Human insulin analogs and preparations containing them

• US 5,149,777 A
• Filed: 03/19/1991
• Issued: 09/22/1992
• Est. Priority Date: 07/20/1988
• Status: Expired due to Fees

• Current Assignee: Novo Nordisk A/S
• Original Assignee: Novo Nordisk A/S
• Inventors: Balschmidt, Per, Hansen, Finn B.
• Primary Examiner(s): NOT, DEFINED
• Assistant Examiner(s): NOT, DEFINED
• Application Number:
  US07/640,308
• Time in Patent Office: 553 Days
• Field of Search: 514/3, 530/303
• US Class Current: 530/303
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61P 3/08 for glucose homeostasis pancreatic hormones A61P5/48
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: C07K 14/62 Insulins
• CPC Class Codes: C07K 2319/02 containing a signal sequence
• CPC Class Codes: C12N 15/81 for yeasts

Abstract

Novel human insulin analogs exhibiting high biological activity and in which the amino acid residue Phe^B25 is substituted by His or Tyr and moreover substitutions may optionally be present in one or more of the positions A4, A8, A17, A21, B9, B10, B12, B13, B21, B26, B27, B28, and B30, as well as the amino acid residue in the B30 position may further be totally missing or may be blocked at the C-terminal in the form of ester or amide.

Claims

1. Human insulin analogs exhibiting high biological activity, characterized in that the amino acid residue in position B25 is His or Tyr, that the amino acid residue in one or more of the positions A4, A8, A17, A21, B9, B10, B12, B13, B21, B26, B27, B28, and B30 is optionally replaced by another amino acid residue, and that the amino acid residue in the B30-position is optionally missing or blocked at the C-terminal in the form of ester or amide, provided that when B25 is Tyr then B30 is different from Ala.

2. Human insulin analogs according to claim 1, characterized by containing [His^B25 ] or [Tyr^B25 ] and at least one substitute amino acid residue selected from the group consisting of [Gln^A4 ], [His^A8 ], [Gln^A17 ], [Asp^A21 ], [Asp^B9 ], [Asp^B10 ], [Ile^B12 ], [Gln^B13 ], [Arg^B13 ], [Gln^B21 ], [Pro^B21 ], [Glu^B26 ], [Arg^B27 ], [Asp^B28 ], [Ala^B30 ], and [Ser^B30 ], provided that when B25 is Tyr then B30 is different from Ala.

3. Human insulin analogs according to claim 1, characterized by containing [^B25 ] or [Tyr^B25 ] and at least two substitute amino acid residues selected from the group consisting of [Gln^A4 ], [His^A8 ], [Gln^A17 ], [Gln^B13 ], [Arg^B13 ], [Gln^B21 ], [Ile^B21 ], [Arg^B27 ], [Ala^B30 ], and [Ser^B30 ], provided that when B25 is Tyr then B30 is different from Ala.

4. Human insulin analogs according to claim 1, characterized by containing [His^B25 ] or [Tyr^B25 ] and at least two substitute amino acid residues selected from the group consisting of [His^A8 ], [Asp^A21 ], [Asp^B9 ], [Asp^B10 ], [Ile^B12 ], [Glu^B26 ], [Asp^B28 ], [Ala^B30 ], and [Ser^B30 ], provided that when B25 is Tyr then B30 is different from Ala.

5. Human insulin analog according to claim 1, characterized by being [Tyr^B25 ]-human insulin.

6. Human insulin analog according to claim 1, characterized by being [Tyr^B25, Asp^B28 ]-human insulin.

7. Human insulin analog according to claim 1, characterized by being [His^B25 ]-human insulin.

8. Human insulin analog according to claim 1, characterized by being [His^B25, Asp^B28 ]-des-[Thr^B30 ]-human insulin.

9. Human insulin analog according to claim 1, characterized by being [Tyr^B25 ]-human insulin-B30-amide.

10. Human insulin analog according to claim 1, characterized by being [His^B25 ]-human insulin-B30-amide.

11. Insulin preparation, characterized by containing at least one human insulin analog in which the amino acid residue in position B25 is His or Tyr, the amino acid residue in one or more of the positions A4, A8, A17, A21, B9, B10, B12, B13, B21, B26, B27, B28, and B30 is optionally replaced by another amino acid residue, and the amino acid residue in the B30-position is optionally missing or blocked at the C-terminal in the form of ester or amide, provided that when B25 is Tyr then B30 is different from Ala.

12. Insulin preparation according to claim 11, characterized by containing at least one human insulin analog comprising [His^B25 ] or [Tyr^B25 ] and at least one substitute amino acid residue selected from the group consisting of [Gln^A4 ], [His^A8 ], [Gln^A17 ], [Asp^A21 ], [Asp^B9 ], [Asp^B10 ], [Ile^B12 ], [Gln^B13 ], [Arg^B13 ], [Gln^B21 ], [Ile^B21 ], [Glu^B26 ], [Arg^B27 ], Asp^B28 ], [Ala^B30 ], and [Ser^B30 ].

13. Insulin preparation according to claim 11, characterized by containing at least one human insulin analog comprising [His^B25 ] or [Tyr^B25 ] and at least two substitute amino acid residues selected from the group consisting of [Gln^A4 ], [His^A8 ], [Gln^A17 ], [Gln^B13 ], [Arg^B13 ], [Gln^B21 ], [Ile^B21 ], [Arg^B27 ], [Ala^B30 ] and [Ser^B30 ].

14. Insulin preparation according to claim 11, characterized by containing at least one human insulin analog comprising [His^B25 ] or [Tyr^B25 ] and at least two substitute amino acid residues selected from the group consisting of [His^A8 ], [Asp^A21 ], [Asp^B9 ], [Asp^B10 ], [Ile^B12 ], [Glu^B26 ], [Asp^B28 ], [Ala^B30 ], and [Ser^B30 ].

15. Insulin preparation according to claim 11, characterized by containing [Tyr^B25 ]-human insulin.

16. Insulin preparation according to claim 11, characterized by containing [Tyr^B25, Asp^B28 ]-human insulin.

17. Insulin preparation according to claim 11, characterized by containing [His^B25 ]-human insulin.

18. Insulin preparation according to claim 11, characterized by containing [His^B25, Asp^B28 ]-des-[Thr^B30 ]-human insulin.

19. Insulin preparation according to claim 11, characterized by containing [Tyr^B25 ]-human insulin-B30-amide.

20. Insulin preparation according to claim 11, characterized by containing [His^B25 ]-human insulin-B30-amide.