-21;[-1A,S71C,L166F,S167G,M168L,P171L,S172E,Q173A,G174V,Y179F,A180E]FGF-21;[-1A,S71C,N121Q,L166F,S167G,M168L,G174V,Y179F,A180E,des181]FGF-21;[-1A,S71C,N121Q,L166F,S167G,M168L,G174V,Y179F,A180E]FGF-21;[-1A,S71C,N121Q,L166F,S167G,M168L,P171L,S172E,Q173A,G174V,Y179F,A180E,des181]FGF-21;[-1A,S71C,N121Q,L166F,S167G,M168L,P171L,S172E,Q173A,G174V,Y179F,A180E]FGF-21;[-1A,121Q,166F,167G,168L,171L,172E,173A,174V,179F,180E,des181]FGF-21;[-1A,71C,121Q,166F,167G,168L,171L,172E,173A,174V,des179-181]FGF-21,[-1A,71C,121Q,166F,168L,173A,174V,179F]FGF-21または[-1A,71C,121Q,166F,168L,174V,179F,180E,des181]FGF21である、請求項1から5のいずれか一項に記載の類似体または誘導体。[-1A, S71C, L166F, S167G, M168L, G174V, Y179F, A180E, des181] FGF-21; [-1A, S71C, L166F, S167G, M168L, G174V, Y179F, A180E] FGF-21; [-1A, S71C, L166F, S167G, M168L, P171L, S172E, Q173A, G174V, Y179F, A180E, des181] FGF-21; [-1A, S71C, L166F, S167G, M168L, P171L, S172E, Q173A, G174V, Y179F, A180E] FGF-21; [-1A, S71C, N121Q, L166F, S167G, M168L, G174V, Y179F, A180E, des181] FGF-21; [-1A, S71C, N121Q, L166F, S167G, M168L, G174V, Y179F, A180E] FGF-21; [-1A, S71C, N121Q, L166F, S167G, M168L, P171L, S172E, Q173A, G174V, Y179F, A180E, des181] FGF-21; [-1A, S71C, N121Q, L166F, S167G, M168L, P171L, S172E, Q173A, G174V, Y179F, A180E] FGF-21; [-1A, 121Q, 166F, 167G, 168L, 171L, 172E, 173A, 174V, 179F, 180E, des181] FGF-21; [-1A, 71C, 121Q, 166F, 167G, 168L, 171L, 172E, 173A, 174V, des179-181] FGF-21, [-1A, 71C, 121Q, 166F, 168L, 173A, 174V, 179F] FGF-21 or [- 1A, 71C, 121Q, 166F, 168L, 174V, 179F, 180E, des181] The analogue or derivative according to any one of claims 1 to 5, which is FGF21. nが14、16または18である、請求項1から6のいずれか一項に記載の誘導体。The derivative according to any one of claims 1 to 6, wherein n is 14, 16 or 18. mが2である、請求項1から7のいずれか一項に記載の誘導体。The derivative according to any one of claims 1 to 7, wherein m is 2. pが2である、請求項1から8のいずれか一項に記載の誘導体。The derivative according to any one of claims 1 to 8, wherein p is 2. qが2、3または4である、請求項1から9のいずれか一項に記載の誘導体。10. The derivative according to any one of claims 1 to 9, wherein q is 2, 3 or 4. nが14であり、m、pおよびqがそれぞれ2であるか、または、 nが16であり、m、pおよびqがそれぞれ2であるか、または、 nが18であり、m、pおよびqがそれぞれ2である、請求項1から6のいずれか一項に記載の誘導体。n is 14, and m, p, and q are each 2, or n is 16, m, p, and q are each 2, or n is 18, and m, p, and The derivative according to any one of claims 1 to 6, wherein each q is 2. S-71-({2-[2-(2-{2-[2-(2-{2-[(S)-4-カルボキシ-4-(15-カルボキシペンタデカノイルアミノ)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)アセチルアミノ]エチルカルバモイル}メチル)[71C,121Q,166F,167G,168L,171L,172E,173A,174V,179F,180E,des181]Ala-FGF21;S-71-({2- [2- (2- {2- [2- (2- {2-[(S) -4-carboxy-4- (15-carboxypentadecanoylamino) butyrylamino] ethoxy} Ethoxy) acetylamino] ethoxy} ethoxy) acetylamino] ethylcarbamoyl} methyl) [71C, 121Q, 166F, 167G, 168L, 171L, 172E, 173A, 174V, 179F, 180E, des181] Ala-FGF21;
