Small Molecule Inhibitors of Toll-Like Receptor 9

a technology of toll-like receptor and inhibitor, which is applied in the field of small molecule inhibitors of toll-like receptor 9, can solve the problems of protective or adverse physiologic outcomes of the hos

Inactive Publication Date: 2010-06-24
LIPFORD GRAYSON B +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Stimulation of the immune system, which includes stimulation of either or both innate immunity and adaptive immunity, is a complex phenomenon that can result in either protective or adverse physiologic outcomes for the host.

Method used

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  • Small Molecule Inhibitors of Toll-Like Receptor 9
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  • Small Molecule Inhibitors of Toll-Like Receptor 9

Examples

Experimental program
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Effect test

example 1

Predicted Activities for Compounds of Formula III

[0342]Based on computer modeling, IC50 values (nM) were predicted in respect of TLR9 activity for compounds according to Formula III wherein R3, R7, and R8 are hydrogen, and R6 is Yi (Ar—Y2). Substitutions for R4 and Y2 were made as shown in Table 1 below. In this set of data the compound with the lowest predicted IC50, 33 nM, had R4=dipip and Y2=dippip.

TABLE 1Y2pipdiaminedipaminedimordipmordipipdippipR4pip83594964485061diamine150564745644849dipamine591207475864879dimor66584150384158dipmor100585242414340dipip69413657395033dippip90463943584337

example 2

Predicted Activities for Compounds of Formula III

[0343]Based on computer modeling, IC50 values (nM) were predicted in respect of TLR9 activity for compounds according to Formula III wherein R3, R6, and R8 are hydrogen, and R7 is Y1 (Ar—Y2). Substitutions for R4 and Y2 were made as shown in Table 2 below. In this set of data the compound with the lowest predicted IC50, 33 nM, had R4=diamine and Y2=dippip.

TABLE 2Y2pipdiaminedipaminedimordipmordipipdippipR4pip67777675738491diamine791207965877533dipamine6867170908165110dimor65798283686636dipmor64759087797790dipip69558678666573dippip75737563728485

example 3

Predicted Activities for Compounds of Formula III

[0344]Based on computer modeling, IC50 values (nM) were predicted in respect of TLR9 activity for compounds according to Formula III wherein R3, R6, and R7 are hydrogen, and R8 is Y1 (Ar—Y2). Substitutions for R4 and Y2 were made as shown in Table 3 below. In this set of data the compound with the lowest predicted IC50, 51 nM, had R4=dimor and Y2=dipip.

TABLE 3Y2pipdiaminedipaminedimordipmordipipdippipR4pip530460120330440410160diamine100987866888382dipamine96888278769172dimor100647392775180dipmor7970771201306966dipip947568777811076dippip65675579607172

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Abstract

Small molecule compounds and compositions containing said compounds useful for inhibiting signaling by certain Toll-like receptors (TLRs), particularly TLR9, are provided. The compounds and compositions can be used to inhibit immune responses, including unwanted immune responses in particular. Compounds, compositions, and methods are provided to treat a variety of conditions involving unwanted immune responses, including for example autoimmune disease, inflammation, transplant rejection, and sepsis.

Description

FIELD OF THE INVENTION[0001]The present invention relates generally to immunology. More particularly, the invention relates to small molecules capable of inhibiting an immune response, pharmaceutical compositions comprising the small molecule inhibitors, and methods of using the inhibitors.BACKGROUND OF THE INVENTION[0002]Stimulation of the immune system, which includes stimulation of either or both innate immunity and adaptive immunity, is a complex phenomenon that can result in either protective or adverse physiologic outcomes for the host. In recent years there has been increased interest in the mechanisms underlying innate immunity, which is believed to initiate and support adaptive immunity. This interest has been fueled in part by the recent discovery of a family of highly conserved pattern recognition receptor proteins known as Toll-like receptors (TLRs) believed to be involved in innate immunity as receptors for pathogen-associated molecular patterns (PAMPs). Compositions an...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/5377C07D413/14A61P37/00A61P37/06
CPCG06Q20/20G06Q40/00G06Q40/12G06Q40/025G06Q40/02A61P37/00A61P37/06G06Q40/03
Inventor LIPFORD, GRAYSON B.ZEPP, CHARLES M.NGUYEN, TOAN B.
Owner LIPFORD GRAYSON B
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