US4937232A
Expired / Lapsed
US
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Inhibition of protein kinase C by long-chain bases
Assignee: Duke University
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Filing: 1988-05-17
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Granted: 1990-06-26
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Expires: 2008-05-17
Abstract
Abstract Compositions for inhibiting protein kinase C, comprising an inhibitory amount of a compound having the formula: ##STR1## wherein Q is a hydrophobic group; wherein X is --CH 2 --CH 2 -- or --CH═CH--, which may be substituted by one or more halogens or C 1 -C 3 alkyl groups, wherein Y is ##STR2## wherein W is a halogen; wherein R 1 and R 2 may be the same or different and are selected from hydrogen, lower alkyl groups having from 1 to 7 carbon atoms, aralkyl, and aryl groups, and wherein Z is a phosphate or an organic group, and a pharmaceutically acceptable carrier material; and a method for inhibiting protein kinase C using such compositions.
Inventors
- 👤 Robert M. Bell
- 👤 Carson Loomis
- 👤 Yusuf Hannun
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-11-04 11:12
CPC Classifications
A; A61; A61K; A61K31/00; A61K31/66; A61K31/683; A61K31/685; C; C07; C07H; C07H15/00; C07H15/02; C07H15/04; C07H15/10
Claims Analysis
Total Claims: 15
Claim 1
Independent Claim
169 words
A method for inhibiting protein kinase C, which comprises contacting a cell containing protein kinase C, with an acylated protein kinase C inhibitor having the formula: ##STR8## wherein Q is CH 3 --(CH 2 ) n -- or CH 3 --(CH 2 ) m --CH═CH--(CH 2 ) p -- wherein n is 2-30; m is 1-15 and p is 1-15; wherein X is --CH 2 --CH 2 -- or --CH═CH--, or such substituted by one or more halogens or C 1 -C 3 alkyl groups; wherein Y is ##STR9## wherein W is a halogen; wherein R 1 and R 2 are the same or different and are selected from hydrogen, lower alkyl groups having from 1 to 7 carbon atoms, aralkyl, and aryl groups wherein one of R 1 or R 2 is an in vivo enzyme-cleavable C 1 -C 8 acyl group or an amino acid, and wherein Z is selected from the group consisting of phosphate, H, galactosyl, sulfogalctosyl, glucosyl, lactosyl, trihexosyl, phosphorylchloine, GalNAc-Gal-Glc, Gal-Gal-Glc, Sia-Gal-Glc, ##STR10##
Claim 2
Independent Claim
169 words
A method for inhibiting protein kinase C, which comprises contacting a cell containing protein kinase C, with an acylated protein kinase C inhibitor having the formula: ##STR8## wherein Q is CH 3 --(CH 2 ) n -- or CH 3 --(CH 2 ) m --CH═CH--(CH 2 ) p -- wherein n is 2-30; m is 1-15 and p is 1-15; wherein X is --CH 2 --CH 2 -- or --CH═CH--, or such substituted by one or more halogens or C 1 -C 3 alkyl groups; wherein Y is ##STR9## wherein W is a halogen; wherein R 1 and R 2 are the same or different and are selected from hydrogen, lower alkyl groups having from 1 to 7 carbon atoms, aralkyl, and aryl groups wherein one of R 1 or R 2 is an in vivo enzyme-cleavable C 1 -C 8 acyl group or an amino acid, and wherein Z is selected from the group consisting of phosphate, H, galactosyl, sulfogalctosyl, glucosyl, lactosyl, trihexosyl, phosphorylchloine, GalNAc-Gal-Glc, Gal-Gal-Glc, Sia-Gal-Glc, ##STR10##
Claim 3
Independent Claim
47 words
A method for inhibiting protein kinase C, which comprises contacting a cell containing protein kinase C, with a lysophingomyelin or a lysosphingaglycolipid having the ability of increasing the intracellular concentration of a protein kinase C inhibitory compound which produces inhibition of protein kinase C activity in vivo.
Claim 4
Independent Claim
47 words
A method for inhibiting protein kinase C, which comprises contacting a cell containing protein kinase C, with a lysophingomyelin or a lysosphingaglycolipid having the ability of increasing the intracellular concentration of a protein kinase C inhibitory compound which produces inhibition of protein kinase C activity in vivo.
