Biogen, Incorporated

Boston University

Health Research, Inc.

John M Maraganore

Joseph A Jakubowski

Toni Kline

Paul R Bourdon

John W Fenton, Ii

Jo-Ann M Jablonski

Betty H Chao

Kathryn L Strauch

Jeffrey S Thompson

This invention relates to novel biologically active molecules which bind to and inhibit thrombin. Specifically, these molecules are characterized by a thrombin anion-binding exosite association moiety (ABEAM); a linker portion of at least 18 .ANG. in length; and a thrombin catalytic site-directed moiety (CSDM). This invention also relates to compositions, combinations and methods which employ these molecules for therapeutic, prophylactic and diagnostic purposes.

Methods for coating invasive devices with inhibitors of thrombin

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.

This invention relates to novel, biologically active molecules which bind to and inhibit the thrombin receptor. These thrombin receptor antagonists are further characterized by their ability to inhibit thrombin-induced platelet aggregation and their inability to inhibit platelet aggregation induced by an internal peptide fragment of the platelet thrombin receptor. More specifically, the thrombin receptor antagonist of this invention comprises the formula: A.sub.1 -X-X-X-A.sub.2 -X-A.sub.3 -X-A.sub.4 -B-X-A.sub.5 -C-X-A.sub.6 ; wherein each of A.sub.1 and A.sub.6, either the same or different, are selected from the group consisting of a positively charged amino acid and an acyl or alkyl chain comprising from 1 to 10 backbone atoms and a positively charged side group; each of A.sub.2, A.sub.3, A.sub.4 and A.sub.5, is a positively charged amino acid, either the same or different; each X is any amino acid, either the same or different; B is an amino acid containing an aryl side chain; and C is a polar amino acid. This invention also relates to compositions and methods which employ these molecules for therapeutic and prophylactic purposes.

Thrombin receptor antagonists

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.

This invention relates to anticoagulant and platelet inhibitory compositions, combinations and methods characterized by biologically active peptides which display the anticoagulant and platelet inhibitory activities of hirudin, or analogs thereof, for therapeutic and prophylactic purposes. The methods, compositions and combinations of this invention are advantageously useful for decreasing or preventing platelet aggregation and platelet activation in a patient or a biological sample. These methods, compositions and combinations are particularly useful in patients for whom standard heparin therapy is contraindicated due to a history of heparin-induced thrombocytopenia or an antithrombin III deficiency. This invention also relates to methods, compositions and combinations for treating extracorporeal blood and for increasing platelet storage life.

Methods and compositions for inhibiting platelet aggregation

The present invention relates to novel, bifunctional inhibitors of both platelet activation and thrombin. These bifunctional inhibitors are characterized by two domains -- a glycoprotein IIb/IIIa inhibitory domain and a thrombin inhibitory domain. The invention also relates to DNA sequences which encode the bifunctional inhibitors of this invention, recombinant DNA molecules which contain these DNA sequences and host transformed with these DNA molecules. The invention further relates to he recombinant expression of the bifunctional inhibitors of this invention by transformed hosts as well as to methods for purifying such recombinant bifunctional inhibitors. This invention also provides compositions and methods employing the novel bifunctional inhibitors alone or together with a fibrinolytic agent. Such compositions may be useful in patients for treating thrombotic disease, increasing reocclusion time, decreasing reperfusion time, simultaneously inhibiting thrombin- and platelet-mediated functions and inhibiting malignant cell growth.

Bifunctional inhibitors of thrombin and platelet activation

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.

Method of inhibiting platelet activation

The present invention relates to polypeptide inhibitors of platelet activation and derivatives thereof, purified from the venom of the North American Water Moccasin and to methods for their purification. This invention also relates to DNA sequences and recombinant DNA molecules which code for these polypeptide inhibitors of platelet activation. And this invention relates to recombinant DNA molecules which code for fusion proteins comprising both a polypeptide inhibitor of platelet activation and an anti-thrombin polypeptide. This invention also relates to pharmaceutically acceptable compositions and methods characterized by at least one of these natural or recombinant inhibitors of platelet activation, alone or in combination with anti-thrombin compounds. The compositions, combinations and methods of this invention are particularly useful in the treatment of thrombotic diseases.

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Tewksbury, MA, United States of America

John M Maraganore