MXPA99001960A - Use of inhibitors of pkc for the manufacture of a medicament for the treatment of central nervous system diseases associated with hiv infection - Google Patents

Abstract

A method for treating central nervous system associated with HIV infection is disclosed, particularly using the isozyme selective PKC inhibitor, (S)-3,4-[N,N'-1, 1'-((2''-ethoxy)-3'''(O)-4'''-(N,N-dimethylamino)-butane)-bis-(3,3'-indolyl)]-1(H)-pyrrole-2,5-dione hydrochloride salt.

Description

USE OF PKC INHIBITORS FOR THE MANUFACTURE OF A MEDICINE FOR THE TREATMENT OF DISEASES OF THE CENTRAL NERVOUS SYSTEM ASSOCIATED WITH HIV INFECTION BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention is broadly directed to the use of a particular class of isozyme-selective Protein Kinase C (PKC) inhibitors for the treatment of central nervous system (CNS) diseases associated with infectious HIV 2. Description of Related Art The HIV epidemic continues to grow at a rapid rate, and the clinical manifestations associated with this viral infection increasingly present medical and socioeconomic problems. Acute HIV infection leads to a period of rapid viral replication followed by viremia that results in infection of 1% or more of circulating T lymphocytes, the primary target of the virus. The viremia is temporary, however, because the HIV-infected cells are removed from the circulation by an effective host immune response that results in a 10 to 100-fold decrease in the T cells infected by VI H. Unfortunately, there is still no effective therapy to prevent viral activation after exposure. Therefore, although the initial response of the host is effective in reducing and controlling the numbers of cells infected by VI H, it is not sufficient to prevent latent post-infection or persistent asymptomatic infections at low level (PN B) of the recipient cells of the host. host, such as lymphocytes Circulating CD4 + T and monocytes / macrophages. Therefore, the final pathogenic effects of HIV are not avoided and after the induction of the latent state of GNP, the acquired immune deficiency syndrome (SI AD) develops. Central nervous system (CNS) disease is a prominent feature of patients infected with VI H who manifest symptoms of SI DA. Symptoms related to this CNS affliction include paralysis, dementia and death. While CNS disease associated with HIV occurs in the establishment of VI H infection, the etiology of the disease is likely due to the host's response to the virus rather than to a direct viral cytolytic effect. No cure has yet been found for HIV infection and CNS diseases associated with it. Current treatments try to slow the progress of the disease or relieve its symptoms. While drugs have been used or have been proposed for treatment of VI H infection, including the recent introduction of several VI H protease inhibitors, none has been shown to be completely effective. In particular, a therapeutic agent specifically addressing CNS diseases associated with HIV infection has not been offered. Therefore, there is a need in the art to develop therapeutic agents to treat CNS diseases associated with VI H infection. COMPENDIUM OF THE INVENTION It is an object of the invention to provide a method for treating diseases of the central nervous system associated with infection by human immunodeficiency virus. These and other objects of the invention are provided by one or more of the modalities described below. One embodiment of the invention provides a method for treating diseases of the central nervous system associated with human immunodeficiency viral infection which comprises administering to a patient in need of such treatment a therapeutically effective amount of a protein kinase C inhibitor. Therefore, the present invention provides the art with effective compounds for treating CNS diseases associated with HIV. DETAILED DESCRIPTION OF THE INVENTION It is a discovery of the present invention that a particular class of protein kinase C inhibitors, ie inhibitors of the protein kinase C-isozyme, and especially selective inhibitors of PKC isozyme β, have therapeutic effects on CNS diseases associated with HIV infection and specifically retard the effect of gp120 on the HIV-infected patient. gp120 is a product of the VI H genome that is protected in the extracellular space of cells infected by VI H. gp120 can induce neurotoxicity both in vitro and in vivo (Gendilman et al., 1994, J. Leukocyte Biol. 56: 389-398; Crow and others, 1994, J. Leukocyte Biol., 56: 215-21 7; Rosenberg Z and Fauci A., 1990. Immunol. Today 1 1: 176-180; Mosier D and Sieburg H. , 1994. Immunol. Today 1 5: 332-339). The cells Astroglial positive for gp120, especially reactive astrocytosis or alternatively called reactive gliosis, have been implicated in CNS damage leading to CNS manifestations seen in HIV-infected patients. It has been demonstrated that no transgenic mouse infected with VI H with the directed over-expression of gp120 to the astroglial cells exhibits neuronal and glial damage that closely resembles what is observed in the brain of HIV-infected patients who exhibit CNS symptoms. (Toggas et al., 1994. Nature 367: 188-193). It is known that gp120 activates PKC, PKC activity is up-modulated in gp120-positive HIV-1 transfected cells, in the CNS of gp120 transgenic mice, and in the specimens of brains of patients infected by VI H. It is known that the presence of gp120 induces a prominent elevation of mRNA levels of the stabilized glial fibrillary acidic protein (GFAP) in gp120 transgenic mice that correlate with PKC activation (Wyss-Coray, et al., J. Clin. Invest., 97 (3): 789-798 (1996)). GFAP causes astrocytosis, a condition closely related to CNS disease. The upregulation of GFAP is implicated in neuronal damage and prominent reactive astrocytosis of central nervous system (CNS) disease associated with VI H. The effects of gp120 are decreased by PKC inhibitors but not by protein ke A inhibitors (Wyss-Coray, et al., J. Clin. Invest., 97 (3): 789-798 (1996)).

