NZ256178A - Use of diureidobenzenedisulphonate oligomers in medicaments - Google Patents

Use of diureidobenzenedisulphonate oligomers in medicaments

Info

Publication number
NZ256178A
NZ256178A NZ256178A NZ25617893A NZ256178A NZ 256178 A NZ256178 A NZ 256178A NZ 256178 A NZ256178 A NZ 256178A NZ 25617893 A NZ25617893 A NZ 25617893A NZ 256178 A NZ256178 A NZ 256178A
Authority
NZ
New Zealand
Prior art keywords
compound
binding
inositol
oligomers
calcium
Prior art date
Application number
NZ256178A
Inventor
Kenneth Alan Stauderman
Original Assignee
Merrell Dow Pharma
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Merrell Dow Pharma filed Critical Merrell Dow Pharma
Publication of NZ256178A publication Critical patent/NZ256178A/en

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Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/74Synthetic polymeric materials
    • A61K31/795Polymers containing sulfur
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Agricultural Chemicals And Associated Chemicals (AREA)

Description

<div class="application article clearfix" id="description"> <p class="printTableText" lang="en">New Zealand No. 256178 International No. PCT/US93/08168 <br><br> Priority Dat»(«): - <br><br> Compter Specification FU*d: <br><br> Clan: IS! <br><br> PuMeafton Data:.. <br><br> P.O. Journal No: <br><br> NO L/ii <br><br> NEW ZEALAND PATENTS ACT 1953 COMPLETE SPECIFICATION <br><br> Title of Invention: <br><br> Method for antagonizing inositol 1,4-5-triphosphate <br><br> Name, address and nationality of applicant(s) as in international application form: <br><br> MERRELL DOW PHARMACEUTICALS INC, of 2110 East Galbraith Road, Cincinnati, Ohio 45215, United States of America a US <br><br> (FOLLOWED BY PAGE 1 A) <br><br> WO 54/07507 <br><br> 25 6 178 <br><br> PCT/US93/08168 <br><br> 5 <br><br> METHOD FOR ANTAGONIZING INOSITOL 1.4,5-TRISPHOSPHATE <br><br> 10 <br><br> BACKGROUND OF THE INVENTION This application relates to a series of diamino benzenedisulfonic acid oligomers that have demonstrated an affinity for the receptor sites of inositol 1,4,5-15 triphosphate (IP3} and are, therefore useful in diminishing the bioactivity of IP3, especially with regard to its effect on the release of intracellular calcium ions. <br><br> DESCRIPTION OF THE PRIOR ART 20 The diamino benzenedisulfonic acid oligomers demonstrating utility as IP3 antagonists according to this invention are described in detail in the European Patent Application published January 22, 1992 under Publication No. 0467185 A2. In that publication, the oligomers of the 25 present invention were described as having utility in the diagnosis and/or treatment of AIDS and AIDS related complex. <br><br> SUMMARY OF THE INVENTION <br><br> 30 The invention herein disclosed relates to the use in the manufacture of a medicament for inhibiting the activity of inositol 1,4,5-triphosphate (IP3) by occupying the receptor sites specific to 2P3 with a compound of the formula: <br><br> WO 94/07507 <br><br> PCT/US93/08168 <br><br> -2- <br><br> H3C"0-K <br><br> S03-Na + <br><br> 0 <br><br> H \—/ H <br><br> S03-Na + <br><br> 5U3-Na + <br><br> J~X» <br><br> khO"ch3 <br><br> wherein n is a whole number selected from the range of 5 to 10 20 inclusive and the pharmaceutical^ acceptable salts thereof. <br><br> 15 <br><br> 20 <br><br> 25 <br><br> DETAILED DESCRIPTION OF THE INVENTION Inositol 1,4,5-triphosphate (IP3) &lt;|s a naturally occurring and active component of animatl physiology. It is formed intracellularly upon the activatlion of cell-surface receptors linked to the enzyme phosphol|pase C. Once generated in sufficient quantities, IP3 \acts to stimulate the release of calcium ions from storage-; organelles within the cell. In this role IP3 is characterized as a "second messenger". Depending upon the type of cell, the calcium released by IP3 functions to stimulate a variety of physiologic processes such as smooth muscle contraction, histamine secretion and the hyperpoleirization of nerve cells. Any compound or agent that can promote or interfere with the function of IP3, will promote or interfere with the generation of calcium ions and thereby elici^ predictable pharmacological effects. <br><br> 30 <br><br> 35 <br><br> The process by which IP3 releases calcium ions begins with the binding of IP3 to a specific receptor protein located on an intracellular calcium storage compartment located typically on the endoplasmic reticulum. This receptor protein has been cloned and has been shown to form a calcium "channel" with unique structural properties when bound to IP3. Therefore, when IP3 binds with its receptor, a calcium channel is opened causing the release of calcium stored in the cell's endoplasmic reticulum. In turn, the <br><br> WO 94/07507 <br><br> PCT/US93/08168 <br><br> -3- <br><br> released calcium will elicit the appropriate cellular response. <br><br> Heretofore, the only verified potent antagonist of the 5 IP3 receptor was heparin, a complex