Biogen, Incorporated

Paul R Bourdon

John M Maraganore

Jo-Ann M Jablonski

This invention relates to coating invasive devies with novel biologically active molecules which bind to and inhibit thrombin. These molecules comprise a catalytic site directed moiety (CSDM) of the formula: ##STR1## wherein X is hydrogen or is characterized by a backbone chain consisting of from 1 to 100 atoms; R.sub.1 is selected from the group consisting of unsubstituted, mono-substituted, di-substituted and tri-substituted saturated ring structures; R.sub.2 is a bond or is characterized by a backbone chain consisting of from 1 to 5 atoms; R.sub.3 is a bond or is characterized by a backbone chain consisting of from 1 to 3 atoms; R.sub.4 is any amino acid; R.sub.5 is any L-amino acid which comprises a guanidinium- or amino-containing side chain group; R.sub.6 is a non-amide bond; and Y is characterized by a backbone chain consisting of from 1 to 9 atoms; or the formula: ##STR2## wherein R.sub.1 ' is selected from the group consisting of unsubstituted, mono-substituted, di-substituted and tri-substituted ring structures; R.sub.4 ' is any amino acid comprising a side chain group characterized by the capacity to accept a hydrogen bond at a pH of between about 5.5 and 9.5; and X, R.sub.2, R.sub.3, R.sub.5, R.sub.6 and Y are defined as above. Preferred thrombin inhibitors are further characterized by a anion binding exosite associating domain (ABEAM) and a linker portion of between 18 .ANG. and 42 .ANG. in length which connects the Y to the ABEAM.

Methods for coating invasive devices with inhibitors of thrombin

This invention relates to novel biologically active molecules which bind to and inhibit thrombin. These molecules comprise a catalytic site directed moiety (CSDM) of the formula: ##STR1## wherein X is hydrogen or is characterized by a backbone chain consisting of from 1 to 100 atoms; R.sub.1 is selected from the group consisting of unsubstituted, mono-substituted, di-substituted and tri-substituted saturated ring structures; R.sub.2 is a bond or is characterized by a backbone chain consisting of from 1 to 5 atoms; R.sub.3 is a bond or is characterized by a backbone chain consisting of from 1 to 3 atoms; R.sub.4 is any amino acid; R.sub.5 is any L-amino acid which comprises a guanidinium- or amino-containing side chain group; R.sub.6 is a non-amide bond; and Y is characterized by a backbone chain consisting of from 1 to 9 atoms; or the formula: ##STR2## wherein R'.sub.1 is selected from the group consisting of unsubstituted, mono-substituted, di-substituted and tri-substituted ring structures; R'.sub.4 is any amino acid comprising a side chain group characterized by the capacity to accept a hydrogen bond at a pH of between about 5.5 and 9.5; and X, R.sub.2, R.sub.3, R.sub.5, R.sub.6 and Y are defined as above. Preferred thrombin inhibitors are further characterized by a anion binding exosite associating domain (ABEAM) and a linker portion of between 18.ANG. and 42.ANG. in length which connects the Y to the ABEAM. This invention also relates to compositions, combinations and methods which employ these molecules for therapeutic, prophylactic and diagnostic purposes.

Inhibitors of thrombin

This invention relates to novel biologically active molecules which bind to and inhibit thrombin. These molecules comprise a catalytic site directed moiety (CSDM) of the formula ##STR1## wherein X is hydrogen or is characterized by a backbone chain consisting of from 1 to 100 atoms; R.sub.1 is selected from the group consisting of unsubstituted, monosubstituted, di-substituted and tri-substituted saturated ring structures; R.sub.2 is a bond or is characterized by a backbone chain consisting of from 1 to 5 atoms; R.sub.3 is a bond or is characterized by a backbone chain consisting of from 1 to 3 atoms; R.sub.4 is any amino acid; R.sub.5 is any L-amino acid which comprises a guanidinium- or amino-containing side chain group; R.sub.6 is a non-amide bond; and Y is characterized by a backbone chain consisting of from 1 to 9 atoms; or the formula: ##STR2## wherein R'.sub.1 is selected from the group consisting of unsubstituted, mono-substituted, di-substituted and tri-substituted ring structures; R'.sub.4 is any amino acid comprising a side chain group characterized by the capacity to accept a hydrogen bond at a pH of between about 5.5 and 9.5; and X, R.sub.2, R.sub.3, R.sub.5, R.sub.6 and Y are defined as above. Preferred thrombin inhibitors are further characterized by a anion binding exosite associating domain (ABEAM) and a linker portion of between 18 .ANG. and 42 .ANG. in length which connects the Y to the ABEAM. This invention also relates to compositions, combinations and methods which employ these molecules for therapeutic, prophylactic and diagnostic purposes.

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Somerville, MA, United States of America

Paul R Bourdon