Method of treating diabetes with tissue-selective insulin analogs

• US 5,446,020 A
• Filed: 06/23/1993
• Issued: 08/29/1995
• Est. Priority Date: 08/08/1991
• Status: Expired due to Term

• Current Assignee: Scios, Inc. (Johnson & Johnson)
• Original Assignee: Scios, Inc. (Johnson & Johnson)
• Inventors: Andy, Robin J., Larson, Eric R.
• Primary Examiner(s): Draper, Garnette D.
• Assistant Examiner(s): CARLSON, KAREN C
• Application Number:
  US08/081,661
• Time in Patent Office: 797 Days
• Field of Search: 514/3, 530/303, 530/866
• US Class Current: 514/6.2
• 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: C07K 14/62 Insulins

Abstract

Human insulin analogs are disclosed. These analogs are tissue-selective. Accordingly, pharmaceutical formulations containing the analogs of the invention provide superior clinical benefits as compared to human insulin when used in the treatment of patients suffering from diabetes. The analogs are modified at amino residue A12, A15 or A19, are different from the naturally occurring residue at said position, and are hepatoselective. Also disclosed are human insulin analogs modified at amino acid residues A12 or A14 or amino acid residues A10 and A13 different from naturally occurring residues or residues at said position or positions and are peripheral selective. DNA sequences and microorganisms comprising sequences coding for human insulin analogs are also provided. Processes for preparing the human insulin analogs are described.

Claims

1. A method of treating diabetes in a human which comprises administering to a human a therapeutically effective amount of an insulin analog wherein position A12_Ser is substituted with Gly and the analog is hepatoselective.

2. A method of treating diabetes in a human which comprises administering to a human a therapeutically effective amount of an insulin analog wherein position A12_Ser is substituted with Thr and the analog is peripherally selective.

3. A method of treating diabetes in a human which comprises administering to a human a therapeutically effective amount of an insulin analog comprising a hydrophilic amino acid substitution at position A19_Tyr, wherein the analog is hepatoselective.

4. The method of claim 3, wherein position A19_Tyr is substituted with either His or Gln.

5. A method of treating diabetes in a human which comprises administering to a human a therapeutically effective amount of an insulin analog comprising amino acid substitutions at both positions A12_Ser and A19_Tyr, wherein position A12_Ser is substituted with Gly and A19_Tyr is substituted with His and the analog is hepatoselective.

6. A method of treating diabetes in a human which comprises administering to a human a therapeutically effective amount of an insulin analog comprising a hydrophobic amino acid substitution at position A14_Tyr, wherein the analog is peripherally selective.

7. The method of claim 6, wherein position A14_Tyr is substituted with Phe.

8. A method of treating diabetes in a human which comprises administering to a human a therapeutically effective amount of an insulin analog comprising a hydrophilic amino acid substitution at position A14_Tyr, wherein the analog is hepatoselective.

9. The method of claim 8, wherein position A14_Tyr is substituted with Gly.

10. A method of treating diabetes in a human which comprises administering to a human a therapeutically effective amount of an insulin analog comprising amino acid substitutions at both positions A12_Ser and A14_Tyr, wherein position A12_Ser is substituted with Thr and position A14_Tyr, is substituted with Gly and the analog is hepatoselective.

11. A method of treating diabetes in a human which comprises administering to a human a therapeutically effective amount of an insulin analog comprising hydrophobic amino acid substitutions at both positions A10_Val and A13_Leu, wherein the analog is peripherally selective.

12. The method of claim 11, wherein position A10_Val is substituted with Pro and position A13_Leu is substituted with Trp.