glycosaminoglycan. The diamino benzenedisulfonic acid oligomers of this invention also appear to antagonize the effects of IP3 by competing for the receptor site. In most cases, these compounds are more effective than heparin and demonstrate fewer secondary 10 effects. In addition to providing utility as laboratory <br><br> "tools" in evaluating the therapeutic potential of other IP3 receptor antagonists, the oligomers of this invention would also be administered to modulate IP3-induced calcium release and have a salutary effect on any number of disorders that 15 are caused or exacerbated by an inordinately productive IP3 second messenger pathway. <br><br> EXPERIMENTALS Measurement of IPi Binding 20 Cerebella from male Sprague-Dawley rats (200 g) were homogenized in 30 volumes of ice-cold buffer A (50 mM Tris, 1 mM dithiothreitol, 1 mM EDTA, pE 7.7 with EC1) with a polytron (setting 9 for 10 seconds). The tissue is then washed twice by centrifugation (20,000 x g, 15 minutes; 25 Sorvall 28-S., SS-34 rotor) and resuspended in 30 volumes of ice-cold buffer A. <br><br> For the binding assays, 1.5 ml eppendorf tubes containing 50 yl of test compound (made up as a lOx stock 30 in water) or water, 50 yl I3H] IP3 (17Ci/mmol; Dupont-NEN; usually made as a 25 nM (lOx) stock solution in buffer), and 350 yl of buffer B (buffer A with pH adjusted to 8.4) on ice. Tubes for non-specific binding also contained 50 yl of non-radioactive IP3 (100 yM stock (lOx); final 35 concentration 10 yM), with an appropriate reduction in the volume of buffer B. Reactions were initiated by the addition of 50 yl tissue to make the final volume 500 yl, <br><br> WO 94/07507 PCT/US93/08168 <br><br> \ .s t <br><br> -4- <br><br> » - followed by vortex mixing. Samples were incubated on ice for 10 minutes and then were centrifuged (14,000 x g) in a roicrofuge (Eppendorf model 5415) for 5 minutes followed by aspiration of the supernatant fraction. The tissue pellets 5 were solubilized overnight in 100 yl of Protosol (Dupont-NEN). After solubilization, 73 yl of glacial acetic acid were added to decrease chemiluminescence, and the mixture was transferred to scintillation vials. To these vials was added 7 ml of Ecoscint-A (National Diagnostics) and the 10 radioactivity determined by liquid scintillation spectrophotometry. <br><br> Specific binding was defined as the difference between total binding (radioactivity in the absence of test 15 compound and cold IP3) and non-specific binding <br><br> (radioactivity in the absence of test compound but in the presence of cold IP3). This number was taken as 100% specific binding. Data points obtained with the test compounds were fit by a computer program (GraphPad-InPlot) 20 to determine their inhibitory potency. The inhibitory potencies of the test compounds were expressed as the concentration of compound that produces 50% inhibition of specific binding (the IC50 value). <br><br> 25 The binding data are presented in Table 1 and demonstrate that compounds within the scope of the present invention effectively compete for [3H] IP3 binding sites in rat cerebellar membranes. The compound identified as HDL 102,869 was the most potent competitor for binding with an 30 IC50 of 50 nM, whereas low molecular weight heparin (5100 MW) had an IC50 of 74 nM. MDL 102,869 is the compound according to the claimed invention wherein n = 15. <br><br> The potency for binding also seems to correlate with 35 the ability to antagonize IP3~induced calcium ion release. Thus, 1 and 3 yM of MDL 102,869 inhibited calcium ion release by 42 and 100%, respectively (see Fig. 1), whereas <br><br> WO 94/07507 <br><br> 2 5 6 17 8 <br><br> PCr/USM/08168 <br><br> -5- <br><br> 10 yM of heparin inhibited release by 90%. MDL 101,828, which had an IC50 binding of 104 nM, inhibited IP3-induced calcium ion release by 72% at 3 micro moles. MDL 101,828 is the compound according to the claimed invention wherein 5 n « 9. <br><br> TABLE 1 <br><br> 10 <br><br> Compound <br><br> Binding IC50 (nM) <br><br> Inhibition of Ins(1,4,5 )Pa-Induced Ca2+-release <br><br> Heparin (low MW) <br><br> 74 <br><br> 90% at 10 yM <br><br> MDL 101,828 <br><br> 104 <br><br> 72% at 3 yM <br><br> MDL 102,869 <br><br> 50 <br><br> 42% at 1 yM 100% at 3 yM <br><br> 15 <br><br> The tracing of Fig. 1, dramatically illustrates the IP3 inhibition data set forth in the third column of Table 1. <br><br> 20 <br><br> 25 <br><br> 30 <br><br> 35 <br><br> The y-axis represents the concentration of free calcium ions in arbitrary units. The tracing shows that two successive additions of 0.1 yM of IP3 stimulated similar amounts of calcium ion release from cerebellar microsomes. The addition of 1 yM of MDL 102,869 stimulated a small increase of calcium ion for unknown reasons. In the presence of 102,869, however, calcium ion release stimulated by 0.1 yM of IP3 was inhibited by 42%. This inhibition was overcome by the addition of 1 yM consistent with competitive antagonism by MDL <br><br></p> </div>

