Screening methods for presqualene diphosphate analogs

Details Screening methods for presqualene diphosphate analogs Screening methods for presqualene diphosphate analogs

2000-03-31

2001-06-26

Gitomer, Ralph (Department: 1623)

Chemistry: molecular biology and microbiology

Measuring or testing process involving enzymes or...

Involving hydrolase

C435S025000

Reexamination Certificate

active

06251622

ABSTRACT:

BACKGROUND OF THE INVENTION
The environment contains a variety of infectious microbial agents, such as viruses, bacteria, fungi and parasites, any one of which can cause pathological damage to the host organism. Consequently, most organisms, such as mammals, i.e. humans, have developed an immune system. The immune system is divided into two functional divisions, the innate immune system and the adaptive immune system.
The innate and adaptive immune systems consists of a variety of molecules and cells distributed throughout the body. The most important cells are leukocytes. Leukocytes are categorized as phagocytes, including polymorphonuclear neutrophils (PMNs), monocytes and macrophages, and lymphocytes, which mediate adaptive immunity.
Inflammation is the body's response to invasion or an injury, such as an invasion by an infectious microbial agent and includes three broad actions. First, the blood supply is increased to the area. Second, capillary permeability is increased, thereby permitting larger molecules to reach the site of infection. Third, leukocytes, particularly PMNs, migrate out of the capillaries and into the surrounding tissue. Once in the tissue, the PMNs migrate to the site of infection or injury by chemotaxis. These events manifest themselves as inflammation. Examples of conditions which cause these reactions to occur include clamping or tourniquet vessel-induced ischemia reperfusion injury, chronic inflammatory conditions such as asthma, rheumatoid arthritis, and inflammatory bowel disease, as well as autoimmune diseases.
Aberrant activation of phagocytic cells, in particular neutrophils, leads to the generation of superoxide anion, which when released to the extracellular milieu can evoke damage to surrounding tissues. Reactive oxygen species derived from neutrophil oxygen burst can play a deleterious role in generating secondary products that lead to loss of function. During surgery, in particular clamping of vessels, there is clear evidence that reperfusion following the release of the clamp involves neutrophil-derived mediators. The neutrophil-derived oxygen radicals and other toxic products that are normally intended for killing of microbial agents once they spill over into the surrounding tissue can lead to second organ injury, most notably in the lung and cardiac tissues, sequelae which are observed following ischemia reperfusion injury (Welboum et al.,
Brit. J. Surg
. 1991; 78:651-655).
Once at the site of infection, PMNs perform phagocytic and degradative functions to combat the infectious agent. As part of the response to the infectious agent, PMNs generate superoxide anions, reactive oxygen species (ROS) to kill infested material and adhere to epithelial cells of mucosal surfaces or vascular endothelial cells of the blood vessels. As a consequence, the host can experience undesirable side effects during the elimination of the infectious agent such as, pain, swelling about the site, and nausea.
SUMMARY OF THE INVENTION
The present invention relates to novel presqualene diphosphate (PSDP) analogs and their use.
In one embodiment, the present invention is directed to a PSDP analog having an active region of natural PSDP and a metabolic transformation region resistant to in vivo metabolism. For example, the analog can inhibit leukocyte activation, leukocyte generation of active oxygen species, adhesion between a leukocyte cell and an epithelial cell or an endothelial cell or leukocyte generation of reactive oxygen species (ROS).
In another embodiment, the present invention is directed to a method for treating or preventing inflammation and/or an inflammatory response in the subject. The method includes administering to a subject an anti-inflammatory amount of a PSDP analog having an active region of natural PSDP and a metabolic transformation region resistant to in vivo metabolism.
In yet another embodiment, the present invention is directed to a compound represented by one of the formulae (Formulae I-IV):
R
1
, R
