Three-dimensional cavities of dendritic cell immunoreceptor (DCIR), compounds binding thereto and therapeutic applications related to inhibition of human immunodeficiency virus type-1 (HIV-1)

Patent metadata

Field	Value
Publication number	US-9731001-B2
Application number	US-201214367741-A
Country	US
Kind code	B2
Filing date	Dec 20, 2012
Priority date	Dec 22, 2011
Publication date	Aug 15, 2017
Grant date	Aug 15, 2017

Abstract

The invention is concerned with compounds, pharmaceutical compositions, screening methods, and therapeutic methods for preventing or reducing a human immunodeficiency virus type-1 (HIV-1) infection and/or propagation associated with dendritic cell immunoreceptor (DCIR). Described herein are compounds which bind on at least one three-dimensional cavity of the DCIR, the cavity(ies) being involved in the interaction between HIV-1 and DCIR. Also described are screening methods for identifying active inhibitors and method of using such inhibitors for the prevention or treatment of virus infections, and more particularly for reducing human immunodeficiency virus type-1 (HIV-1) binding, entry and/or replication in human cells.

First claim

The invention claimed is:

1. A method of reducing a human immunodeficiency virus type-1 (HIV-1) infection and/or HIV-1 propagation in a subject, comprising: administering to said subject a therapeutically effective amount of a compound which binds with a dendritic cell immunoreceptor (DCIR) (SEQ ID NO: 1) on a first or on a second three-dimensional cavity, wherein:
the first three-dimensional cavity of DCIR comprises residues Phe113, Asn116, Tyr118, Val143, Ile144, Trp178 and Glu231; and
the second three-dimensional cavity of DCIR comprises residues Arg194, Glu195, Pro196, Ser197, Asp198, His175, Trp176 and Glu201;

and wherein said compound decreases human immunodeficiency virus type-1 (HIV-1) production and/or attachment in a dendritic cell or a CD4 + T cell.

2. The method of claim 1 , wherein said decrease is observed once said DCIR-expressing cell has been pre-treated or contacted with said compound.

3. The method of claim 1 , wherein said compound is a compound of Formula IB, or a pharmaceutically acceptable salt thereof:

wherein
Cy is aryl optionally substituted with a C1-C6 alkyl substituent, or heteroaryl;
X is NH or CH;
Y is C(O), or O—N═N; and
n is 0 or 1;

when n is 0 then A and B are both carbons fused to a phenyl group to create a 8-membered bicyclic ring; or
when n is 1 then A and B are each independently CH; or B is CH, CCH3 or CCH2CH3.

4. The method of claim 3 , wherein the compound is selected from the group consisting of B1, B2, B3, B4, B5, B6, and pharmaceutically acceptable salts thereof:

Cpd No.
Compound Structure

B1

B2

B3

B4

B5

B6

5. The method of claim 4 , wherein the compound is selected from the group consisting of B1, B2, B3, and pharmaceutically acceptable salts thereof.

6. A method of reducing a human immunodeficiency virus type-1 (HIV-1) infection and/or HIV-1 propagation in a subject, comprising administering to said subject a therapeutically effective amount of a compound of Formula IB, or a pharmaceutically acceptable salt thereof:

wherein
Cy is aryl optionally substituted with a C1-C6 alkyl substituent, or heteroaryl;
X is NH or CH;
Y is C(O), or O—N═N; and
n is 0 or 1;

when n is 0 then A and B are both carbons fused to a phenyl group to create a 8-membered bicyclic ring; or
when n is 1 then A and B are each independently CH; or B is CH, CCH3 or CCH2CH3.

7. The method of claim 6 , wherein said compound is selected from the group consisting of compounds B1, B2, B3, B4, B5 B6, and pharmaceutically acceptable salts thereof:

Cpd No.
Compound Structure

B1 

B2 

B3 

B4 

B5 

B6

Assignees

• Univ Laval

Inventors

• Gilbert Caroline
• Tremblay Michel J
• Lin Sheng-Xiang
• Azzi Arezki
• Lambert Alexandra

Classifications

• C07D405/06

  linked by a carbon chain containing only aliphatic carbon atoms · CPC title

• G16B35/00

  ICT specially adapted for in silico combinatorial libraries of nucleic acids, proteins or peptides · CPC title

• C07D215/58

  with hetero atoms directly attached to the ring nitrogen atom · CPC title

• A61K31/501

  not condensed and containing further heterocyclic rings · CPC title

• A61K31/12

  Ketones · CPC title