Pyrrole derivatives and cell death inhibitors

Details Pyrrole derivatives and cell death inhibitors Pyrrole derivatives and cell death inhibitors

2001-08-06

2003-07-08

Powers, Fiona T. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C548S455000

Reexamination Certificate

active

06589977

ABSTRACT:

This application is a 371 of PCT/JP00/00675 filed Feb. 8, 2000.
TECHNICAL FIELD
The present invention relates to a cell death inhibitor capable of inhibiting cell death induced by various substances in living body or foreign stimulants, or stimuli such as temperature, radiation and so on; its use as drugs for treating neurodegenerative diseases, diseases of circulatory organs, hepatitis, renal diseases, inflammatory skin disorders, radiation disorders, viral diseases, prion diseases, functional deficiency of transplanted organs, or the like, or preventing progress of the symptoms of the diseases; use as preservatives for organs, tissues and cells isolated from a living body.
BACKGROUND ART
Recent progress of the study as to cell death have revealed that cell death of cells essential for living body, particularly apoptosis is involved in progress and exacerbation of a variety of diseases (Science, Vol. 267, p. 1456, 1995). Apoptosis is a type of cell death in which cells commit a death using their own molecular machinery, characterized generally by (1) chromatin aggregation, (2) cell shrinkage, (3) blebbing of plasma membrane (formation of processes), (4) nuclear fragmentation, (5) formation of apoptotic bodies, (6) DNA fragmentation, and (7) phagocytosis (scavenging cell debris) by neighboring cells and macrophages. In contrast, there is another type of cell death, called necrosis, characterized by cell swelling and lysis, which occurs without executing the apoptotic processes when cells are exposed to excessive radiation, heat, noxious stimulants or the like. However, the cell death caused by the own molecular machinery does not always show a full set of the apoptosis characteristics described above, depending on species of cells, environments under which cells are present, and species and strength of cell death stimulants. Likewise, necrosis in view of pathology sometimes contains a cell death which some own molecular machinery is responsible for. In the invention, such cell death is also included in apoptosis.
Examples of the diseases whose progress and exacerbation are caused by apoptotic cell death are as follows: neurodegenerative diseases such as Alzheimer's disease [Bio Science terminology library: apoptosis/separate volume of “Jikken Igaku (Experimental Medicine)”, p. 168, 1996], spinal muscular atrophy (SMA) [Bio Science terminology library: apoptosis/separate volume of “Jikken Igaku (Experimental Medicine)”, p. 173, 1996], amyotrophic lateral screrosis (ALS) [Bio Science terminology library: apoptosis/separate volume of “Jikken Igaku (Experimental Medicine)”, p. 176, 1996], Parkinson's disease (J. Neurochem., Vol. 69, p. 1612, 1997), Huntington's disease (J. Neurosci., Vol. 15, p. 3775, 1995), pigmentary degeneration of the retina and glaucoma [Bio Science terminology library: apoptosis/separate volume of “Jikken Igaku (Experimental Medicine)”, p. 196, 1996], cerebellar degeneration and neonatal jaundice (Progress in Drug Research, Vol. 48, p. 55, 1997); myasthenia gravis (J. Clinical Investigation, Vol. 99, p. 2745, 1997); brain ischemia from apoplexy and the like, and successive delayed neuronal death (DND) [Bio Science terminology library: apoptosis/separate volume of “Jikken Igaku (Experimental Medicine)”, p. 180, p. 182, 1996], ischemic heart disease due to myocardial infarction (myocardial ischemia and disorder after reperfusion), viral myocarditis, autoimmune myocarditis (congestive cardiomyopathy and chronic myocarditis), myocardial disorders or death due to hypertrophic heart and heart failure, arrythmogenic right ventricular cardiomyopathy [Bio Science terminology library: apoptosis/separate volume of “Jikken Igaku (Experimental Medicine)”, p. 198, 1996; “Kekkan to Naihi (Blood Vessel and Endothelium), Vol. 7, p. 357, p. 364, p. 370, 1997]; alcoholic hepatitis, viral hepatitis [Bio Science terminology library: apoptosis/separate volume of “Jikken Igaku (Experimental Medicine)”, p. 190, 1996], renal diseases such as