Claim 5
Dependent Claim
153 words
A unit dosage composition for inhibiting protein linase C upon routine administration in vivo, which comprises a protein kinase C inhibitory concentration of a compound having the formula: ##STR11## wherein Q is CH 3 --(CH 2 ) n -- or CH 3 (CH 2 ) m --CH═CH--(CH 2 ) p -- wherein n is 2-30; m is 1-15 and p is 1-15; wherein X is --CH 2 --CH 2 -- or --CH═CH--, or such substituted by one or more halogens or C 1 -C 3 alkyl groups; wherein Y is ##STR12## wherein W is a halogen; wherein R 1 and R 2 are the same or different and are selected from hydrogen, lower alkyl groups having from 1 to 7 carbon atoms, aralkyl, and aryl groups, and wherein Z is selected from the group consisting of phosphate, H, galactosyl, sulfogalactosyl, glucosyl, lactosyl, trihexosyl, phosphorycholine, GalNAc-Gal-Glc, Gal-GaI-Gla, Sia-Gal-Glc, ##STR13## and a physiologically acceptable carrier.
Claim 6
Dependent Claim
153 words
A unit dosage composition for inhibiting protein linase C upon routine administration in vivo, which comprises a protein kinase C inhibitory concentration of a compound having the formula: ##STR11## wherein Q is CH 3 --(CH 2 ) n -- or CH 3 (CH 2 ) m --CH═CH--(CH 2 ) p -- wherein n is 2-30; m is 1-15 and p is 1-15; wherein X is --CH 2 --CH 2 -- or --CH═CH--, or such substituted by one or more halogens or C 1 -C 3 alkyl groups; wherein Y is ##STR12## wherein W is a halogen; wherein R 1 and R 2 are the same or different and are selected from hydrogen, lower alkyl groups having from 1 to 7 carbon atoms, aralkyl, and aryl groups, and wherein Z is selected from the group consisting of phosphate, H, galactosyl, sulfogalactosyl, glucosyl, lactosyl, trihexosyl, phosphorycholine, GalNAc-Gal-Glc, Gal-GaI-Gla, Sia-Gal-Glc, ##STR13## and a physiologically acceptable carrier.
Claim 7
Dependent Claim
10 words
The composition of claim 3, wherein said compound is sphingosine.
Claim 8
Dependent Claim
10 words
The composition of claim 3, wherein said compound us sphinganine.
Claim 9
Dependent Claim
10 words
The composition of claim 3, wherein said compound is psychosine.
Claim 10
Dependent Claim
9 words
The composition of claim 3, wherein Y is ##STR14##
Claim 11
Dependent Claim
16 words
The composition of claim 3, wherein said physiologically acceptable carrier is a sterile liquid or cream.
Claim 12
Dependent Claim
164 words
A composition for inhibiting protein kinase C upon routine administration in vivo, which comprises a protein kinase C inhibitory concentration of a compound having the formula: ##STR15## wherein Q is CH 3 --(CH 2 ) n -- or CH 3 --(CH 2 ) m --CH═CH--(CH 2 ) p -- wherein n is 2-30; m is 1-15 and p is 1-15; wherein X is --CH 2 --CH 2 -- or --CH═CH--, or such substituted by one or more halogens or C 1 -C 3 alkyl groups; wherein Y is ##STR16## wherein w is a halogen; wherein R 1 and R 2 are the same or different and are selected from hydrogen, lower alkyl groups having from 1 to 7 carbon atoms, aralkyl, and aryl groups, and wherein Z is selected from the group consisting of phosphate, H, galactosyl, sulfogalactosyl, glucosyl, actosyl, trihexosyl, phosphorylcholine, GalNAc-Gal-Glc, al-Gal-Glc, Sia-GalGlc, ##STR17## with the proviso that R 1 and R 2 are not both hydrogen, and a physiologically acceptable carrier.
Claim 13
Dependent Claim
164 words
A composition for inhibiting protein kinase C upon routine administration in vivo, which comprises a protein kinase C inhibitory concentration of a compound having the formula: ##STR15## wherein Q is CH 3 --(CH 2 ) n -- or CH 3 --(CH 2 ) m --CH═CH--(CH 2 ) p -- wherein n is 2-30; m is 1-15 and p is 1-15; wherein X is --CH 2 --CH 2 -- or --CH═CH--, or such substituted by one or more halogens or C 1 -C 3 alkyl groups; wherein Y is ##STR16## wherein w is a halogen; wherein R 1 and R 2 are the same or different and are selected from hydrogen, lower alkyl groups having from 1 to 7 carbon atoms, aralkyl, and aryl groups, and wherein Z is selected from the group consisting of phosphate, H, galactosyl, sulfogalactosyl, glucosyl, actosyl, trihexosyl, phosphorylcholine, GalNAc-Gal-Glc, al-Gal-Glc, Sia-GalGlc, ##STR17## with the proviso that R 1 and R 2 are not both hydrogen, and a physiologically acceptable carrier.
Claim 14
Dependent Claim
9 words
The composition of claim 9, wherein Y is ##STR18##
Claim 15
Dependent Claim
16 words
The composition of claim 9, wherein said physiologically acceptable carrier is a sterile liquid or cream.
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