Anti-proprotein convertase subtilisin kexin type 9 (anti-PCSK9) nano-formulation of compounds and methods of using the same
Disclosed are Nanoformulated compounds that modulate the physiological action of the proprotein convertase subtilisin kexin type 9 (PCSK9), as well as therapeutic methods for use of such compounds to reduce LDL- and related cholesterol levels and/or for the treatment and/or prevention of cardiovascular disease (CVD), including treatment of hypercholesterolemia.
1. A nanoparticle comprising at least one PCSK9 antagonist encapsulated within the nanoparticle, wherein said PCSK9 antagonist is a compound of Formula (I):
including pharmaceutically acceptable salts and stereoisomers of said compound,
wherein R 1 is H or CH 3 ; R 2 and R 3 are independently selected from the group consisting of H, halogen, (C 1 -C 3 )-alkyl and (C 1 -C 3 )-alkoxy; and R 4 is selected from the group consisting of CO 2 R 5 , CONR 5 R 6 , aryl, and heteroaryl, wherein R 5 and R 6 are independently selected from the group consisting of H and (C 1 -C 3 )-alkyl, wherein said aryl and heteroaryl are independently substituted or unsubstituted,
wherein said nanoparticle comprises polyvinyl pyrrolidone (PVP) and hydroxypropyl methylcellulose acetate succinate (HPMC-AS), and
wherein said nanoparticle comprises a liver targeting moiety on the exterior of the nanoparticle.
2. The nanoparticle of claim 1 , wherein R 4 is an aryl or heteroaryl.
3. The nanoparticle of claim 2 , wherein R 4 is selected from the group consisting of 2-oxazole, 2-oxazoline, 2-benzoxazole and 2-benzimidazole.
4. The nanoparticle of claim 1 , wherein said PCSK9 antagonist is a compound of Formula (II):
including pharmaceutically acceptable salts and stereoisomers of said compounds,
wherein R 1 is H or CH 3 ; R 2 is H or methoxy; R 3 is H or halogen; and R 7 is independently selected from the group consisting of H and (C 1 -C 2 )-alkyl or R 7 are taken together to form an optionally substituted 6-membered carbocycle.
5. The nanoparticle of claim 4 , wherein when R 1 is H, then R 2 is H, and when R 1 is methyl then R 2 is methoxy.
6. The nanoparticle of claim 4 , wherein R 7 are taken together to form an aryl.
7. The nanoparticle of claim 1 , wherein said halogen is fluorine.
8. The nanoparticle of claim 1 , wherein said PCSK9 antagonist is selected from the group consisting of
9. The nanoparticle of claim 1 , wherein said PCSK9 antagonist is
10. The nanoparticle of claim 1 , wherein said nanoparticles are hydrophobic.
11. The nanoparticle of claim 1 , wherein said liver targeting moiety is selected from the group consisting of glycyrrhetinic acid (GA), lactobionic acid (LA), alginic acid and combinations thereof.
12. The nanoparticle of claim 1 , wherein said nanoparticle further encapsulates at least one other LDL-lowering substance.
13. The nanoparticle of claim 12 , wherein said LDL-lowering substance is an anti-dyslipidemia agent.
14. The nanoparticle of claim 13 , wherein said anti-dyslipidemia agent is a statin, ezetimibe, bempedoic acid, a thyroid hormone receptor beta agonist, or a combination thereof.
15. A composition comprising a nanoparticle of claim 1 and a physiologically compatible carrier medium.
16. A method for delivering a PCSK9 antagonist to the liver of a subject, said method comprising administering at least one nanoparticle claim 1 to said subject.
17. The method of claim 16 , wherein said subject is human.
18. The methods of claim 16 , wherein said nanoparticle is administered to said subject in a composition further comprising a physiologically compatible carrier medium.
19. A method for lowering low-density lipoprotein cholesterol (LDL-C), in a subject, said method comprising administering at least one nanoparticle of claim 1 to said subject.
20. The method of claim 19 , wherein said subject is human.
21. The methods of claim 19 , wherein said nanoparticle is administered to said subject in a composition further comprising a physiologically compatible carrier medium.
22. The method of claim 19 , wherein said subject has hypercholesterolemia.
23. A method for treating hypercholesterolemia, in a patient in need of said treatment, the method comprising administering to said patient a therapeutically effective amount of at least one nanoparticle of claim 1 .
24. The methods of claim 23 , wherein said nanoparticle is administered to said subject in a composition further comprising a physiologically compatible carrier medium.
25. The method of claim 16 , further comprising the administration of at least one other LDL-lowering substance.
26. The method of claim 25 , wherein said LDL-lowering substance is an anti-dyslipidemia agent.
27. The method of claim 26 , wherein said anti-dyslipidemia agent is a statin, ezetimibe, bempedoic acid, a thyroid hormone receptor beta agonist, or a combination thereof.
28. A compound selected from the group consisting of
29. The compound of claim 28 which is
30. The compound of claim 28 which is