Agonists that enhance binding of integrin-expressing cells to integrin receptors

Patent metadata

Field	Value
Publication number	US-10287264-B2
Application number	US-201615334890-A
Country	US
Kind code	B2
Filing date	Oct 26, 2016
Priority date	Nov 16, 2010
Publication date	May 14, 2019
Grant date	May 14, 2019

Abstract

A method of enhancing binding of cells to an integrin-binding ligand comprises treating integrin-expressing cells in vitro with an agonist of integrin, wherein the integrin is selected from the group consisting of α4β1, α5β1, α4β7, αvβ3 and αLβ2, and contacting the treated cells with an integrin-binding ligand; integrin agonist compounds having the general formula I; methods of treating integrin-expressing cells with such agonists to enhance binding; and therapeutic methods comprising administering agonist-treated cells or agonist compounds to a mammal.

First claim

What is claimed is:

1. A chemical compound having the general formula (I)

wherein
R 1 is selected from the group consisting of aryl and aralkyl,
R 2 is C 1 -C 6 alkyl, aryl, or aralkyl,
M 1 is CH 2 ,
M 2 is CO,
M 3 is O, S, or NR 6 , wherein
R 6 when present is C 1 -C 6 alkyl,
M 4 is CH 2 ,
M 5 is (CHR 12 ),
R 12 is selected from the group consisting of NR 21 CONR 22 R 23 , NR 21 COR 24 , NR 21 SO 2 R 24 , and NR 21 COOR 24 ,

R 21 and R 22 , when present, are independently selected from the group consisting of hydrogen or C 1 -C 6 alkyl,
R 23 , when present, is selected from the group consisting of hydroxyalkyl, alkoxyalkyl, alkyl, aryl, aralkyl and alkoxycarbonylalkyl,
R 24 , when present, is selected from the group consisting of alkyl, aryl, aralkyl, heterocyclyl, cycloalkyl, cycloalkylalkyl, and heterocyclylalkyl,
M 6 is (CH 2 ) q , wherein q is an integer from 0 to 6,
R 3 is selected from the group consisting of hydrogen, CONR 13 R 14 , NR 15 COOR 16 , NR 15 COR 16 , NR 15 CO NR 13 R 14 , NR 15 SO 2 R 16 , OCOR 16 , COOR 16 , OR 16 , SR 16 , heterocyclyl, hydroxyl, hydroxyalkyl, guanadino, alkyl and aryl, wherein
R 13 and R 15 , when present, are independently hydrogen or C 1 -C 6 alkyl,
R 14 , when present, is independently selected from the group consisting of hydrogen, alkyl, aryl, aralkyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, and heterocyclylalkyl,
R 16 , when present, is independently selected from the group consisting of alkyl, aryl, aralkyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, and heterocyclylalkyl, and
R 1 , R 2 , R 3 , R 12 , R 14 , R 16 , R 23 and R 24 may independently be either unsubstituted or substituted.

2. A chemical compound of claim 1 , wherein:
R 1 is phenyl or thienyl,
R 2 is C 1 -C 6 alkyl, or —CH 2 -aryl,
M 1 is CH 2 ,
M 2 is CO,
M 3 is O, or NR 6 wherein R 6 is C 1 -C 6 alkyl,
M 4 is CH 2 ,
M 5 is (CHR 12 ),
R 12 is selected from the group consisting of NR 21 CONR 22 R 23 , NR 21 COR 24 , NR 21 SO 2 R 24 , NR 21 COOR 24 ,
R 21 and R 22 , when present, are independently selected from the group consisting of hydrogen, or C 1 -C 6 alkyl,
R 23 , when present, is selected from the group consisting of hydroxyalkyl, alkoxyalkyl, alkyl, aryl, aralkyl, and alkoxycarbonylalkyl,
R 24 , when present, is selected from the group consisting of alkyl, aryl, aralkyl, heterocyclyl, cycloalkyl, cycloalkylalkyl and heterocyclylalkyl,
M 6 is (CH 2 ) q , wherein q is an integer of 0 to 6,
R 3 is selected from the group consisting of hydrogen, CONR 13 R 14 , NR 15 COOR 16 , NR 15 COR 16 , NR 15 CO NR 13 R 14 , NR 15 SO 2 R 16 , OCOR 16 , COOR 16 , OR 16 , SR 16 , heterocyclyl, hydroxyl, hydroxyalkyl, guanadino, alkyl and aryl, wherein
R 13 and R 15 when present are independently hydrogen or C 1 -C 6 alkyl,
R 14 , when present, is selected from the group consisting of hydrogen, alkyl, aryl, aralkyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, and heterocyclylalkyl,
R 16 , when present, is selected from the group consisting of alkyl, aryl, aralkyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, and heterocyclylalkyl, and
R 1 , R 2 , R 3 , R 12 , R 14 , R 16 , R 23 and R 24 may independently be either unsubstituted or substituted.

