EP-3911640-B1 - PCSK9 INHIBITORS FOR USE IN THERAPY, ESPECIALLY THE TREATMENT OF CARDIOVASCULAR DISEASE

Inventors

• SERRANO-WU, MICHAEL, H.
• HUBBARD, BRIAN, K.
• KAUSHIK, Virendar
• DANIELS, Doug

Dates

Publication Date

20260513

Application Date

20200116

Claims (4)

1. A pharmaceutical composition comprising an inhibitor of PCSK9 and a pharmaceutically acceptable excipient for use in therapy, wherein the inhibitor of PCSK9 binds to a binding pocket defined by amino acid residues Val589 and Ser636 of human PCSK9, and wherein the inhibitor is a compound of formula (I): wherein: A is selected from halo, hydroxy, alkyl, thioalkyl, alkenyl, alkoxy, acyloxy, cyano, cycloalkyl, -C(O)OR 6 , and -C(O)NR 6 R 7 ; B is selected from H, alkyl, and halo, or A and B are taken together with the carbon atoms to which they are attached to form a 5- or 6-membered heteroaryl; X is NR 5 ; R 1 and R 1' are each independently selected from H and alkyl; or R 1 and R 1' , together with the atoms to which they are attached, form a 4-8 membered cycloalkyl or cycloalkenyl ring; R 2 is selected from H, halo, alkyl, alkoxy, amidoalkyl, aminoalkyl, hydroxyalkyl, alkylamino, cyano, and hydroxy; or R 1 and R 2 , together with the atoms to which they are attached, form a 3-8 membered cycloalkyl or heterocyclyl ring; or R 1' and R 2 , together with the atoms to which they are attached, form a 3-8 membered cycloalkyl or heterocyclyl ring; R 2' is selected from H, halo, alkyl, alkoxy, amidoalkyl, aminoalkyl, and cyano, or R 2 and R 2' , taken together with the carbon atom to which they are attached, form a 3-to 8-membered cycloalkyl or heterocyclyl ring; and R 5 is H; each R 6 and R 7 is independently H or alkyl; Y is selected from aryl, heteroaryl and heterocyclyl; and n is 0.
2. A pharmaceutical composition comprising an inhibitor of PCSK9 and a pharmaceutically acceptable excipient for use in the treatment or prevention of a cardiovascular disease, wherein the inhibitor of PCSK9 binds to a binding pocket defined by amino acid residues Val589 and Ser636 of human PCSK9, and wherein the inhibitor is a compound of formula (I): wherein: A is selected from halo, hydroxy, alkyl, thioalkyl, alkenyl, alkoxy, acyloxy, cyano, cycloalkyl, -C(O)OR 6 , and -C(O)NR 6 R 7 ; B is selected from H, alkyl, and halo, or A and B are taken together with the carbon atoms to which they are attached to form a 5- or 6-membered heteroaryl; X is NR 5 ; R 1 and R 1' are each independently selected from H and alkyl; or R 1 and R 1' , together with the atoms to which they are attached, form a 4-8 membered cycloalkyl or cycloalkenyl ring; R 2 is selected from H, halo, alkyl, alkoxy, amidoalkyl, aminoalkyl, hydroxyalkyl, alkylamino, cyano, and hydroxy; or R 1 and R 2 , together with the atoms to which they are attached, form a 3-8 membered cycloalkyl or heterocyclyl ring; or R 1' and R 2 , together with the atoms to which they are attached, form a 3-8 membered cycloalkyl or heterocyclyl ring; R 2' is selected from H, halo, alkyl, alkoxy, amidoalkyl, aminoalkyl, and cyano, or R 2 and R 2' , taken together with the carbon atom to which they are attached, form a 3-to 8-membered cycloalkyl or heterocyclyl ring; and R 5 is H; each R 6 and R 7 is independently H or alkyl; Y is selected from aryl, heteroaryl and heterocyclyl; and n is 0.
3. The composition for use of claim 1 or 2, wherein the inhibitor is selected from
4. An in vitro or ex vivo method of inhibiting PCSK9, comprising contacting PCSK9 with a PCSK9 inhibitor as defined in any one of claims 1 to 3.

