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Details for Patent: 5,425,936

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Details for Patent: 5,425,936

Title: Inhibitors of thrombin
Abstract: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.
Inventor(s): Maraganore; John M. (Tewksbury, MA), Jablonski; Jo-Ann M. (Middleborough, MA), Bourdon; Paul R. (Somerville, MA)
Assignee: Biogen, Inc. (Cambridge, MA)
Filing Date:Jul 31, 1992
Application Number:07/924,549
Claims:1. A catalytic site-directed thrombin inhibitor characterized by the formula: ##STR10## wherein X is HN; R.sub.1 is cyclohexyl; R.sub.2 is CH.sub.2 --CH; R.sub.3 is C.dbd.O; R.sub.4 is Pro or any amino acid comprising a side chain group characterized by the capacity to accept a hydrogen bond at a pH of between 5.5 and 9.5; 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 that retards or prevents the cleavage of said inhibitor by thrombin; and Y is selected from the group consisting of sarcosine, N-methyl alanine, hydroxyproline and any naturally occurring L-.alpha.-amino acid; and the amino acid defined by components X, R.sub.1, R.sub.2 and R.sub.3 is in the D configuration.

2. The thrombin inhibitor according to claim 1, having the amino acid sequence:

3. The thrombin inhibitor according to claim 1, wherein R.sup.4 is selected from the group consisting of histidine, thioproline and isonipecotic acid.

4. The thrombin inhibitor according to claim 1, wherein said inhibitor is labelled with a radioisotope.

5. A composition for imaging of a fibrin or a platelet thrombus in a patient, said composition comprising a pharmaceutically acceptable buffer and a thrombin inhibitor according to claim 4.

6. A method for imaging of a fibrin or a platelet thrombus in a patient comprising the steps of:

(a) administering to said patient a composition according to claim 5; and

(b) using ex vivo detecting means to observe the thrombin inhibitor present in said composition.

7. The method according to claim 6, wherein said patient is a human.

8. The thrombin inhibitor according to claim 4, wherein said radioisotope is selected from the group consisting of .sup.123 I, .sup.125 I and .sup.111 In.
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