3. A chemical compound of claim 1 , wherein:
R 1 is phenyl or thienyl,
R 2 is C 1 -C 6 alkyl, or —CH 2 -aryl,
M 1 is CH 2 ,
M 2 is CO,
M 3 is O, or S
M 4 is CH 2 ,
M 5 is (CHR 12 ),
R 12 is selected from the group consisting of NR 21 CONR 22 R 23 , NR 21 COR 24 , NR 21 COOR 24
R 21 and R 22 , when present, are independently selected from the group consisting of hydrogen, or C 1 -C 6 alkyl,
R 23 , when present, is selected from the group consisting of hydroxyalkyl, alkoxyalkyl, alkyl, aryl, aralkyl, and alkoxycarbonylalkyl,
R 24 , when present, is selected from the group consisting of alkyl, and heterocyclyl,
M 6 is (CH 2 ) q , wherein q is an integer of 0 to 6,
R 3 is selected from the group consisting of hydrogen, CONR 13 R 14 , NR 15 COOR 16 , NR 15 COR 16 , NR 15 CO NR 13 R 14 , NR 15 SO 2 R 16 , OCOR 16 , COOR 16 , OR 16 , SR 16 , heterocyclyl, hydroxyl, hydroxyalkyl, guanadino, alkyl and aryl, wherein
R 13 and R 15 when present are independently hydrogen or C 1 -C 6 alkyl,
R 14 , when present, is selected from the group consisting of hydrogen, alkyl, aryl, aralkyl, cycloalkyl, heterocyclyl, cycloalkyl alkyl, and heterocyclylalkyl,
R 16 , when present, is selected from the group consisting of alkyl, aryl, aralkyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, and heterocyclylalkyl, and
R 1 , R 2 , R 3 , R 12 , R 14 , R 16 , R 23 and R 24 when present may independently be either unsubstituted or substituted.

4. A chemical compound of claim 2 , wherein:
R 1 is phenyl or thienyl,
R 2 is C 1 -C 6 alkyl, or —CH 2 -aryl,
M 1 is CH 2 ,
M 2 is CO,
M 3 is O, or NR 6 wherein R 6 is C 1 -C 6 alkyl,
M 4 is CH 2 ,
M 5 is (CHR 12 ),
R 12 is selected from the group consisting of NR 21 CONR 22 R 23 , NR 21 COR 24 , NR 21 COOR 24 ,
R 21 and R 22 , when present, are independently selected from the group consisting of hydrogen, or C 1 -C 6 alkyl,
R 23 , when present, is selected from the group consisting of hydroxyalkyl, alkoxyalkyl, alkyl, aralkyl, and alkoxycarbonylalkyl,
R 24 , when present, is selected from the group consisting of alkyl, heterocyclyl,
M 6 is (CH 2 ) q , wherein q is an integer of 0 to 6,
R 3 is selected from the group consisting of hydrogen, NR 15 COOR 16 , alkyl, wherein
R 15 when present are independently hydrogen or C 1 -C 6 alkyl,
R 16 , when present, is selected from the group consisting of alkyl, aralkyl, and
R 1 , R 2 , R 3 , R 12 , R 14 , R 16 , R 23 and R 24 may independently be either unsubstituted or substituted.

5. A chemical compound of claim 1 , wherein R 1 , R 2 , R 3 , R 12 , R 14 , R 16 , R 23 and R 24 is further substituted with one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heterocyclylaryl, hydroxy, alkoxy, azido, haloalkoxy, hydroxyalkyl, aryloxy, hydroxyaryl, alkoxyaryl, halo, haloalkyl, haloaryl, amino, alkylamino, dialkylamino, arylamino, diarylamino, —NHCO(alkyl), —NHCO(aryl), —NHCO(aralkyl), —NHCO(haloalkyl), —NHSO 2 (alkyl), —NHSO 2 (aryl), —NHSO 2 (aralkyl), alkoxycarbonyl, alkoxycarbonylalkyl, —OCO(C 1 -C 6 alkylamino), and —OCO(dialkylamino).

6. A chemical compound of claim 2 , wherein R 1 , R 2 , R 3 , R 12 , R 14 , R 16 , R 23 and R 24 is further substituted with one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heterocyclylaryl, hydroxy, alkoxy, azido, haloalkoxy, hydroxyalkyl, aryloxy, hydroxyaryl, alkoxyaryl, halo, haloalkyl, haloaryl, amino, alkylamino, dialkylamino, arylamino, diarylamino, —NHCO(alkyl), —NHCO(aryl), —NHCO(aralkyl), —NHCO(haloalkyl), —NHSO 2 (alkyl), —NHSO 2 (aryl), —NHSO 2 (aralkyl), alkoxycarbonyl, alkoxycarbonylalkyl, —OCO(C 1 -C 6 alkylamino), and —OCO(dialkylamino).

7. A chemical compound of claim 3 , wherein R 1 , R 2 , R 3 , R 12 , R 14 , R 16 , R 23 and R 24 is further substituted with one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heterocyclylaryl, hydroxy, alkoxy, azido, haloalkoxy, hydroxyalkyl, aryloxy, hydroxyaryl, alkoxyaryl, halo, haloalkyl, haloaryl, amino, alkylamino, dialkylamino, arylamino, diarylamino, —NHCO(alkyl), —NHCO(aryl), —NHCO(aralkyl), —NHCO(haloalkyl), —NHSO 2 (a

Assignees

• Texas Heart Inst

Inventors

• Biediger Ronald J
• Gundlach Iv William C
• Market Robert V
• Savage Michael M
• Vanderslice Peter

Classifications

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• C07D317/60

  Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals · CPC title

• C07D333/24

  Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals · CPC title

• C07D333/20 Primary

  by nitrogen atoms (nitro, nitroso radicals C07D333/12) · CPC title

• C07C271/20

  to carbon atoms of hydrocarbon radicals substituted by nitrogen atoms not being part of nitro or nitroso groups · CPC title