S-71-({2-[2-(2-{2-[2-(2-{2-[(S)-4-カルボキシ-4-(17-カルボキシヘプタデカノイルアミノ)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)アセチルアミノ]エチルカルバモイル}メチル)[71C,121Q,166F,167G,168L,171L,172E,173A,174V,179F,180E]Ala-FGF21;S-71-({2- [2- (2- {2- [2- (2- {2-[(S) -4-carboxy-4- (17-carboxyheptadecanoylamino) butyrylamino] ethoxy} Ethoxy) acetylamino] ethoxy} ethoxy) acetylamino] ethylcarbamoyl} methyl) [71C, 121Q, 166F, 167G, 168L, 171L, 172E, 173A, 174V, 179F, 180E] Ala-FGF21;
S-71-({2-[2-(2-{2-[2-(2-{2-[(S)-4-カルボキシ-4-(17-カルボキシヘプタデカノイルアミノ)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)アセチルアミノ]エチルカルバモイル}メチル)[71C,121Q,166F,167G,168L,171L,172E,173A,174V,179F,180E,des181]Ala-FGF21;S-71-({2- [2- (2- {2- [2- (2- {2-[(S) -4-carboxy-4- (17-carboxyheptadecanoylamino) butyrylamino] ethoxy} Ethoxy) acetylamino] ethoxy} ethoxy) acetylamino] ethylcarbamoyl} methyl) [71C, 121Q, 166F, 167G, 168L, 171L, 172E, 173A, 174V, 179F, 180E, des181] Ala-FGF21;
S-71-({2-[2-(2-{2-[2-(2-{2-[(S)-4-カルボキシ-4-(17-カルボキシヘプタデカノイルアミノ)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)アセチルアミノ]エチルカルバモイル}メチル)[71C,121Q,166F,167G,168L,171L,172E,173A,174V,des179-181]Ala-FGF21;S-71-({2- [2- (2- {2- [2- (2- {2-[(S) -4-carboxy-4- (17-carboxyheptadecanoylamino) butyrylamino] ethoxy} Ethoxy) acetylamino] ethoxy} ethoxy) acetylamino] ethylcarbamoyl} methyl) [71C, 121Q, 166F, 167G, 168L, 171L, 172E, 173A, 174V, des179-181] Ala-FGF21;
S-71-({2-[2-(2-{2-[2-(2-{2-[(S)-4-カルボキシ-4-(17-カルボキシヘプタデカノイルアミノ)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)アセチルアミノ]エチルカルバモイル}メチル)[71C,121Q,166F,167G,168L,174V,179F,180E,des181]Ala-FGF21;S-71-({2- [2- (2- {2- [2- (2- {2-[(S) -4-carboxy-4- (17-carboxyheptadecanoylamino) butyrylamino] ethoxy} Ethoxy) acetylamino] ethoxy} ethoxy) acetylamino] ethylcarbamoyl} methyl) [71C, 121Q, 166F, 167G, 168L, 174V, 179F, 180E, des181] Ala-FGF21;
S-71-({2-[2-(2-{2-[2-(2-{2-[(S)-4-カルボキシ-4-(17-カルボキシヘプタデカノイルアミノ)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)アセチルアミノ]エチルカルバモイル}メチル)[71C,121Q,166F,168L,173A,174V,179F]Ala-FGF21;S-71-({2- [2- (2- {2- [2- (2- {2-[(S) -4-carboxy-4- (17-carboxyheptadecanoylamino) butyrylamino] ethoxy} Ethoxy) acetylamino] ethoxy} ethoxy) acetylamino] ethylcarbamoyl} methyl) [71C, 121Q, 166F, 168L, 173A, 174V, 179F] Ala-FGF21;
S-71-({2-[2-(2-{2-[2-(2-{2-[(S)-4-カルボキシ-4-(17-カルボキシヘプタデカノイルアミノ)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)アセチルアミノ]エチルカルバモイル}メチル)[71C,166F,167G,168L,171L,172E,173A,174V,179F,180E,des181]Ala-FGF21;S-71-({2- [2- (2- {2- [2- (2- {2-[(S) -4-carboxy-4- (17-carboxyheptadecanoylamino) butyrylamino] ethoxy} Ethoxy) acetylamino] ethoxy} ethoxy) acetylamino] ethylcarbamoyl} methyl) [71C, 166F, 167G, 168L, 171L, 172E, 173A, 174V, 179F, 180E, des181] Ala-FGF21;