2
and R
3
are each independently, selected from the group consisting of hydrogen, F, Cl, Br, I, CH
3
and substituted or unsubstituted, linear or branched alkyl, alkoxy, aryl, aralkyl or heteroaryl groups. Y
1
, Y
2
, Y
3
, Y
4
, and Y
5
are each independently selected from hydrogen atoms or lower alkyl groups. X
1
is an oxygen atom, a sulfur atom, an N═N group, a methylene or, NR
5
, wherein R
5
is a hydrogen atom or a substituted or unsubstituted, linear or branched alkyl, aryl, aralkyl or heteroaryl group. X
2
is an OH group, SH, CH
3
, or NR
6
R
7
, wherein R
6
and R
7
are each independently, a hydrogen atom or a substituted or unsubstituted, linear or branched alkyl, aryl, aralkyl or heteroaryl group. A
1
, A
2
, A
3
, and A
4
are each independently, a substituted or unsubstituted aromatic or nonaromatic carbocyclic or heterocyclic group. Preferably, carbon-carbon bonds are not formed between one or more of C
1
and C
4
, C
2
and C
5
, and C
3
and C
6
carbon atoms. Salts of Formulae I-IV are also included in the present invention.
In yet another embodiment, the present invention is directed to a pharmaceutical composition comprising an effective amount of a compound represented by one or more of the formulae (Formulae I-IV):
R
1
, R
2
and R
3
are each independently, selected from the group consisting of hydrogen, F, Cl, Br, I, CH
3
and substituted or unsubstituted, linear or branched alkyl, alkoxy, aryl, aralkyl or heteroaryl groups. Y
1
, Y
2
, Y
3
, Y
4
, and Y
5
are each independently selected from hydrogen atoms or lower alkyl groups. X
1
is an oxygen atom, a sulfur atom, an N═N group, a methylene or, NR
5
, wherein R
5
is a hydrogen atom or a substituted or unsubstituted, linear or branched alkyl, aryl, aralkyl or heteroaryl group. X
2
is an OH group, SH, CH
3
, or NR
6
R
7
, wherein R
6
and R
7
are each independently, a hydrogen atom or a substituted or unsubstituted, linear or branched alkyl, aryl, aralkyl or heteroaryl group. A
1
, A
2
, A
3
, and A
4
are each independently, a substituted or unsubstituted aromatic or nonaromatic carbocyclic or heterocyclic group. Preferably, carbon-carbon bonds are not formed between one or more of C
1
and C
4
, C
2
and C
5
, and C
3
and C
6
carbon atoms. The present invention also includes pharmaceutically acceptable salts of Formulae I-IV.
In still another embodiment, the invention is directed to a method for treating or preventing inflammation and/or an inflammatory response in the subject, comprising: administering to a subject an anti-inflammatory amount of more or more compounds having the formulae (Formulae I-IV):
R
1
, R
2
and R
3
are each independently, selected from the group consisting of hydrogen, F, Cl, Br, I, CH
3
and substituted or unsubstituted, linear or branched alkyl, alkoxy, aryl, aralkyl or heteroaryl groups. Y
1
, Y
2
, Y
3
, Y
4
, and Y
5
are each independently selected from hydrogen atoms or lower alkyl groups. X
1
is an oxygen atom, a sulfur atom, an N═N group, a methylene or, NR
5
, wherein R
5
is a hydrogen atom or a substituted or unsubstituted, linear or branched alkyl, aryl, aralkyl or heteroaryl group. X
2
is an OH group, SH, CH
3
, or NR
6
R
7
, wherein R
6
and R
7
are each independently, a hydrogen atom or a substituted or unsubstituted, linear or branched alkyl, aryl, aralkyl or heteroaryl group. A
1
, A
2
, A
3
, and A
4
are each independently, a substituted or unsubstituted aromatic or nonaromatic carbocyclic or heterocyclic group. Preferably, carbon-carbon bonds are not formed between one or more of C
1
and C
4
, C
2
and C
5
, and C
3
and C
6
carbon atoms. The present invention also includes pharmaceutically acceptable salts of Formulae I-IV.
In still another embodiment, the present invention is directed to a method of screening for a compound which modulates phospholipase D (PLD) activity. The method includes combining the compound with phospholipase D (PLD), thereby forming a mixture and treating the mixture with phosphatidylcholine, such that a cleavage reaction between phosphatidylcholine an

Affiliated with

Also associated with

Rating

Screening methods for presqualene diphosphate analogs does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Screening methods for presqualene diphosphate analogs, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Screening methods for presqualene diphosphate analogs will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-2476657