Description

BACKGROUND PCSK9, also referred to as "proprotein convertase subtilisin/kexin 9", is a member of the secretory proprotein convertase family and plays an important role in cholesterol metabolism. PCSK9 increases the levels of circulating LDL cholesterol via the enhanced degradation of the LDL receptors independently of its catalytic activity. Secreted PCSK9 binds to the Epidermal Growth Factor domain A (EGFA) of the LDL receptor (LDLR) at the cell surface and the PCSK9/LDL receptor complex is internalized into endosomal/lysosomal compartments. The enhanced binding affinity of PCSK9 to the LDL receptor at the acidic pH of late endosomes/lysosomes reduces LDL receptor recycling and instead targets LDL receptors for lysosomal degradation. Genetic association studies have demonstrated that loss-of-function mutations in PCSK9 are associated with low plasma LDL-C levels and a reduction in the incidence of adverse cardiovascular events. Another biological pathway involving the effect of PCSK9 on LDL receptors is the onset of septic shock. Septic shock is an often fatal complication of a severe microbial infection (sepsis) that triggers an uncontrolled systemic inflammatory response and subsequent organ failure. Sepsis originates with the microbial cell walls that contain pathogenic lipid moieties such as lipopolysaccharide (LPS; Gram-negative bacteria). LPS are potent ligands for mammalian innate immune receptors [Toll-like receptors (TLRs)] and thus figure prominently in the septic inflammatory response (septic shock, or sepsis). PCSK9 reduces LPS uptake by the liver's LDL receptors, such that free LPS overstimulates the body's immune response to the pathogen leading to sepsis. Thus, inhibiting PCSK9 is beneficial in retaining liver LDL receptors to effect systemic pathogen clearance and detoxification in response to sepsis. However, beyond antibiotic therapy, there are currently no effective treatments for sepsis or septic shock. For cardiovascular disease, few options exist for inhibiting PCSK9. Statins actually upregulate PCSK9 in HepG2 cells and in human primary hepatocytes through the increased expression of SREBP-2, a transcription factor that upregulates both the LDLR and PCSK9 genes. Since an elevated level of PCSK9 decreases the abundance of LDL receptor on the cell surface, increasing doses of statins have failed to achieve proportional LDL-cholesterol lowering effects. Two monoclonal antibodies (mAbs) that bind selectively to extracellular PCSK9 and prevent its interaction with the LDL receptor, alirocumab and evolocumab, have recently received FDA approval for lowering LDL-C levels. In clinical trials, alirocumab showed an about 50% decrease in LDL levels compared to placebo. Elbitar et al., Expert Opin Therapeutic Patents 2016 26:1377-1392. Patients taking evolocumab showed an about 60-75% decrease in LDL levels. The potency of these drugs demonstrates the potential for inhibitors of PCSK9 to be effective treatments for those with hypercholesterolemia and other cardiovascular diseases. However, both antibody drugs require intravenous administration and can cause allergic reactions or other deleterious immune responses in the body. Designing and developing efficacious drugs is often aided by information about how a compound interacts with its biological target, such as PCSK9. Cunningham et al. have described the three-dimensional crystal structure of PCSK9 and identified different regions, such as the C-terminal domain which is more flexible than other sections of the protein. (Cunningham et al. Nature Struct. Bio. 2007 14:413-419). Thus, interest in inhibitors of PCSK9 has been focused on how various small molecules can interact with the surface or pockets in PCSK9. WO 2005/123686 A1 describes chemical compounds which bind and activate lecithin: cholesterol acyltransferase (LCAT), and which can be used for treating hypercholesterolemia and associated cardiovascular diseases. WO 2009/055783 A2 describes compositions and methods for treating disorders of cholesterol homeostasis and lipid metabolism by administration of an anti-PCSK9 antibody or a peptide inhibitor of PCSK9. WO 2006/126081 describes a class of pyridine pyrazinone compounds, and pharmaceutical compositions comprising said compounds, which inhibit the enzyme cyclic guanylate monophosphate-specific phosphodiesterase type 5 (PDE-5), and can be used to treat hypertension and related diseases. WO 2013/137371 describes organopolysiloxanes which can be used to treat high cholesterol and related conditions. WO 2018/165718 discusses pyrimidine-based heterocyclic compounds which are suggested to be suitable for treating cardiovascular disease. Cardiovascular diseases often require management over a person's lifetime, unlike an infection that could be episodic. Thus, ease of dosing and administration become key factors to patient compliance with maintenance drug treatments. There is a need for PCSK9 inhibitors with increased efficacy and greater eas