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US 5,493,007 AGranted
Platelet aggregation inhibitors having high specificity for GPIIBIIIA
AssigneeGenentech, Inc.
InventorsJohn P. Burnier, Thomas Gadek, Robert S. McDowell
Life of this patent
Estimating the term…
Abstract
A peptide containing the tripeptide recognition sequences RGD or KGD in a cycle and an exocyclic group bearing a positive charge is provided. The compound is provided in therapeutic form for administration to a mammal and exhibits high specificity and potency as a platelet aggregation inhibitor without undesireable side effects.
Claims4
A peptide having an IC.sub.50 in a human platelet aggregation inhibition assay of no more than at least about 3 .mu.M, represented by a sequence selected from the group consisting of:
- Xaa.sub.1 -Arg-Gly-Asp-Xaa.sub.2, and
- Xaa.sub.1 -Lys-Gly-Asp-Xaa.sub.2
- where;
- Xaa.sub.1 is a single amino acid selected from;
- Gly,
- D-Ala,
- D-Val,
- D-Leu,
- D-lie,
- D-Phe,
- D-Tyr, and
- D-Pro
- Xaa.sub.2 represents an .alpha.-amino acid bonded to Xaa.sub.1 selected from Cys and Pen, and where a positively charged nitrogen containing exocyclic moiety is bonded to Xaa.sub.2 through a functional group of Xaa.sub.2,
- wherein the positively charged exocyclic moiety is a D or L .alpha.-amino acid selected from;
- His,
- Lys,
- Arg, and
- Orn,
- wherein the .alpha.-carboxyl group of the D or L .alpha.-amino acid is optionally derivatized with an amino or lower alkyl substituted amino group.
16 more elements
A peptide selected from the group:
- cyclo-S-acetyl-dTyr-Arg-Gly-Asp-Cys-Arg-NH.sub.2 ;
- cyclo-S-acetyl-dTyr-Arg-Gly-Asp-Cys-dArg-NH.sub.2 ;
- cyclo-S-acetyl-dTyr-Arg-Gly-Asp-Cys-L ys-NH.sub.2 ;
- cyclo-S-acetyl-dTyr-Arg-Gly-Asp-Cys-dLys-NH.sub.2 ;
- cyclo-S-acetyl-dTyr-Arg-Gly-Asp-Cys-Orn-NH.sub.2 ;
- cyclo-S-acetyl-dTyr-Arg-Gly-Asp-Cys-dOrn-NH.sub.2 ;
- cyclo-S-acetyl-dTyr-Arg-Gly-Asp-Cys-Tyr-Arg-NH.sub.2 ;
- cyclo-S-acetyl-dTyr-Arg-Gly-Asp-Cys-NH-X (X=butylamine);
- cyclo-S-acetyl-dTyr-Arg-Gly-Asp-Cys-NH-X (X=pentylamine);
- cyclo-S-acetyl-dTyr-Arg-Gly-Asp-Cys-NH-X (X=hexylamine);
- cyclo-S-acetyl-dTyr-Lys-Gly-Asp-Cys-NH-X (X=butylamine);
- cyclo-S-acetyl-dTyr-Lys-Gly-Asp-Pen-NH-X (X=butylamine);
- cyclo(1-5)dTyr-Arg-Gly-Asp-L-.alpha.-aminoadipic acid-Arg-NH.sub.2 ;
- cyclo(1-5)dTyr-Arg-Gly-Asp-L-.alpha.-aminoadipic acid-Lys-NH.sub.2 ;
- cyclo( 1-5)dTyr-Arg-Gly-Asp-L-.alpha.-aminoadipic-butylamine;
- cyclo-S-acetyl-dTyr-Arg-Gly-Asp-Cys-NH-X (X=propylamine);
- cyclo-S-acetyl-dTyr-Arg-Gly-Asp-Cys-NH-X (X-ethylamine);
- cyclo-S-acetyl-dTyr-Lys-Gly-Asp-Pen-Arg-NH.sub.2 ;
- cyclo-S-acetyl-dTyr-Lys-Gly-Asp-Pen-Lys-NH.sub.2 ;
- cyclo-S-acetyl-dTyr-Arg-Gly-Asp-Cys-Arg-OH;
- cyclo-S-acetyl-dTyr-Arg-Gly-Asp-Cys-Lys-OH;
- cyclo-S-acetyl-dTyr-Lys-Gly-Asp-Pen-Arg-OH;
- cyclo-S-acetyl-dTyr-Arg-Gly-Asp-Cys-Gln-NH.sub.2 ;
- cyclo-S-acetyl-Tyr-Arg-Gly-Asp-Cys-Arg-NH.sub.2 ;
- cyclo-S-acetyl-dTyr-Arg-Gly-Asp-Cys-Arg-NH.sub.2 Sulfoxide (isomer 1);
- cyclo-S-acetyl-dTyr-Arg-Gly-Asp-Cys-Arg-NH.sub.2 Sulfoxide (isomer 2);
- cyclo-S-acetyl-dTyr-Arg-Gly-Asp-Cys-dArg-NH.sub.2 Sulfoxide (isomer 1);
- cyclo-S-acetyl-dTyr-Arg-Gly-Asp-Cys-dArg-NH.sub.2 Sulfoxide (isomer 2);
- cyclo-S-acetyl-dTyr-Arg-Gly-Asp-Cys-Lys-NH.sub.2 Sulfoxide (isomer 1);
- cyclo-S-acetyl-dTyr-Arg-Gly-Asp-Cys-Lys-NH.sub.2 Sulfoxide (isomer 2);
- cyclo-S-acetyl-dTyr-Arg-Gly-Asp-Cys-dLys-NH.sub.2 Sulfoxide (isomer 1);
- cyclo-S-acetyl-dTyr-Arg-Gly-Asp-Cys-dLys-NH.sub.2 Sulfoxide (isomer 2);
- cyclo-S-acetyl-dTyr-Arg-Gly-Asp-Cys-Orn-NH.sub.2 Sulfoxide (isomer 1);
- cyclo-S-acetyl-dTyr-Arg-Gly-Asp-Cys-Orn-NH.sub.2 Sulfoxide (isomer 2);
- cyclo-S-acetyl-dTyr-Arg-Gly-Asp-Cys-dOrn-NH.sub.2 Sulfoxide (isomer 1);
- cyclo-S-acetyl-dTyr-Arg-Gly-Asp-Cys-dOrn-NH.sub.2 Sulfoxide (isomer 2);
- cyclo-S-acetyl-dTyr-Arg-Gly-Asp-Cys-Tyr-Arg-NH.sub.2 Sulfoxide (isomer 1);
- and cyclo-S-acetyl-dTyr-Arg-Gly-Asp-Cys-Tyr-Arg-NH.sub.2 (Sulfoxide (isomer 2).
35 more elements
Dependencies are inferred from the claim text.