Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Reexamination Certificate
1998-03-24
2001-04-10
Criares, Theodore J. (Department: 1579)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
C514S576000, C514S544000, C514S568000
Reexamination Certificate
active
06214879
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The invention is generally related to pharmaceuticals which are useful for allosterically modifying pyruvate kinase.
2. Description of the Prior Art
Mammalian pyruvate kinase (PK) is a key regulatory glycolytic enzyme that exhibits allosteric kinetic behavior. The basic mechanism of the allosteric regulation of PK at the molecular level is still not known. There are reports that PK undergoes conformational changes and that the changes involve domain events. PK is found in all cells and tissues. It catalyzes the conversion of phospho-enolpyruvate (PEP) and adensosine diphosphate (ADP) into pyruvate and adenosine triphosphate (ATP), as shown in reaction scheme 1.
PEP+Mg.ADP+H
+
→(Mg
2+
, K
+
)→Mg.ATP+Pyruvate (1)
The reaction proceeds in two steps. First, the 2-phosphate is removed from PEP to yield ATP and the enolate ion form of pyruvate. The second step involves the protonation and tautomerization of the ion to yield the keto form of pyruvate. The enzyme requires three cation cofactors, two divalent (Mg
2+
or Mn
2+
) and one monovalent (K
+
). Positive factors of PK include fructose 1,6 diphosphate, PEP, and low pH. Negative factors of PK include ATP, high pH, and glycogenic amino acids such as alanine and phenylalanine. The products of reaction scheme 1, pyruvate and ATP, are involved in a wide variety of metabolic pathways; therefore, PK can be considered a key enzyme in the glycolytic pathway as well as many other pathways in the cellular metabolism.
In mammals, PK has four isoenzymes which are identified as M-1, M-2, L and R type. The R type PK exists exclusively in red blood cells and its biochemical properties change with cell maturation. Congenital R-PK deficiency in erythrocytes is one of the most frequent enzymopathies involving the glycolytic pathway. It is an autosomal recessive disorder, and in hemozygotes, causes nonspherocytic hemolytic anemia. Heterozygotes do not show symptoms of hemolytic anemia, but have lowered residual PK activity, with increased 2,3-diphosphoglycerate (2,3-DPG) and fairly stable ATP levels. Thus, it appears quite possible that similar results will be obtained pharmacologically from partial inhibition of erythrocyte PK. Because ATP can be synthesized in erythrocytes only by glycolysis, a decreased PK activity causes severe disturbances of the erythrocyte energy metabolism and leads to greatly diminished lifetime of the red blood cells.
SUMMARY OF THE INVENTION
It is an object of this invention to provide pharmaceuticals suitable for allosterically modifying PK.
It is another object of this invention to use a family of pharmaceuticals to regulate the 2,3-DPG and ATP levels in vivo.
It is yet another object of this invention to use a family of pharmaceuticals to regulate the glycolytic pathway in vivo.
According to the invention, a family of compounds has been identified which allosterically modify pyruvate kinase. One group within the family will be useful for the delivery of additional oxygen to tissues by increasing the 2,3-DPG concentration in vivo, and this can be useful in a wide variety of clinical conditions and disease states including radiation oncology, whole body and tissue hypothermia, sepsis, wound healing, diabetic ulcers, pressure sores, tissue transplants, stroke, shock, cardiovascular and angina applications, acute respiratory distress syndrome (ARDS), chronic respiratory insufficiency, pulmonary fibrosis, interstitial lung disease, peripheral vascular disease (e.g., intermittent claudication), ischemia, etc. Another group within the family cause depletion of 2,3-DPG much faster than the control metabolic rate and should be useful in the treatment of sickle cell anemia and other disorders (anticancer therapy, e.g., causing increase in tumor hypoxia thus enhancing hypoxic cell sensitizers such as terapazamine). PK contributes to the establishment of steady-state levels of 2,3-DPG which is important since 2,3-DPG is an allosteric effector of oxygen binding to hemoglobin. PK was found to have an inverse relationship with 2,3-DPG levels in human erythrocytes. An increase in the level of 2,3-DPG induces a rightward shift of the oxygen-hemoglobin dissociation curve, indicating that the quaternary conformational equilibrium of hemoglobin is perturbed toward the T, or deoxygenated state. In other words, oxygen is more quickly being delivered from blood to tissues. Similarly, a decrease in the level of 2,3-DPG concentration induces a leftward shift of the oxygen-hemoglobin dissociation curve and shifts the allosteric equilibribrium to the R, or oxygenated state. Such agents will be useful as antisickling agents. Increasing erythrocyte 2,3-DPG concentrations through the intervention of PK inhibition will find use in many clinical settings where more delivery of tissue oxygenation is desired. The activators of PK will also be useful as antisickling agents since they would produce a therapeutic inhibition of the intracellular polymerization that underlies sickling by increasing oxygen affinity due to the 2,3-DPG depletion, thereby stabilizing the more soluble oxy-hemoglobin. In addition, as discussed above, the activators can also be used in anticancer treatments.
REFERENCES:
patent: 5278168 (1994-01-01), Spector et al.
patent: 5599974 (1997-02-01), Abraham et al.
CA: vol. 76, No. 22396e (Carminatti et al), 1972.
Abraham Donald J.
Boyiri Telih
Danso-Danquah Richmond E.
Gerber Michael J.
Hoffman Stephen J.
Criares Theodore J.
McGuireWoods LLP
Virginia Commonwealth University
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