Liver targeted conjugates

Statins, which are HMGCoA reductase inhibitors, are widely prescribed for lowering plasma cholesterol. Statins accumulate in the liver, and this is due at least in part to the abundance of the statin target protein, HMGCoA reductase, in the liver.

Therapeutic conjugates containing a statin or a modified statin (collectively “statin”) linked to a therapeutic agent (also referred to as a drug herein) are disclosed. The therapeutic agent can be any therapeutic agent. In some cases the therapeutic agent is an anti-inflammatory agent (e.g., an NSAID) in other cases the therapeutic agent is a nucleic acid molecule. The conjugates are targeted to the liver by the statin or modified statin and thereby deliver the therapeutic agent to liver cells. Without being bound by any particular theory, it is thought that the statin portion of the conjugate is recognized by hepatocytes. This can allow increased local concentration of the conjugate in the liver. Thus, the conjugate can effectively reach various types of liver cells, including Kuppfer cells and vascular endothelial cells. Is some cases the conjugate is intracellularly processed, e.g., by enzymatic cleavage, to release the statin and the therapeutic agent which can act within the cell or diffuse to other cells. In some cases one or both of the therapeutic agent and the statin are active when conjugated, and in some cases one or both are active when the conjugate is enzymatically cleaved to release the therapeutic agent and the statin.

The therapeutic conjugates are bi-functional in that they provide both a statin, which allows the conjugate to be targeted to liver cells (and can inhibit HMGCoA reductase), and a second, therapeutic agent, for example, an anti-inflammatory agent. Because the statin or modified statin targets the conjugate to the liver, the second therapeutic agent can be administered at a lower dosage than would otherwise be efficacious. This allows administration of the second therapeutic agents at dosages that elicit fewer or less severe side-effects. Thus, under some circumstances, the therapeutic conjugates can be used to administer a therapeutic agent that was previously considered undesirable either generally or for treatment of particular conditions or disorders due to unacceptable toxicity in some or all patients.

In some cases, the therapeutic conjugate is processed in vivo, by an esterase, such that the therapeutic agent is released from the statin. In some cases the statin will have the ability to inhibit HMGCoA reductase before processing. In some cases the statin will not have the ability to inhibit HMGCoA reductase before processing, but will gain this ability upon processing. In some cases the statin will not have the ability to inhibit HMGCoA reductase before or after processing. In such cases the statin serves a targeting function, but not necessarily a therapeutic function.

Depending on the nature of the therapeutic agent linked to the statin, the conjugates are useful for treating liver disorders such as hepatocellular carcinoma, liver inflammation hepatitis (e.g., hepatitis A, B, C, D and E), and liver fibrosis. The conjugates are also useful for treating disorders in which liver inflammation or another liver dysfunction play a role, for example, diabetes.

The statin can be linked to the therapeutic agent through a linker, for example, a linker that is cleaved in a liver cell to release the statin and the therapeutic agent. The cleavage can occur at one or more bonds within the linker. The bonds between the statin and the second therapeutic agent, the statin and the linker (where a linker is present) and the therapeutic agent and the linker (where a linker is present) can be covalent. Suitable linkers include: an ester group, an amide group, a carbamate group, a carbonate group, a cycloketal group, a thioester group, a thioamide group, and a thiocarbamate group. In some cases the cleavage yields an unmodified therapeutic agent and a statin. In other cases one or both of the released therapeutic agent and the released statin are modified by the presence of additional atoms derived from the linker.

The statin can be, for example, simvastatin, fluvastatin, pravastatin, cerivastatin, lovastatin, or atorvastatin.

Suitable molecules include those having Formula I and Formula II, below:

wherein Z is a therapeutic agent;
R₃ and R₄ are independently selected from —CH₃, —OH, H, a halogen, —CH₂CH₃ and cyclopropyl;
R₁ and R₅ are independently selected from —CH₃ and H;
R₂ is selected from:

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