Aminosterol compounds useful as inhibitors of the sodium/proton exchanger (NHE), pharmaceutical methods and compositions employing such inhibitors, and processes for evaluating the NHE-inhibitory efficacy of compounds

a technology of sodium/proton exchanger and aminosterol, which is applied in the direction of instruments, organic chemistry, material analysis, etc., can solve the problems of cell death, decreased contractility, and arrhythmias

Inactive Publication Date: 2005-11-24
MAGAININ PHARMA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The rise in internal Ca+ concentrations leads to cell death, decreased contractility, and arrhythmias.
However, these inhibitors do not target the other known NHE isoforms—e.g., NHE3 is unaffected.

Method used

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  • Aminosterol compounds useful as inhibitors of the sodium/proton exchanger (NHE), pharmaceutical methods and compositions employing such inhibitors, and processes for evaluating the NHE-inhibitory efficacy of compounds
  • Aminosterol compounds useful as inhibitors of the sodium/proton exchanger (NHE), pharmaceutical methods and compositions employing such inhibitors, and processes for evaluating the NHE-inhibitory efficacy of compounds
  • Aminosterol compounds useful as inhibitors of the sodium/proton exchanger (NHE), pharmaceutical methods and compositions employing such inhibitors, and processes for evaluating the NHE-inhibitory efficacy of compounds

Examples

Experimental program
Comparison scheme
Effect test

example 1

Preparation of Shark Liver Isolates

[0053] In addition to squalamine, at least ten other distinctly different aminosterols have been recovered from extracts of dogfish shark liver. To prepare the aminosterols, shark liver was extracted in methanol:acetic acid. The aqueous extract was adsorbed to C18 silica and eluted with 70% acetonitrile, and the eluate was adsorbed to SP-sephadex and eluted with 1.5 M NaCl. The eluate was adjusted to 5M NaCl, and the steroids salted out. The precipitate was filtered over Celite and eluted with hot water, followed by methanol. The eluate was reduced in volume and applied to a 1-inch C18 column, and subjected to chromatography utilizing an increasing gradient in acetonitrile. Fractions were collected, concentrated by evaporation, and analyzed separately by thin layer chromatography (TLC).

[0054] The HPLC profile of the aminosterols isolated from 40 kg of shark liver is shown in FIG. 9. Final HPLC purification was performed as described in Moore et a...

example 2

Synthesis of Aminosterols

[0084] In addition to the above compounds, which were isolated from shark liver, synthetic aminosterol compounds have been developed. Various polyaminosterol compounds, including those specified in Examples A-G, are described in U.S. Ser. No. 08 / 416,883, which is the U.S. national phase of International Application No. PCT / US94 / 10265, filed Sep. 13, 1994, the disclosure of which is herein incorporated by reference. Compounds exemplified therein include the following:

[0085] Additional aminosterol compounds have now been developed. Preferred compounds of the invention include those exemplified below.

example h

[0086] Preparation of compound 353 and compound 354:

[0087] The above compounds were prepared by reductive coupling of 5α-cholestan-3-one to spermine (4 equivalents) with sodium cyanoborohydride in a manner analogous to the preparation of compound 303. Purification was achieved on silica gel (gradient elution with 9:3:1 to 3:3:1 chloroform:methanol:isopropylamine). Compound 353 (more polar) and compound 354 (less polar) were converted to their hydrochloride salts in the same manner as for compound 303. α-Amino compound 354: 1H NMR (200 MHz, CD3OD) δ: 3.47 (m, 1H), 3.3-2.9 (m, 12H), 2.3-1.0 (m, 39H), 1.0-0.8 (m, 12H), 0.70 (s, 3H); IR (KBr, cm−1): 3396, 2934, 1594, 1457, 1383; MS(+FAB): 573.6 (M+1); Anal. calcd. for C37H72N4-4HCl—H2O: C=60.31, H=10.67, N=7.60; Found: C=60.01, H=10.83, N=7.67. β-Amino compound 353: 1H NMR (200 MHz, CD3OD) δ: 3.3-3.0 (m, 13H), 2.2-1.0 (m, 39H), 1.0-0.8 (m, 12H), 0.70 (s, 3H); IR (KBr, cm−1): 2945, 1596, 1466, 1383; MS exact mass (+FAB) calcd.: 573.583...

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Abstract

Aminosterol compounds are described that are useful as inhibitors of the sodium / proton exchanger (NHE). Methods of using such aminosterols compounds are also enclosed, including those employing compounds that are inhibitors of a spectrum of NHEs as well as those using compounds that are inhibitors of only one specific NHE. Advantageous screening techniques and assays for evaluating a compound's therapeutic activity are also disclosed.

Description

CROSS-REFERENCE TO RELATED APPLICATION [0001] This application is related to U.S. Ser. No. 08 / 416,883, which is the U.S. national phase of International Application No. PCT / US94 / 10265, filed Sep. 13, 1994.FIELD OF THE INVENTION [0002] The present invention relates to aminosterol compounds useful as inhibitors of the sodium / proton exchanger (NHE). The invention is also directed to pharmaceutical compositions containing such compounds, and the use of such compounds for inhibiting NHE. The invention is further directed to assaying techniques for screening compounds for their efficacy as NHE inhibitors. BACKGROUND OF THE INVENTION [0003] Each of the body's cells must maintain its acid-base balance or, more specifically, its hydrogen ion or proton concentration. Only slight changes in hydrogen ion concentration cause marked alterations in the rates of chemical reactions in the cells—some being depressed and others accelerated. In very broad and general terms, when a person has a high con...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/56C07J9/00C07J41/00G01N33/50
CPCA61K31/56C07J9/00C07J41/0005G01N33/5008G01N33/5011G01N2500/00G01N33/505G01N33/5061G01N33/5064G01N33/5088G01N33/5091G01N33/5044
Inventor ZASLOFF, MICHAELSHINNAR, ANNKINNEY, WILLIAMJONES, STEVEN
Owner MAGAININ PHARMA INC
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