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

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.

Claims8

Dependent claims

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.

3 more elements

Dependencies are inferred from the claim text.

Facts

Application

15/753,725Filed 19 Aug 2016 · us provisional application

Priority

21 Aug 2015

Published

US 2020/0207718 A12 Jul 2020

Granted

15 Dec 2020

Term ends

Not estimatedThe source records don’t support an estimate.

Classification7 codes

C07D 217/24
With hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals,…:…
A61P 3/06
Drugs for disorders of the metabolism: antihyperlipidemics
C07D 217/02
Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems: with only hydrogen atoms or radicals containing only…
A61K 45/06
Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00: mixtures of active ingredients without…

Composition and methods of use of tetrahydroisoquinoline small molecules to bind and modulate PCSK9 protein activity

Life of this patent

Composition and methods of use of tetrahydroisoquinoline small molecules to bind and modulate PCSK9 protein activity

Life of this patent

Abstract

Claims8