glomerulonephritis, hemolytic uremic syndrome and the like [Bio Science terminology library: apoptosis/separate volume of “Jikken Igaku (Experimental Medicine)”, p. 192, 1996], acquired immunodeficiency syndrome (AIDS) [Bio Science terminology library: apoptosis/separate volume of “Jikken Igaku (Experimental Medicine)”, p. 156, 1996; “Ketsueki, Meneki, Shuyou (Blood, Immunity, Cancer)”, Vol.2, p. 432, 1997], inflammatory skin disorders such as toxic epidermal necrolysis (TEN) and multiform exudative erythema, alopecia, graft versus host disease (GVH) [Bio Science terminology library: apoptosis/separate volume of “Jikken Igaku (Experimental Medicine)”, p. 194, 1996], radiation disorders [Bio Science terminology library: apoptosis/separate volume of “Jikken Igaku (Experimental Medicine)”, p. 160, 1996], side effects due to anti-cancer drugs, anti-viral drugs and the like, disorders due to toxic agents such as sodium azide, potassium cyanide and the like [Bio Science terminology library: apoptosis/separate volume of “Jikken Igaku (Experimental Medicine)”, p. 162, 1996], sepsis (Critical Care Medicine, Vol. 25, p. 1298, 1997), osteomyelo-dysplasia such as aplastic anemia and the like (Leukemia, Vol. 7, p. 144, 1993), insulin dependent diabetes (Diabetes, Vol. 44, p. 733, 1995), prion diseases such as Creutzfeldt-Jakob's disease (J. Neural Transmission, Supplementum, Vol. 50, p. 191, 1997), and so on. In organ transplantation, it has been suggested that apoptosis due to reactive oxygen species and various chemical mediators generated after reperfusion of anoxic organs by isolation or cardiac arrest of a donor is responsible for functional deficiency of transplanted organs (for example, “Ishoku (Transplantation)”, Vol. 27, p. 15, 1992). Probably, rejection reaction after transplantation of an organ, tissues, or cells may be a result of apoptosis of the transplanted cells, which occurs when they are attacked by recipient immune cells. It is thus reasonably concluded that chemical compounds capable of inhibiting cell death can be a promising drug that heals these diseases effectively, or inhibits or stops progress and exacerbation of the symptoms of these diseases.
In the transplantation of organs or tissues, graft survival rate after transplantation depends on the preserving conditions of the organs or tissues isolated from a donor. Accordingly, it is expected to improve organ and tissue preservation by adding chemical compounds inhibiting cell death into preservation liquids for the organs and tissues. Unlike immortalized cells or cancer cells, primary cultured cells isolated from a living body are usually difficult to culture in vitro. For long time cultivation, appropriate concentration of additives including various growth factors are required in the culture medium depending on species of the cells, and apoptosis easily occurs in case that the culture conditions are improper. When cells are cultured for research or medical purposes, it is expected that addition of a chemical compound inhibiting cell death would lead successful cell cultivation.
Apoptosis is known to be triggered by a wide variety of physiological substances such as cytokines including interleukins, hormones including glucocorticoids, excitotoxic amino acids including glutamic acid and NMDA, and membrane proteins represented by Fas ligand, depending on cell types. It is also triggered by deprivation of a specific growth factor or the like in some cell types. There are common apoptosis triggers irrespective of cell type, such as reactive oxygen species generators including hydrogen peroxide and the like, NO generators including SNP and the like, heat, and radiation. A number of chemical compounds are also reported to be able to induce apoptosis. Recent studies have shown that apoptotic signal transduction systems where a variety of signal transduction systems participate at the upstream, appear to converge on caspase activating mechanisms at the

Affiliated with

Also associated with

Rating

Pyrrole derivatives and cell death inhibitors does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Pyrrole derivatives and cell death inhibitors, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Pyrrole derivatives and cell death inhibitors will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-3040346