OXYNTOMODULIN ANALOGS
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IPC분류정보
국가/구분 |
United States(US) Patent
공개
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국제특허분류(IPC7판) |
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출원번호 |
US-0686760
(2015-04-14)
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공개번호 |
US-0307580
(2015-10-29)
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발명자
/ 주소 |
- CARRINGTON, Paul E.
- EIERMANN, George J.
- MARSH, Donald J.
- METZGER, Joseph M.
- POCAI, Alessandro
- SINHA ROY, Ranabir
- BIANCHI, Elisabetta
- INGALLINELLA, Paolo
- PESSI, Antonello
- PRETE, Alessia
- CAPITO, Elena
- DIMARCHI, Richard
- WARD, Brian
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출원인 / 주소 |
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인용정보 |
피인용 횟수 :
0 인용 특허 :
0 |
초록
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Peptide analogs of oxyntomodulin (OXM, glucagon-37), which have been modified to be resistant to cleavage and inactivation by dipeptidyl peptidase IV (DPP-IV) and to increase in vivo half-life of the peptide analog while enabling the peptide analog to act as a dual GLP-1/glucagon receptor (GCGR) ago
Peptide analogs of oxyntomodulin (OXM, glucagon-37), which have been modified to be resistant to cleavage and inactivation by dipeptidyl peptidase IV (DPP-IV) and to increase in vivo half-life of the peptide analog while enabling the peptide analog to act as a dual GLP-1/glucagon receptor (GCGR) agonist are described. The peptide analogs are useful for treatment of metabolic disorders such as diabetes and obesity.
대표청구항
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1-9. (canceled) 10. A peptide analog comprising the structure Z1-P-M-Z2wherein P is a peptide having the amino acid sequence (SEQ ID NO: 110)HX1QGTFTSDX2SX3YLDX4X5X6AX7DFVQWLX8NTKX9X10wherein X1 is a D-serine, α-aminoisobutyric acid (aib), 1-Amino-1-cyclobutane carboxylic acid (Acb) residue, 1-Amino
1-9. (canceled) 10. A peptide analog comprising the structure Z1-P-M-Z2wherein P is a peptide having the amino acid sequence (SEQ ID NO: 110)HX1QGTFTSDX2SX3YLDX4X5X6AX7DFVQWLX8NTKX9X10wherein X1 is a D-serine, α-aminoisobutyric acid (aib), 1-Amino-1-cyclobutane carboxylic acid (Acb) residue, 1-Amino-1-cyclohexane carboxylic acid (Acx); alpha-aminobutyric acid (Abu); D-alpha-aminobutyric acid (D-Abu); Aminovaleric acid (Nva); beta-cyclopropyl-alanine (Cpa); propargylglycine (Prg); Allylglycine (Alg); 2-Amino-2-cyclohexyl-propanoic acid (2-Cha); D-tertbutylglycine (D-tbg); Vinylglycine (Vg); 1-Amino-1-cyclopropane carboxylic acid (Acp); or 1-Amino-1-cyclopentane carboxylic acid (Acpe) residue;X2 is a tyrosine (Y) or lysine (K) residue;X3 is serine (S) or lysine (K) residue;X4 is serine (S), α-aminoisobutyric acid (aib), or glutamic acid (E) residue;X5 is an arginine (R) or glutamic acid (E) residue;X6 is an arginine (R) or alanine (A) residue;X7 is a glutamine (Q) or lysine (K) residue;X8 is a methionine (M), norleucine (Nle), methionine sulfoxide (m), or O-methyl-L-homoserine (o) residue;X9 is a gamma glutamic acid (γGlu) residue;X10 is a gamma glutamic acid (γGlu) residue or absent;Z1 is an optionally present protecting group that, if present, is joined to the N-terminal amino group,M is (i) a cysteine residue covalently linked to a cholesterol moiety by a hydrophilic linker, (ii) a lysine residue covalently linked to a lipid moiety by a spacer comprising one or more gamma glutamic acid residues, or (iii) a lipid moiety, wherein M is covalently linked to a C-terminal or internal amino acid of P by a spacer comprising one or more gamma-glutamic acid residues; andZ2 is an optionally present protecting group that, if present, is joined to the C-terminal carboxy group; and pharmaceutically acceptable salts thereof,wherein the peptide analog or salt thereof has a pI of less than 6.0 and is a dual GLP-1 receptor agonist and glucagon receptor agonist. 11. The peptide analog of claim 10, wherein M is a cysteine residue covalently linked to a cholesterol moiety with a hydrophilic linker and the cysteine residue is linked to the C-terminus of P. 12. The peptide analog of claim 10, wherein M is a lysine residue covalently linked to a lipid moiety by a spacer comprising one or more gamma glutamic acid residues and the lysine residue is linked to the C-terminus of P. 13. The peptide analog of claim 10, wherein M is a lysine residue covalently linked to a lipid moiety by a spacer comprising one or more gamma glutamic acid residues and the lysine residue is at position X2 or X7 of P. 14. The peptide analog of claim 10, wherein the hydrophilic linker is an ethoxy polymer that includes one to twenty-four ethoxy units. 15. The peptide analog of claim 10, wherein the hydrophilic linker is an ethoxy polymer that includes four ethoxy units. 16. The peptide analog of claim 10, wherein the lipid moiety is a palmitoyl moiety. 17. The peptide analog of claim 10, wherein the peptide analog is OXM317 (SEQ ID NO:60); OXM318 (SEQ ID NO:61); OXM319 (SEQ ID NO:62); OXM323 (SEQ ID NO:64); OXM327 (SEQ ID NO: 66); or OXM329 (SEQ ID NO:67). 18. The peptide analog of claim 10, wherein the peptide analog is OXM345 (SEQ ID NO:69); OXM355 (SEQ ID NO:70); OXM357 (SEQ ID NO:71); OXM359 (SEQ ID NO:72); OXM361 (SEQ ID NO:73); OXM373 (SEQ ID NO:74); OXM374 (SEQ ID NO:75); OXM380 (SEQ ID NO:76); OXM381 (SEQ ID NO:77); OXM383 (SEQ ID NO:78); OXM388 (SEQ ID NO:79); OXM399 (SEQ ID NO:83); OXM400 (SEQ ID NO:84); OXM401 (SEQ ID NO:85); OXM404 (SEQ ID NO:86); OXM406 (SEQ ID NO:87); OXM407 (SEQ ID NO:88); OXM408 (SEQ ID NO:89); OXM410 (SEQ ID NO: 91); OXM411 (SEQ ID NO:92); OXM412 (SEQ ID NO:93); OXM414 (SEQ ID NO:95); OXM415 (SEQ ID NO:96); OXM418 (SEQ ID NO:99); OXM419 (SEQ ID NO:100); OXM420 (SEQ ID NO:101); OXM421 (SEQ ID NO:102); MM111 (SEQ ID NO:113); MM114 (SEQ ID NO:115); MM115 (SEQ ID NO:116); MM116 (SEQ ID NO:117); MM117 (SEQ ID NO:118); MM121 (SEQ ID NO:119); or MM132 (SEQ ID NO:121). 19. The peptide analog of claim 10 wherein M is a lysine residue covalently linked to a lipid moiety by a spacer comprising one or more gamma glutamic acid residues and the lysine residue is linked to the C-terminus of P or M is a lysine residue covalently linked to a lipid moiety by a spacer comprising one or more gamma glutamic acid residues and the lysine residue is at position X2 or X7 of P. 20. The peptide analog of claim 19, wherein the lipid moiety is a palmitoyl, myristoyl, or stearoyl moiety.
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