Claims (4)

<div class="application article clearfix printTableText" id="claims"> <p lang="en"> 256178<br><br> -b-<br><br> •WHAT^WE; CLAiH-<br><br> WHAT 10 CLAIMED 10 i'<br><br>
1. The use in the manufacture of a medicament foe 5 inhibiting the activity of inositol 1,4,5-triaphosphate by occupying a receptor site specific to inositol 1,4,5-trisphosphate, of a compound of the formula:<br><br> 10<br><br> 15<br><br> wherein n is a whole number within the range of 5-20 and the pharmaceutical^ acceptable salts thereof.<br><br> 2Q
2. The use of a compound according to claim 1 wherein n is 9.<br><br>
3. The use of a compound according to claim 1 wherein n is 15.<br><br>
4. The use as defined in claim 1 substantially as herein described vith reference to any example thereof.<br><br> hoc..<br><br> By the authorised agents A J PARK &amp; SON<br><br> </p> </div>
NZ256178A 1992-09-28 1993-08-30 Use of diureidobenzenedisulphonate oligomers in medicaments NZ256178A (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
US95239392A 1992-09-28 1992-09-28

Publications (1)

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NZ256178A true NZ256178A (en) 1997-03-24

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Country Status (13)

Country Link
EP (1) EP0661982A1 (en)
JP (1) JPH08502068A (en)
KR (1) KR950703347A (en)
AU (1) AU670962B2 (en)
CA (1) CA2145681A1 (en)
HU (1) HUT70192A (en)
IL (1) IL107066A (en)
MX (1) MX9305933A (en)
NO (1) NO951163L (en)
NZ (1) NZ256178A (en)
TW (1) TW260663B (en)
WO (1) WO1994007507A1 (en)
ZA (1) ZA936978B (en)

Families Citing this family (11)

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WO1996000586A2 (en) * 1994-06-30 1996-01-11 MAX-PLANCK-Gesellschaft zur Förderung der Wissenschaften e.V. Methods for treating cell proliferative disorders by modulating signal transduction
US5780483A (en) * 1995-02-17 1998-07-14 Smithkline Beecham Corporation IL-8 receptor antagonists
JPH11503110A (en) 1995-02-17 1999-03-23 スミスクライン・ビーチャム・コーポレイション IL-8 receptor antagonist
US6083920A (en) * 1995-12-21 2000-07-04 Ayurcore, Inc. Compositions for modulating intracellular inositol trisphosphate concentration
US6005008A (en) * 1996-02-16 1999-12-21 Smithkline Beecham Corporation IL-8 receptor antagonists
US6211373B1 (en) 1996-03-20 2001-04-03 Smithkline Beecham Corporation Phenyl urea antagonists of the IL-8 receptor
US6262113B1 (en) 1996-03-20 2001-07-17 Smithkline Beecham Corporation IL-8 receptor antagonists
US6133319A (en) * 1996-06-27 2000-10-17 Smithkline Beecham Corporation IL-8 receptor antagonists
WO1997049286A1 (en) 1996-06-27 1997-12-31 Smithkline Beecham Corporation Il-8 receptor antagonists
CA2427757A1 (en) * 2000-11-09 2002-05-16 Contrimmune Biotechnology Inc. Therapeutic uses for ip3 receptor-mediated calcium channel modulators
CN103930165B (en) 2011-09-02 2018-05-25 纽约市哥伦比亚大学理事会 To treat CaMKII, IP3R of the metabolic disorder of obesity, calcineurin, P38 and MK2/3 inhibitor

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GB781479A (en) * 1953-08-27 1957-08-21 Ciba Ltd New polyureas and process for making them
US5276182A (en) * 1990-07-09 1994-01-04 The Dow Chemical Company Process for preparing polyurea oligomers

Also Published As

Publication number Publication date
IL107066A (en) 1998-01-04
IL107066A0 (en) 1993-12-28
CA2145681A1 (en) 1994-04-14
MX9305933A (en) 1994-04-29
NO951163D0 (en) 1995-03-27
WO1994007507A1 (en) 1994-04-14
HU9500891D0 (en) 1995-05-29
ZA936978B (en) 1994-04-18
KR950703347A (en) 1995-09-20
NO951163L (en) 1995-03-27
AU4841793A (en) 1994-04-26
HUT70192A (en) 1995-09-28
AU670962B2 (en) 1996-08-08
EP0661982A1 (en) 1995-07-12
JPH08502068A (en) 1996-03-05
TW260663B (en) 1995-10-21

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