Compounds, formulations, and methods of protein kinase C inhibition

摘要

The invention provides a method of inhibiting atypical protein kinase C (aPKC) comprising contacting an aPKC with a compound having a structure selected from the group consisting of structural formulas (I) to (IX). The invention further provides a method of inhibiting or reducing vascular permeability. The method comprising administering to a subject a composition comprising an amount of a compound having a structure selected from the group consisting of structural formulas (I) to (IX) effective to inhibit or reduce vascular permeability. A method of treating or preventing a disease or disorder characterized by abnormal vascular permeability, a method of inhibiting angiogenesis, a method of inhibiting cancer cell proliferation, a formulation, and a method of preparing a formulation also are provided.

主权项

1. A method of inhibiting or reducing vascular permeability comprising:
administering to a subject in need thereof a composition comprising a compound in an amount effective to inhibit or reduce vascular permeability, the compound having a structure selected from the group consisting of structural formula (I) to (VIII): structural formula (I): structural formula (II): structural formula (III): structural formula (IV): structural formula (V): structural formula (VI): structural formula (VII): and structural formula (VIII): wherein X1 is selected from the group consisting of O, S, NH, and NMe; wherein n has a value of zero (0), one (1), or two (2); wherein R1 is selected from the group consisting of CH2, CH(CH3), C(CH3)2, C2H4, and C2H2; wherein R2 is selected from the group consisting of H, CH3, CH2OH, C2H5, C2H5O, CH(CH3)2, C(CH3), CH2CH(CH3)2, and CH2C(CH3)3; wherein X2 is selected from the group consisting of O, S, NH and N; when X2 is O, S, or NH, R3 is selected from the group consisting of an aryl residue, an alkyl residue having 1 to 10 carbon atoms, an alkoxy residue having 1 to 10 carbon atoms, and a polyglycol residue having two to twelve carbon atoms; when X2 is N, R3 is either two independently selected residues each selected from the group consisting of an aryl residue, an alkyl residue having 1 to 10 carbon atoms, an alkoxy residue having 1 to 10 carbon atoms, and a polyglycol residue having two to twelve carbon atoms; or X2 and R3 are a cyclic group (X2—R3) having five or six members and optionally one or more additional heteroatoms; wherein R4 and R8 are individually selected from the group consisting of H, F, Cl, OH, and OCH3; wherein R5 and R7 are individually selected from the group consisting of H, F, Cl, Br, CH3, C2H5, OH, OCH3, OCH2CH3, OCH2OCH3, S(CH3)2+, and N(alkyl)3+; wherein R6 is selected from the group consisting of H; F; Cl; Br; CH3; C2H5; NO2; OH; OCH3; OCH2CH3; OCH2OCH3; OCH2CH2OH; OCH2CH2OCH3; OCH2CH2OCH2CH3; polyglycol residue selected from the group consisting of methylene glycols, ethylene glycols, propylene glycols and mixtures thereof; and an aryl group; wherein Ar is selected from the group consisting of phenyl, napthyl, pyridyl, pyrrolidyl, furanyl, pyranyl, azepinyl, oxepinyl, imidizolyl, oxazolyl, pyrimidinyl, purinyl, dimethoxyphenyl, chlorophenyl, dichlorophenyl, bromophenyl, hydroxyphenyl, trimethylphenyl, fluorophenyl, nitrophenyl, methoxyphenyl, dihydrobenzopyran, pyridine, dimethyl aminophenyl, aminophenyl, piperonyl, fluoromethoxyphenyl, acetamidophenyl, and carbomoylphenyl; wherein R9 is selected from the group consisting of H, CH3, CH2N(CH3)2, and phenyl; wherein when either R5 or R7 is Cl and the other is H, R6 is not Cl; and wherein the compound is not isopropyl 2-amino-4-(3,4-dichlorophenyl)thiophene-3-carboxylate.