Inhibitors of CXCR2

Patent metadata

Field	Value
Publication number	US-11945805-B2
Application number	US-202117243872-A
Country	US
Kind code	B2
Filing date	Apr 29, 2021
Priority date	Nov 19, 2015
Publication date	Apr 2, 2024
Grant date	Apr 2, 2024

Abstract

Compounds are provided as inhibitors of CXCR2, having the structure:

First claim

What is claimed is:

1. A method of assaying a compound for CXCR2 antagonistic activity, said method comprising
(a) contacting the compound with cells expressing CXCR2 and a radioactive CXCR2 ligand to form a reaction mixture;
(b) transferring the reaction mixture onto a GF/B glass filter pre-soaked in a polyethyleneimine solution;
(c) measuring the amount radioactivity remaining on the GF/B glass filter, wherein said method comprises performing steps (a)-(c) with a positive control sample having a formula represented by the structure

or a pharmaceutically acceptable salt thereof, wherein
R 1 is selected from the group consisting of Cl and CH 3 ;
R 3b is selected from the group consisting of H and D;
R 4 is a member selected from the group consisting of H and C 1-8 alkyl, wherein the C 1-8 alkyl is optionally substituted with —CONR a R b , —OC(O)NR a R b , —NR a C(O)R b , —NR a C(O) 2 R c , —NR a R b , and —OR a , wherein each R a and R b is independently selected from hydrogen, C 1-4 alkyl, C 1-4 hydroxyalkyl and C 1-4 haloalkyl, and RC is selected from C 1-4 alkyl, C 1-4 hydroxyalkyl and C 1-4 haloalkyl;
R 5a and R 5b are each members independently selected from the group consisting of H, F, Cl and CH 3 ;
R 6a and R 6b are each members independently selected from the group consisting of H, C 1-4 alkyl, C 1-4 hydroxyalkyl and C 1-4 haloalkyl; or optionally R 6a and R 6b are taken together to form oxo (═O).

2. The method of claim 1 , wherein said cells expressing CXCR2 are HEK-293 cells or human neutrophils.

3. The method of claim 1 , wherein said radioactive CXCR2 ligand is CXCL8.

4. The method of claim 1 , wherein said reaction mixture comprises an assay buffer comprising 20 mM HEPES, 140 mM NaCl, 1 mM CaCl 2 ), and 5 mM MgCl 2 , wherein the assay buffer has a pH of 7.1.

5. The method of claim 1 , wherein R 3b is H; R 4 is H or CH 3 ; R 5a is H, F or Cl; R 5b is H, F, Cl; R 6a and R 6b are independently selected from the group consisting of H and CH 3 , or are taken together to form oxo (═O) for the positive control sample of Formula (Ia).

6. The method of claim 1 , wherein R 3b is D; R 4 is H or CH 3 ; R 5a is H, F or Cl; R 5b is H, F, Cl; R 6a and R 6b are independently selected from the group consisting of H and CH 3 , or are taken together to form oxo (═O) for the positive control sample of Formula (Ia).

7. The method of claim 1 , wherein the positive control sample is selected from the group consisting of

or a pharmaceutically acceptable salt thereof.

8. The method of claim 1 , wherein the positive control sample has the formula

9. The method of claim 1 , wherein the positive control sample has the formula

Assignees

• Chemocentryx Inc

Inventors

• Chen Xi
• Dragoli Dean R
• Fan Junfa
• Kalisiak Jaroslaw
• Leleti Manmohan Reddy
• Malathong Viengkham
• Mcmahon Jeffrey
• Tanaka Hiroko
• Yang Ju
• Yu Chao
• Zhang Penglie
• Mali Venkat

Classifications

• C07D405/12 Primary

  linked by a chain containing hetero atoms as chain links · CPC title

• A61K31/4035 Primary

  Isoindoles, e.g. phthalimide · CPC title

• A61K31/422

  not condensed and containing further heterocyclic rings · CPC title

• A61K31/4439

  containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole (nicotine A61K31/465) · CPC title

• A61K45/06

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