Cyclic cell adhesion modulation compounds
First Claim
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1. A compound of the formula ##STR54## and pharmaceutically acceptable salts thereof, wherein L1 and L2 are each, or are together, a residue of an amino acid, an amino acid analog or an amino acid mimetic having a functional group suitable for the formation of a cyclizing bridge between L1 and L2 ;
- Z is a cyclizing moiety or bond between L1 and L2 ;
1is optional and, where present, is selected from the group consisting of Leu, Sar, D-Nal, Tyr, Phe, Ile, Pro, Gly, Ala, Val, norLeu, norVal, β
-Ala, Trp, and (Ada -Ala;
2 is selected from the group consisting of Arg, homoArg and norArg.4 is selected from Asp and, where 2 is norArg, Glu.5 is optional and, where present, is selected from the group consisting of Ser, Thr, Tyr, Trp, Ala, Val, Phe ##STR55## wherein m is 2, 3 or 4;
6is optional and, where present, is selected from the group consisting Pro, 3-thioPro, 1,1-ACC, Dhp, Hyp, homoPro and Phe;
X1 and Y1 are each optional and, where present, are independently selected from sequences of 1 to 4 D- or L-amino acids or amino acid analogs;
X2 is an optional N.sup.α
-substituent selected from R'"'"'-(including hydrogen) and R'"'"'CO--; and
Y2 is an optional carboxyl terminal substituent selected from the group consisting of --OR'"'"' (including hydroxy), --NR'"'"'2 (including --NH2 and --NHR'"'"'), --NHNH2 and --SR'"'"';
and wherein each R'"'"' is individually a pharmaceutically suitable substituent group, preferably one selected from the group consisting of hydrogen, linear and branched, unsubstituted and substituted C1 -C8 lower alkyls, C2 -C8 alkenyls, C2 -C8 alkenyls, C2 -C8 alkynyls, C6 -C14 aryls, C7 -C14 alkaryls, C7 -C14 alkaryls and C3 -C14 cycloalkyls, and, in the case of --NR'"'"'2, from cyclized groups forming (in an attachment with the nitrogen atom) a 5-8 membered heterocyclic ring optionally containing oxygen, nitrogen or sulfur as a further ring heteroatom.
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Abstract
Cyclized integrin receptor antagonist compounds useful in modulating cell adhesion to integrin receptors, including adhesion related to fibronectin and/or fibronectin receptors, are disclosed. Methods for synthesizing, testing, formulating, and using the compounds as therapeutic agents are also disclosed.
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Citations
15 Claims
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1. A compound of the formula ##STR54## and pharmaceutically acceptable salts thereof, wherein L1 and L2 are each, or are together, a residue of an amino acid, an amino acid analog or an amino acid mimetic having a functional group suitable for the formation of a cyclizing bridge between L1 and L2 ;
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Z is a cyclizing moiety or bond between L1 and L2 ; 1is optional and, where present, is selected from the group consisting of Leu, Sar, D-Nal, Tyr, Phe, Ile, Pro, Gly, Ala, Val, norLeu, norVal, β
-Ala, Trp, and (Ada -Ala;2 is selected from the group consisting of Arg, homoArg and norArg. 4 is selected from Asp and, where 2 is norArg, Glu. 5 is optional and, where present, is selected from the group consisting of Ser, Thr, Tyr, Trp, Ala, Val, Phe ##STR55## wherein m is 2, 3 or 4;
6is optional and, where present, is selected from the group consisting Pro, 3-thioPro, 1,1-ACC, Dhp, Hyp, homoPro and Phe;X1 and Y1 are each optional and, where present, are independently selected from sequences of 1 to 4 D- or L-amino acids or amino acid analogs; X2 is an optional N.sup.α
-substituent selected from R'"'"'-(including hydrogen) and R'"'"'CO--; andY2 is an optional carboxyl terminal substituent selected from the group consisting of --OR'"'"' (including hydroxy), --NR'"'"'2 (including --NH2 and --NHR'"'"'), --NHNH2 and --SR'"'"'; and wherein each R'"'"' is individually a pharmaceutically suitable substituent group, preferably one selected from the group consisting of hydrogen, linear and branched, unsubstituted and substituted C1 -C8 lower alkyls, C2 -C8 alkenyls, C2 -C8 alkenyls, C2 -C8 alkynyls, C6 -C14 aryls, C7 -C14 alkaryls, C7 -C14 alkaryls and C3 -C14 cycloalkyls, and, in the case of --NR'"'"'2, from cyclized groups forming (in an attachment with the nitrogen atom) a 5-8 membered heterocyclic ring optionally containing oxygen, nitrogen or sulfur as a further ring heteroatom. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15)
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9. A compound of claim 1 wherein L1 is directly bonded to L2 via an amide bond.
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10. A compound of claim 1 wherein the sequence 1-2-L1 -4-5-6-L2 is selected from the group consisting of
Leu-Arg-Cys-Asp-Ser-Pro-Cys, Arg-Cys-Asp-Ser-Pro-Cys, and Arg-Cys-Asp-Pro-Cys. -
11. A compound of claim 1 selected from the group consisting of ##STR57##
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12. A compound of claim 1 useful in modulating adhesion of a cell expressing a fibronectin receptor.
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13. A pharmaceutical composition comprising a compound of claim 1.
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14. A compound of claim 1 having an IC50 in a U937 fibronectin adhesion assay of less than about 500 μ
- M.
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15. A compound of claim 1 having an IC50 in a U937 fibronectin adhesion assay of less than about 100 μ
- M.
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Specification