S-71-({2-[2-(2-{2-[2-(2-{2-[(S)-4-カルボキシ-4-(17-カルボキシヘプタデカノイルアミノ)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)アセチルアミノ]エチルカルバモイル}メチル)[71C,166F,167G,168L,174V,179F,180E]Ala-FGF21;S-71-({2- [2- (2- {2- [2- (2- {2-[(S) -4-carboxy-4- (17-carboxyheptadecanoylamino) butyrylamino] ethoxy} Ethoxy) acetylamino] ethoxy} ethoxy) acetylamino] ethylcarbamoyl} methyl) [71C, 166F, 167G, 168L, 174V, 179F, 180E] Ala-FGF21;
S-71-({2-[2-(2-{2-[2-(2-{2-[(S)-4-カルボキシ-4-(17-カルボキシヘプタデカノイルアミノ)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)アセチルアミノ]エチルカルバモイル}メチル)[71C,166F,167G,168L,174V,179F,180E,des181]Ala-FGF21;S-71-({2- [2- (2- {2- [2- (2- {2-[(S) -4-carboxy-4- (17-carboxyheptadecanoylamino) butyrylamino] ethoxy} Ethoxy) acetylamino] ethoxy} ethoxy) acetylamino] ethylcarbamoyl} methyl) [71C, 166F, 167G, 168L, 174V, 179F, 180E, des181] Ala-FGF21;
S-71-({2-[2-(2-{2-[2-(2-{2-[(S)-4-カルボキシ-4-(19-カルボキシノナデカノイルアミノ)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)アセチルアミノ]エチルカルバモイル}メチル)[-1A,71C,121Q,166F,167G,168L,171L,172E,173A,174V,179F,180E,des181]Ala-FGF21またはS-71-({2- [2- (2- {2- [2- (2- {2-[(S) -4-carboxy-4- (19-carboxynonadecanoylamino) butyrylamino] ethoxy} Ethoxy) acetylamino] ethoxy} ethoxy) acetylamino] ethylcarbamoyl} methyl) [-1A, 71C, 121Q, 166F, 167G, 168L, 171L, 172E, 173A, 174V, 179F, 180E, des181] Ala-FGF21 or
S-71-({2-[2-(2-{2-[2-(2-{2-[(S)-4-カルボキシ-4-(17-カルボキシヘプタデカノイルアミノ)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)アセチルアミノ]エチルカルバモイル}メチル)[-1A,71C,121Q,166F,168L,174V,179F,180E,des181]FGF21である、請求項1から11のいずれか一項に記載の誘導体。S-71-({2- [2- (2- {2- [2- (2- {2-[(S) -4-carboxy-4- (17-carboxyheptadecanoylamino) butyrylamino] ethoxy} 12. Ethoxy) acetylamino] ethoxy} ethoxy) acetylamino] ethylcarbamoyl} methyl) [-1A, 71C, 121Q, 166F, 168L, 174V, 179F, 180E, des181] FGF21 any one of claims 1 to 11 The derivative according to item. Met-FGF21の効力に対して少なくとも30%の効力を有する、請求項1から12のいずれか一項に記載のFGF21、類似体または誘導体。13. FGF21, analog or derivative according to any one of claims 1 to 12, having an efficacy of at least 30% relative to that of Met-FGF21. 請求項1から13のいずれか一項に記載のFGF21、類似体または誘導体を含む医薬。A medicament comprising the FGF21, analogue or derivative according to any one of claims 1 to 13. 糖尿病、脂質異常症、肥満、心血管疾患、メタボリック症候群および/または非アルコール性脂肪性肝疾患(NAFLD)の治療または予防のための、請求項14に記載の医薬。15. The medicament according to claim 14, for the treatment or prevention of diabetes, dyslipidemia, obesity, cardiovascular disease, metabolic syndrome and / or non-alcoholic fatty liver disease (NAFLD).
JP2013513645A 2010-06-08 2011-06-06 FGF21 analogs and derivatives Withdrawn JP2013533227A (en)

Applications Claiming Priority (7)

Application Number Priority Date Filing Date Title
PCT/EP2010/057986 WO2010142665A1 (en) 2009-06-11 2010-06-08 Glp-1 and fgf21 combinations for treatment of diabetes type 2
EPPCT/EP2010/057986 2010-06-08
CN2010001099 2010-07-21
CN2010/001099 2010-07-21
US37329010P 2010-08-13 2010-08-13
US61/373,290 2010-08-13
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