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US 5,665,705 AGranted
Glucagon analogs with serine replacements
AssigneeThe Rockefeller University
InventorsRobert B. Merrifield, Cecilia G. Unson
Life of this patent
Estimating the term…
Abstract
Glucagon analogs characterized principally by substitution of amino acid residues at positions 9, 11, 16, and 21 with or without a histidine residue at the amino terminus are useful adjuncts to insulin therapy.
Claims30
A glucagon analog peptide wherein
- (a) histidine at the 1-position is either present or absent;
- (b) the aspartic acid residue at the 9-position is either absent or replaced with another amino acid residue;
- (c) the serine residue at the 11-position is optionally replaced with an aliphatic amino acid residue;
- (d) the serine residue at the 16-position is replaced with an aliphatic amino acid residue;
- (e) the aspartic acid residue at the 21-position is optionally replaced with an aliphatic amino acid residue;
- and
- (f) the carboxy terminus is optionally amidated;
- said analog being further characterized by a relative membrane receptor binding activity compared to glucagon of at least about 40%, an inhibition index less than 10 and an adenylate cyclase activity less than 1% of that of glucagon;
- and pharmaceutically acceptable acid addition salts thereof wherein said analog is selected from the group consisting of wherein said analog is selected from the group consisting of des-His.sup.1 Nle.sup.9 Ala.sup.16 glucagon (SEQ ID NO:
- 16), Nle.sup.9 Ala.sup.11 Gln.sup.16 glucagon (SEQ ID NO:
- 17), Nle.sup.9 Ala.sup.11 Ala.sup.16 glucagon (SEQ ID NO:
- 18) or the amide thereof (SEQ ID NO:
- 9), des-His.sup.1 Nle.sup.9 Ala.sup.11 Ala.sup.16 glucagon (SEQ ID NO:
- 19), des-His.sup.1 Trp.sup.9 Ala.sup.11 Ala.sup.16 glucagon (SEQ ID NO:
- 20) or the amide thereof (SEQ ID NO:
- 11), des-His.sup.1 Leu.sup.9 Ala.sup.11 Ala.sup.16 glucagon (SEQ ID NO:
- 21) or the amide thereof (SEQ ID NO:
- 12), des-His.sup.1 Phe.sup.9 Ala.sup.11 Ala.sup.16 glucagon (SEQ ID NO:
- 22), des-His.sup.1 Nle.sup.9 Ala.sup.11 Gln.sup.16 glucagon (SEQ ID NO:
- 23), and des-His.sup.1 Glu.sup.9 Ala.sup.11 Ala.sup.16 Glu.sup.21 glucagon (SEQ ID NO:
- 24).
18 more elements
A pharmaceutical composition for control of glucogenesis in humans comprising an amount which is effective to achieve such control of a peptide consisting of a glucagon analog peptide wherein
- (a) histidine at the 1-position is either present or absent;
- (b) the aspartic acid residue at the 9-position is either absent or replaced with another amino acid residue;
- (c) the serine residue at the 11-position is optionally replaced with an aliphatic amino acid residue;
- (d) the serine residue at the 16-position is replaced with an aliphatic amino acid residue;
- (e) the aspartic acid residue at the 2-position is optionally replaced with an aliphatic amino acid residue;
- and
- (f) the carboxy terminus is optionally amidated;
- said analog being further characterized by a relative membrane receptor binding activity of at least about 40% compared to glucagon, an inhibition index less than 10 and an adenylate cyclase activity which is less than 1% of that of glucagon;
- and the pharmaceutically acceptable acid addition salts thereof wherein said analog is selected from the group consisting of des-His.sup.1 Nle.sup.9 Ala.sup.16 glucagon (SEQ ID NO:
- 16), Nle.sup.9 Ala.sup.11 Gln.sup.16 glucagon (SEQ ID NO:
- 17), Nle.sup.9 Ala.sup.11 Ala.sup.16 glucagon (SEQ ID NO:
- 18) or the amide thereof (SEQ ID NO:
- 9), des-His.sup.1 Nle.sup.9 Ala.sup.11 Ala.sup.16 glucagon (SEQ ID NO:
- 19), des-His.sup.1 Trp.sup.9 Ala.sup.11 Ala.sup.16 glucagon (SEQ ID NO:
- 20) or the amide thereof (SEQ ID NO:
- 11), des-His.sup.1 Leu.sup.9 Ala.sup.11 Ala.sup.16 glucagon (SEQ ID NO:
- 21) or the amide thereof (SEQ ID NO:
- 12), des-His.sup.1 Phe.sup.9 Ala.sup.11 Ala.sup.16 glucagon (SEQ ID NO:
- 22) des-His.sup.1 Nle.sup.9 Ala.sup.11 Gln.sup.16 glucagon (SEQ ID NO:
- 23), and des-His.sup.1 Glu.sup.9 Ala.sup.11 Ala.sup.16 Glu.sup.21 glucagon (SEQ ID NO:
- 24), together With a pharmaceutically acceptable carrier therefor.
18 more elements
Dependencies are inferred from the claim text.