Modulators of coagulation factors with enhanced stability

Assignee: Regado Biosciences, Inc.

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Quick Facts

Patent No.: US 7,531,524
App. No.: 11/546,190
Granted: May 12, 2009
Kind: B2

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Abstract

The invention provides improved nucleic acid ligands with enhanced stability that inhibit coagulation and improved modulators of the nucleic acids to provide ideal modulators of coagulation. These improved nucleic acids and modulators are particularly useful for inhibiting coagulation in a host undergoing a therapeutic regime such as surgery or coronary artery bypass.

Claims (87)

1. A composition comprising a nucleic acid sequence of one of SEQ ID NOs. 19, 39, and 55-59 linked to a polyethylene glycol molecule at a 5′ terminus via a linker moiety, or a pharmaceutically acceptable salt thereof.

2. The composition of claim 1 of the formula:

wherein ligand is selected from one of SEQ ID NO. 19, 39, or 55-59 or a pharmaceutically acceptable salt thereof.

3. The composition of claim 1 wherein the composition is produced by conjugating a linker precursor to a nucleic acid molecule to form a nucleic acid linker-composition and further, conjugating a polyethylene glycol precursor moiety to the linker of the nucleic acid-linker composition.

4. The composition of claim 3 in which the linker precursor is selected from the group consisting of:

6-(trifluoroacetamido)hexanol (2-cyanoethyl-N,N-diisopropyl)phosphoramidite of the structure:

TFA-amino C4 CED phosphoramidite of the structure:

5′-amino modifier C3 TFA of the structure:

5′-amino modifier 5 of the structure:

5′-amino modifier C12 of the structure:

and 5′thiol-modifier C6 of the structure:

5. The composition of claim 3 wherein the polyethylene glycol precursor is selected from:

6. The composition of claim 1 wherein the polyethylene glycol has a total mass of about 40 kD.

7. The composition of claim 1 wherein the composition comprises two polyethylene glycol moieties.

8. The composition of claim 7 wherein each moiety has a total mass of about 20 kD.

9. The composition of claim 1 wherein the nucleic acid comprises SEQ ID NO: 19.

10. The composition of claim 1 wherein the nucleic acid comprises SEQ ID NO: 39.

11. The composition of claim 1 comprising the structure:

5′-O-[6-[N 2 -(monomethoxy 20K polyethylene glycol carbamoyl)-N 6 -(monomethoxy 20K polyethylene glycol carbamoyl)]-lysylamido]hexyl]-2′-methoxy-2′-deoxguanylyl-(3′-5′)-2′-methoxy-2′-deoxyuridylyl-(3′-5′)-2′-methoxy-2′-deoxyguanylyl-(3′-5′)-2′-methoxy-2′-deoxyguanylyl-(3′-5′)-2′-methoxy-2′-deoxyadenylyl-(3′-5′)-2′-fluoro-2′-deoxycytidylyl-(3′-5′)-2′-fluoro-2′-deoxyuridylyl-(3′-5′)-2′-methoxy-2′-deoxyadenylyl-(3′-5′)-2′-fluoro-2′-deoxyuridylyl-(3′-5′)-2′-methoxy-2′-deoxyadenylyl-(3′-5′)-2′-fluoro-2′-deoxycytidylyl-(3′-5′)-2′-fluoro-2′-deoxcytidylyl-(3′-5′)-2′-methoxy-2′-deoxyguanylyl-(3′-5′)-2′-fluoro-2′-deoxycytidylyl-(3′-5′)-2′-methoxy-2′-deoxyguanylyl-(3′-5′)-2′-fluoro-2′-deoxyuridylyl-(3′-5′)-2′-methoxy-2′-deoxyadenylyl-(3′-5′)-2′-methoxy-2′-deoxyadenylyl-(3′-5′)-2′-fluoro-2′-deoxyuridylyl-(3′-5′)-2′-methoxy-2′-deoxyguanylyl-(3′-5′)-2′-fluoro-2′-deoxycytidylyl-(3′-5′)-2′-methoxy-2′-deoxyuridylyl-(3′-5′)-riboguanylyl-(3′-5′)-2′-methoxy-2′-deoxycytidylyl-(3′-5′)-2′-fluoro-2′-deoxycytidylyl-(3′-5′)-2′-fluoro-2′-deoxyuridylyl-(3′-5′)-2′-methoxy-2′-deoxcytidylyl-(3′-5′)-2′-methoxy-2′-deoxytidylyl-(3′-5′)-2′-methoxy-2′-deoxyadenylyl-(3′-5′)-2′-methoxy-2′-deoxcytidylyl-(3′-3′)-thymidine.

12. The composition of claim 1 of the formula: