TCR/MHCII-collagen interaction inhibitors useful for the treatment of rheumatoid arthritis

Patent metadata

Field	Value
Publication number	US-9994524-B2
Application number	US-201715469411-A
Country	US
Kind code	B2
Filing date	Mar 24, 2017
Priority date	Mar 30, 2012
Publication date	Jun 12, 2018
Grant date	Jun 12, 2018

Abstract

The T cells specific to human collagen type II, one of the possible autoantigens, have a crucial role in the development of rheumatoid arthritis in the context of HLA-DR4. The protein-protein interactions between the T cell receptor (TCR) and the type II collagen linked to the allele MHC of class II HLA-DR4 may thus represent the target for the development of new drugs against rheumatoid arthritis. Using computational virtual screening techniques, families of pharmacologically active molecules have been identified that interfere with the TCR/collagen II-MHCII interaction. The compounds identified here open up new possibilities in the treatment of rheumatoid arthritis.

First claim

The invention claimed is:

1. A method for treating rheumatoid arthritis, comprising administering an inhibitor of interaction between T cells and a complex of MHC-II and human collagen type II or an antigenic fragment thereof to a patient who is HLA-DR4 positive, HLA-DR7 positive, or both HLA-DR4 positive and HLA-DR7 positive; wherein said inhibitor is comprised of compounds of formula (II):

wherein R and R 1 are independently selected from the group consisting of hydrogen, chlorine, bromine and iodine; R 2 is a substituent selected from the group consisting of hydroxyl, methyl, ethyl, n-propyl, and isopropyl; R 3 is N or CH; R 4 is N or CH; and said inhibitor is in the form of a racemic mixture of enantiomers or their salts.

2. The method according to claim 1 , wherein said compound is selected from the group consisting of:

(II)

 1.
R = —Cl

R 1 = —Cl

R 2 = —OH

 2.
R = —Br

R 1 = —Br

R 2 = —OH

 3.
R = —I

R 1 = —I

R 2 = —OH

 4.
R = —H

R 1 = —H

R 2 = —OH

 5.
R = —Cl

R 1 = —Cl

R 2 = —CH 3

 6.
R = —Br

R 1 = —Br

R 2 = —CH 3

 7.
R = —I

R 1 = —I

R 2 = —CH 3

Assignees

• Consiglio Nazionale Ricerche
• Univ Cattolica Del Sacro Cuore

Inventors

• De Rosa Maria Cristina
• Ria Francesco
• Giardina Bruno
• Ferraccioli Gianfranco
• Pirolli Davide
• Nicolo′ Chiara

Classifications

• A61K31/403

  condensed with carbocyclic rings, e.g. carbazole · CPC title

• A61K31/165

  having aromatic rings, e.g. colchicine, atenolol, progabide · CPC title

• C07D209/86 Primary

  with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the ring system · CPC title

• A61K31/343

  condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone · CPC title

• A61K31/40

  having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil · CPC title