# US 10,865,185 B2 · Composition and methods of use of tetrahydroisoquinoline small molecules to bind and modulate PCSK9 protein activity

> Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt

- Number: US 10,865,185 B2
- Document ID: US10865185B2
- Status: Granted
- Kind: B2
- Application number: 15/753,725
- Filed: 2016-08-19
- Published: 2020-07-02
- Granted: 2020-12-15
- Earliest claimed: 2015-08-21
- Assignees: SRX Cardio, LLC
- Applicants: SRX Cardio, LLC
- Inventors: Thomas E. Barta; Jonathan William Bourne; Kyle D. Monroe; Michael M. Muehlemann; Anjali Pandey; Simeon Bowers
- Web page: https://patentgrep.com/patent/US10865185B2

## CPC

- C07D 217/24: Oxygen atoms
- A61P 3/06: Antihyperlipidemics
- C07D 217/02: with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)

## Abstract

This invention is related to the field of PCSK9 biology and the composition and methods of use of small organic compounds as ligands for modulation of PCSK9 biological activity. In particular, the invention provides compositions of small organic compounds that modulate circulating levels of low density lipoproteins by altering the conformation of the protein PCSK9. Binding these small organic compound ligands to PCSK9 alters the conformation of the protein, modifying the interaction between PCSK9 and an endogenous low density lipoprotein receptor, and can lead to reduced or increased levels of circulating LDL-cholesterol. High LDL-cholesterol levels are associated with increased risk for heart disease. Low LDL-cholesterol levels may be problematic in other conditions, such as liver dysfunction; thus, there is also utility for small organic compound ligands that can raise LDL levels.

## Claims

### Claim 1

A method for treating hypercholesterolemia or for reducing LDL levels in a mammal in need thereof by administering a compound of Formula I:
wherein
i) R1 and R2 are independently selected from the group consisting of H, lower alkyl, halogen, haloalkyl, hydroxylalkyl, alkoxyl, and nitrile;
ii) R3 and R4 are independently selected from the group consisting of absent, lower alkyl, halogen, —OH, and amino;
iii) X1 through X5 are independently CH;
iv) Ring B is a phenyl or a saturated ring, if Ring B is a saturated ring then W is CH, and if Ring B is phenyl then W is C;
or a pharmaceutically acceptable salt, hydrate, or solvate thereof.

### Claim 2 (depends on 1)

The method of claim 1, wherein the compound of Formula I is formulated as a pharmaceutical composition comprising the compound of Formula I and a pharmaceutically acceptable carrier or excipient.

### Claim 3 (depends on 2)

The method of claim 2, wherein said pharmaceutical composition further comprises a second pharmaceutical drug compound.

### Claim 4 (depends on 3)

The method of claim 3, wherein said second pharmaceutical drug compound is selected from the group consisting of a statin, a cardiovascular drug, a metabolic drug, and an antihypertensive drug.

### Claim 5 (depends on 1)

The method of claim 1, wherein the method is for reducing LDL levels.

### Claim 6 (depends on 1)

The method of claim 1, wherein the method is for treating hypercholesterolemia.

### Claim 7 (depends on 1)

The method of claim 1, wherein the compound modulates PCSK9 protein activity.

### Claim 8

A method for treating hypercholesterolemia or for reducing LDL levels in a mammal in need thereof by administering a compound selected from
7-phenyl-1,2,3,4-tetrahydroisoquinoline;
3-(1,2,3,4-tetrahydroisoquinolin-7-yl)phenol;
6-methyl-7-phenyl-1,2,3,4-tetrahydroisoquinoline;
(7R,8aR)-7-phenyldecahydroisoquinoline;
6-ethyl-7-phenyl-1,2,3,4-tetrahydroisoquinoline;
7-(2-fluorophenyl)-6-methyl-1,2,3,4-tetrahydroisoquinoline;
7-(2-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline;
3-(6-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)phenol;
6-bromo-7-phenyl-1,2,3,4-tetrahydroisoquinoline;
5-methyl-7-phenyl-1,2,3,4-tetrahydroisoquinoline;
4-fluoro-3-(6-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)phenol;
7-phenyl-1,2,3,4-tetrahydroisoquinoline-6-carbonitrile;
7-(3-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline;
7-(m-tolyl)-1,2,3,4-tetrahydroisoquinoline;
7-(2,3-difluorophenyl)-1,2,3,4-tetrahydroisoquinoline;
5-chloro-7-phenyl-1,2,3,4-tetrahydroisoquinoline;
7-phenyl-6-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline; and
6-methoxy-7-phenyl-1,2,3,4-tetrahydroisoquinoline;
or a pharmaceutically acceptable salt thereof.