Pyrrolidine Compounds as Potential Lipid-Lowering Therapeutic in Cardiovascular Disease

Important Compound Classes

Title

Pyrrolidine Compounds

Patent Publication Number

WO 2020/247429 A1

Publication Date

December 10, 2020

Priority Application

EP 19382477.8

Priority Date

June 7, 2019

Inventors

Blanco, C. L.; Buezo, N. D.; Perez, J. A. M.; Gil, G. C. S.; Soler, J. P.

Assignee Company

Eli Lilly and Company [US/US]; Lilly Corporate Center, Indianapolis, Indiana 46206-6288, United States

Disease Area

Cardiovascular disease

Biological Target

Lipoprotein(a) [Lp(a)]

Summary

The treatment of cardiovascular disease (CVD) has seen significant advances; however, patients continue to experience CVD events such as stroke, angina, and myocardial infarction, which may lead to death if they remain untreated. Elevated blood pressure, which is not only limited to patients with overt hypertension but also to healthy individuals, represents one of the most important risk factors for CVDs. In addition, elevated blood pressure causes cumulative damage over time, and treatment at a later age is unable to diminish the cardiovascular risk.

Lipid disorder or dyslipidemia, which may lead to elevated lipoprotein(a) [Lp(a)], is strongly associated with an increase in CVD and remains a major risk factor. Lipid disorders can be divided into four general risk factors: elevated lipoprotein(a) [Lp(a)], elevated low-density lipoprotein cholesterol (LDL-c), low high-density lipoprotein cholesterol (HDL-c), and elevated triglycerides (TG). Low-density lipoprotein (LDL-c)-targeted therapies are the backbone of atherosclerotic cardiovascular risk reduction in many care populations. Statin therapy is now used broadly, and 56 million Americans ages 40–75 years are eligible to receive a statin; however, significant risk remains in patients who participate in clinical trials as more events occur with patients on statin therapy than events prevented by statin.

It is estimated that there are over 1.4 billion people worldwide with plasma Lp(a) levels over 50 mg dL-1 with at least 5 million patients worldwide with elevated Lp(a).

There is renewed interest in the importance of Lp(a) as a causal risk factor for atherosclerotic cardiovascular disease (ASCVD) due to new genetic studies and the availability of RNA-based therapies that lower the plasma concentrations of Lp(a) by more than 80%. Furthermore, there is an intensive development of new and effective Lp(a) treatments based on antisense oligonucleotides (ASOs) and small-interfering RNAs (siRNAs). In spite of these advances, the underlying mechanisms of CVD are still far from being clarified.

There are a variety of treatment regimens targeting elevated LDL-c, low HDL-c, and elevated triglycerides. However, there are few approved treatment options for patients with elevated Lp(a). Though apheresis may be used to filter the blood to remove LDL and Lp(a), its effect remains temporal and may require repeated treatment every 2 weeks.

There is a need for pharmaceutical treatment for patients with elevated Lp(a). The current standard of care therapies include diet, exercise, and/or the use of one or more drugs such as statins, fibrates, and niacin. This Patent Highlight presents an invention that may offer another treatment option for patients suffering from CVD. The exemplary compounds are efficacious at reducing plasma Lp(a) levels in vivo and support the proposition that they can be used to reduce the Lp(a) plasma concentrations.

Definitions

L = selected from the group consisting of -CH₂NHCH₂-, -CH₂NH-, -NH-, -OCH₂-, -S-, -S(O)-, -S(O)₂-, -NHSO₂NH- and -OCH₂CH₂O-;

R¹, R², R³, and R⁴ are each independently selected from the group consisting of H and CH₃ or a pharmaceutically acceptable salt thereof.

Key Structures

Biological Assay

In vitro Apo(a) binding assay and Lp(a) assembly assay. The ability of compounds to reduce the steady-state Lp(a) level in vivo was assessed in a transgenic mouse model capable of producing humanized Lp(a) particles.

Biological Data

The Table below indicates the ability of the compounds to inhibit the assembly of Lp(a) from Apo(a) and the LDL particle.

Recent Review Articles

• 1.Wernly B.; Zhou Z.. Am. J. Physiol. 2020, 319, H723.
• 2.Mourikis P.; Zako Saif; Dannenberg L.; Nia A. M.; Heinen Y.; Busch L.; Richter H.. et al. Pharncol. Ther. 2020, 213, 107592.
• 3.Vuorio A.; Watts G. F.; Schneider W. J.; Tsimikas S.; Kovanen P. T.. J. Int. Med. 2020, 287, 2.
• 4.Lippi G.; Favaloro E. J.; Sanchis-Gomar F. E.. J. Int. Med. 2020, 76, 8.
• 5.Youssef A.; Clark J. R.; Koschinsky M.; Marlys L.; Boffa M. B.. Trends. Cardiovasc. Med. 2020, 10.1016/j.tcm.2020.06.001.
• 6.Doerfler A. M.; Walkey C. J.; Lagor W. R.. Curr. Opin. Cardiol. 2020, 35, 242.

The author declares no competing financial interest.