Peptide boronic acid inhibitors of trypsin-like proteases
First Claim
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1. A compound of the formula ##STR10## wherein Y1 and Y2, independently, are --OH or F or, taken together, form a moiety derived from a dihydroxy compound having at least two hydroxy groups separated by at least two connecting atoms in a chain or ring, said chain or ring comprising 1 to about 20 carbon atoms and, optionally, a heteroatom which can be N, S, or O;
- R2 is a substituted alkyl selected from the group consisting of --(CH2)z --X, --CH(CH3)--(CH2)2 --X, --CH2 CH(CH3)--CH2 --X, --(CH2)2 --CH(CH2)--X, and --(CH2)2 --CH(CH3)2 --X, where X is --NH2, --NH--C(NH)--NH2 or --S--C(NH)--NH2, and z is 3 to 5;
n, o, p, and q are, independently, either 1 or 0;
A1, A2 and A3, independently, are amino acids of L- or D-configuration selected from the group consisting of Ala, Arg, Asn, Asp, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr and Val; and
R1 is H or an N-terminal protecting group;
or a physiologically acceptable salt thereof.
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Abstract
Peptides comprising C-terminal boronic acid derivatives of lysine, ornithine, and arginine, homoarginine and corresponding isothiouronium analogs thereof, are reversible inhibitors of trypsin-like serine proteases such as thrombin, plasma kallikrein and plasmin.
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Citations
51 Claims
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1. A compound of the formula ##STR10## wherein Y1 and Y2, independently, are --OH or F or, taken together, form a moiety derived from a dihydroxy compound having at least two hydroxy groups separated by at least two connecting atoms in a chain or ring, said chain or ring comprising 1 to about 20 carbon atoms and, optionally, a heteroatom which can be N, S, or O;
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R2 is a substituted alkyl selected from the group consisting of --(CH2)z --X, --CH(CH3)--(CH2)2 --X, --CH2 CH(CH3)--CH2 --X, --(CH2)2 --CH(CH2)--X, and --(CH2)2 --CH(CH3)2 --X, where X is --NH2, --NH--C(NH)--NH2 or --S--C(NH)--NH2, and z is 3 to 5; n, o, p, and q are, independently, either 1 or 0; A1, A2 and A3, independently, are amino acids of L- or D-configuration selected from the group consisting of Ala, Arg, Asn, Asp, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr and Val; and R1 is H or an N-terminal protecting group; or a physiologically acceptable salt thereof. - 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, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51)
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Specification