Cyclic peptide surface feature mimics of endothelin
First Claim
1. A substantially pure peptide of formula (III):
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space="preserve" listing-type="equation">cyclo(X.sup.1 -X.sup.2 -X.sup.3 -X.sup.4 -L-Trp) (III)or a pharmaceutically acceptable salt thereof, wherein;
X1 is D-Leu, D-Val, D-lle, D-Ala, Gly, Aib, D-Nva, D-Nle or D-Alle;
X2 is L-Val, L-lle, L-Leu, L-Ala, L-Gln, L-Gly, Aib, L-Nva, L-Nlle or L-Alle;
X3 is D-Pro, D-Hyp, D-Ala, D-Val, D-lle, Gly, Aib, D-Nva, D-Nle or D-Alle; and
X4 is L-Asp, L-Glu, L-Tyr, L-Ser, L-Thr, L-Cys(O3 H) or L-Pen(O3 H).
3 Assignments
0 Petitions
Accused Products
Abstract
Cyclic peptides and pharmaceutically acceptable salts and esters thereof are provided. The cyclic peptides and pharmaceutically acceptable salts and esters thereof mimic surface features of the C-terminus of endothelin and thereby can be used modulate or alter the activity of the endothelin family of peptides. More particularly, cyclic pentapeptides, cyclic hexapeptides, cyclic heptapeptides and pharmaceutically acceptable derivatives of the peptides that specifically inhibit the activity of endothelin are provided. Among the cyclic peptides are those that have the formula: cyclo(X1 -X2 -X3 -X4 -D-Trp): X1 is D-Tyr or D-Asp; X2 is Phe, Ala, Ac3 c or Pro; X3 is D-His, D-Ala, D-Val, Gly or β-Ala; and X4 is His, Ala, β-Ala, Aib, Gly, D-His-gly or Leu; cyclo(X1 -L-Phe-X3 -X4 -X5) in which X1 is D-Tyr, D-Asp or D-Glu, X3 is selected from among D-His, β-Ala-D-His or gly-D-His; X4 is Ser, Gly or β-Ala, and X5 is D-Trp or N-Me-D-Trp; cyclo(X1 -X2 -X3 -X4 -L-Trp) in which X1 is D-Ala, Aib, Gly, D-Val, D-Leu, D-lle, D-Nva, D-Nle, or D-Alle; X2 is D-Val, D-Leu, D-lle, D-Ala, D-Gln, Gly, Aib, D-Nva, D-Nle, or D-Alle; X3 is Pro, Gly, Aib, Val, Leu, L-Nva, L-Nle, L-Alle or L-Hyp and X4 is D-Asp, D-Glu, D-Ser, D-Thr, D-Tyr, D-Cys(O3 H) or D-Pen(O3 H); and cyclo(X1 -X2 -X3 -X4 -L-Trp) in which X1 is D-Leu, D-Val, D-lle, D-Ala, Gly, Aib, D-Nva, D-Nle or D-Alle; X2 is Val, lle, Leu, Ala, Gln, Gly, Aib, L-Nva, L-Nle or L-Alle; X3 is D-Pro, D-Hyp, D-Ala, D-Val, D-lle, Gly, Aib, D-Nva, D-Nle or D-Alle; and X4 is Asp, Glu, Tyr, Ser, Thr, L-Cys(O3 H) or L-Pen(O3 H). Pharmaceutical compositions containing the peptides and methods of modulating the activity of endothelin peptides are also provided.
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Citations
41 Claims
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1. A substantially pure peptide of formula (III):
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space="preserve" listing-type="equation">cyclo(X.sup.1 -X.sup.2 -X.sup.3 -X.sup.4 -L-Trp) (III)or a pharmaceutically acceptable salt thereof, wherein; X1 is D-Leu, D-Val, D-lle, D-Ala, Gly, Aib, D-Nva, D-Nle or D-Alle;
X2 is L-Val, L-lle, L-Leu, L-Ala, L-Gln, L-Gly, Aib, L-Nva, L-Nlle or L-Alle;
X3 is D-Pro, D-Hyp, D-Ala, D-Val, D-lle, Gly, Aib, D-Nva, D-Nle or D-Alle; and
X4 is L-Asp, L-Glu, L-Tyr, L-Ser, L-Thr, L-Cys(O3 H) or L-Pen(O3 H). - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41)
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Specification