Treatment for osteoarthritis in a joint by administering a means for inhibiting MDM2

Patent metadata

Field	Value
Publication number	US-9993472-B2
Application number	US-201515114762-A
Country	US
Kind code	B2
Filing date	Jan 28, 2015
Priority date	Jan 28, 2014
Publication date	Jun 12, 2018
Grant date	Jun 12, 2018

Abstract

Methods are provided herein for selectively killing senescent cells and for treating senescence-associated diseases and disorders by administering a senolytic agent. Senescence-associated diseases and disorders treatable by the methods using the senolytic agents described herein include cardiovascular diseases and disorders associated with or caused by arteriosclerosis, such as atherosclerosis; idiopathic pulmonary fibrosis; chronic obstructive pulmonary disease; osteoarthritis; senescence-associated ophthalmic diseases and disorders; and senescence-associated dermatological diseases and disorders.

First claim

What is claimed is:

1. A method for treating an osteoarthritic joint in a subject, comprising administering to the joint a pharmaceutical composition that contains a senolytic agent and a pharmaceutically compatible excipient such that the senolytic agent contacts and eliminates senescent cells in or around the joint, thereby relieving symptoms of osteoarthritis in the joint,
wherein the senolytic agent is a means for inhibiting MDM2.

2. The method of claim 1 , wherein the means for inhibiting MDM2 is an imidazoline compound.

3. The method of claim 2 , wherein the imidazoline compound is 4-[[(4S,5R)-4,5-bis(4-chlorophenyl)-4,5-dihydro-2-[4-methoxy-2-(1-methylethoxy)phenyl]-1H-imidazol-1-yl]carbonyl]-2-piperazinone or a pharmaceutically acceptable salt thereof (Nutlin-3a).

4. The method of claim 1 , wherein the means for inhibiting MDM2 is selected from Nutlin-1, Nutlin-2, RG-7112, RG7388, DS-3032b, MI-63, MI-126, MI-122, MI-142, MI-147, MI-219, MI-220, MI-221, MI-773, 3-(4-chlorophenyl)-3-((1-(hydroxymethyl)cyclopropyl)methoxy)-2-(4-nitrobenzyl)isoindolin-1-one, Serdemetan, AM-8553, CGM097, RO-2443, RO-5963,
5-[(3 S)-3-(4-chlorophenyl)-4-[(R)-1-(4-chlorophenyl)ethyl]-2,5-dioxo-7-phenyl-1,4-diazepin-1-yl]valeric acid,
5-[(3 S)-7-(2-bromophenyl)-3-(4-chlorophenyl)-4-[(R)-1-(4-chlorophenyl)ethyl]-2,5-dioxo-1,4-diazepin-1-yl]valeric acid,
TDP521252, TDP665759, NSC279287, and pharmaceutically acceptable salts thereof.

5. The method of claim 1 , wherein the treating of the osteoarthritic joint includes administering to the joint
a therapeutically effective course of therapy that includes a period of treatment with the pharmaceutical composition, followed by a non-treatment interval of at least two weeks during which the pharmaceutical composition is not administered.

6. The method of claim 5 , wherein the non-treatment interval is at least two months.

7. The method of claim 5 , wherein the therapeutically effective course of therapy includes a single dose of the pharmaceutical composition followed by the non-treatment interval.

Assignees

• Buck Inst Res Aging
• Unity Biotechnology Inc
• Mayo Found Medical Education & Res
• Univ Johns Hopkins
• Univ Johns Hopkins

Inventors

• Laberge Remi-Martin
• Campisi Judith
• Davalos Albert
• Demaria Marco
• David Nathaniel
• Vasserot Alain Philippe
• Kirkland James L
• Tchkonia Tamar
• Van Deursen Jan M A
• Elisseeff Jennifer
• Kim Chaekyu
• Jeon Okhee
• Zhu Yi

Classifications

• A61P19/02

  for joint disorders, e.g. arthritis, arthrosis · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• A61K31/496 Primary

  Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin · CPC title

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61K31/428

  condensed with carbocyclic rings · CPC title