Inhibitors of retroviral protease

• US 5,342,922 A
• Filed: 03/08/1989
• Issued: 08/30/1994
• Est. Priority Date: 03/08/1989
• Status: Expired due to Fees

• Current Assignee: Washington University In St Louis
• Original Assignee: Washington University In St Louis
• Inventors: Marshall, Garland R., Toth, Mihaly V.
• Primary Examiner(s): Cashion, Jr., Merrell C.
• Assistant Examiner(s): MARSHALL, SANDRA GISELE
• Application Number:
  US07/320,742
• Time in Patent Office: 2,001 Days
• Field of Search: 530/329, 514/17
• US Class Current: 530/329
• 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 14/005 from viruses
• CPC Class Codes: C07K 7/02 Linear peptides containing at least one abnormal peptide link
• CPC Class Codes: C12N 2740/16222 New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes

Abstract

Novel inhibitors of retroviral protease, e.g., HIV protease, are provided which are peptides having from about 4 to about 8 amino acid residues and which are substrates for said protease derived from known cleavage sites and modified to contain an internal CH₂ NH bond isostere.

Claims

1. An inhibitor of HIV protease of claim 1 selected from the group consisting of

Ac-Gln-Asn-Tyr-Ψ

[CH₂ N]-Pro-Ile-Val-NH₂,

Ac-Gly-Asn-Tyr-Ψ

[CH₂ N]-Pro-Val-Gln-NH₂,

Ac-Thr-Ile-Met-Ψ

[CH₂ NH]-Met-Gln-Arg-NH₂,

Ac-Thr-Ile-Nle-Ψ

[CH₂ NH]-Nle-Gln-Arg-NH₂,

Ac-Thr-Ile-Leu-Ψ

[CH₂ NH]-Leu-Gln-Arg-NH2,

Ac-Thr-Ile-Nle-Ψ

[CH₂ NH]-Leu-Gln-Arg-NM₂,

Ac-Thr-Ile-Nle-Ψ

[CH₂ NH]-Cha-Gln-Arg-NH₂,

Ac-Thr-Ile-Nle-Ψ

[CH₂ NH]-Phe-Gln-Arg-NH₂,

Ac-Thr-Ile-Nle-Ψ

[CH₂ NH]-Cle-Gln-Arg-NH₂,

Ac-Thr-Ile-Nle-Ψ

[CH₂ NH]-MeNle-Gln-Arg-NH₂,

Ac-Thr-Ile-Nle-Ψ

[CH₂ NH]-Nle-Gln-D-Arg-NH₂,

Ac-Thr-Ile-Nle-Ψ

[CH₂ NH]-Ile-Gln-Arg-NH₂,

Ac-D-Thr-Ile-Nle-Ψ

[CH₂ NH]-Nle-Gln-Arg-NH₂,

Ac-Thr-Ile-Nle-Ψ

[CH₂ NH]-Nle-Gln-Nva-NH₂,

Ac-Arg-Gln-Nle-Ψ

[CH₂ NH]-Nle-Ile-Thr-NH₂,

Ac-Thr-Ile-Nle-Ψ

[CH₂ NH]-Nle-Gln-NH₂,

Ac-Ile-Nle-Ψ

[CH₂ NH]-Nle-Gln-Arg-NH₂,

Ac-Phe-Asn-Phe-Ψ

[CH₂ N]-Pro-Gln-Ile-NH₂,

Ac-Ser-Phe-Asn-Phe-Ψ

[CH₂ N]-Pro-Gln-Ile-NH₂,

Ac-Leu-Ala-Ala-Ψ

[CH₂ N]-Pro-Gln-Phe-NH₂,

Ac-Leu-Asn-Phe-Ψ

[CH₂ N]-Pro-Ile-Ser-OH,

H₂ N-Thr-Leu-Asn-Phe-Ψ

[CH₂ N]-Pro-Ile-Ser-OH,

Ac-Leu-Asn-Leu-Ψ

[CH₂ N]-Pro-Val-Ala-NH₂, and

H₂ N-Ser-Leu-Asn-Leu-Ψ

[CH₂ N]-Pro-Val-Ala-OH.

2. The inhibitor of claim 1 having the following structure:

Ac-Lue-Asn-Phe-Ψ

[CH₂ N]-Pro-Ile-Ser-OH.