Although we do not wish to be limited to any technical explanation, applicants think neurotoxicity of the SNC related to HIV is due to PKC activation induced by gp120 and reactive gliosis. The PKC pathway is a necessary component in reactive gliosis that occurs in patients with CNS diseases related to HIV. The ability of PKC inhibitors to block the activation of astroglial cells induced by gp120 demonstrates that therapy that specifically interferes with the PKC pathway could block reactive astrogliosis and its concomitant neurotoxicity that leads to the clinical symptomatology associated with CNS disease related to HIV. Therefore, the present invention proposes PKC inhibitor compounds, selectively displaying the β-isozyme, to be used therapeutically to slow or stop the progression of CNS disorders and decrease paralysis, dementia and death associated with CNS complications related to VI H. The method of this invention preferably utilizes those protein ke C inhibitors that effectively inhibit the β-isozyme. A suitable group of compounds is generally described in the prior art as bis-indolylmaleimides or macrocyclic bis-indolylmaleimides. The bis-indolylmaleimides well recognized in the prior art include those compounds described in the Patents of E.U.A. Nos. 5,621,098, 5,552,396, 5,545,636, 5,481, 003, 5,491, 242 and 5,057,614, incorporated herein by reference. The macrocyclic bis-indolylmaleimides are in particular represented by the compounds of the formula I. These compounds and methods for their preparation have been described in the Patent of E. U.A. Do not. ,552,396, which is incorporated herein by reference. These compounds are administered in a therapeutically effective amount to a human to treat CNS diseases associated with HIV infection, especially to inhibit the effects of gp120 in HIV-infected patients. & These compounds can also be administered to patients who are at risk for the disease conditions mentioned above as prophylactics. A preferred class of compounds for use in the method of the invention has the formula (I) where. W is -O-, -S-, -SO-, -S02-, -CO-, C2-C6 alkylene, substituted alkylene, C2-C6 alkenylene, -aryl, -aryl (CH2) mO-, -heterocycle -, heterocycle- (CH2) m-, bicyclic fused-, -cyclic fused- (CH2) mO, - NR3-, -ÑOR3-, -CON H-, or -N HCO-; X and Y are independently C1-C4 alkylene, substituted alkylene, or together X, Y, and W combine to form - (CH2) n-AA-; R1 are hydrogen or up to four optional substituents independently selected from halo, C1-C alkyl, hydroxy, d-C4 alkoxy, haloalkyl, nitro, -NR4R5, or -N HCO (C1-C4 alkyl); R2 is hydrogen, CH3CO-, -N H2 or hydroxy; R 3 is hydrogen, - (CH 2) -aryl, C 1 -C 4 alkyl, -COO (C 1 -C 4 alkyl), -CON R 4 R 5, - (C = NH) N 2, -SO (d-C 4 alkyl), -SO2 (NR4R5) or -SO2 (C? -C alkyl); R4 and R5 are independently hydrogen, C? -C alkyl, phenyl, benzyl or is combined with the nitrogen which are attached to form a saturated or unsaturated 5 or 6 membered ring; AA is an amino acid residue; m is independently 0, 1, 2, or 3; and n is independently 2, 3, 4, or 5, or a pharmaceutically acceptable salt, prodrug or ester thereof. A more preferred class of the compounds for use in this invention is represented by the formula I wherein the -X-W-Y- portions contain from 4 to 8 atoms, which may be substituted or unsubstituted. More preferably, the -X-W-Y- portions contain 6 atoms. Other preferred compounds for use in the method of this invention are those of the formula I wherein R1 and R2 are hydrogen; and W is a substituted alkylene, -O-, S-, -CONH-, -NHCO- or -NR3-. Particularly preferred compounds for use in the invention are compounds of formula 1 a: wherein Z is - (CH2) P- or - (CH2) p-O- (CH2) p-; R 4 is hydroxy, -SH, C 1 -C 4 alkyl, (CH 2) maryl, -N H (aryl), -N (CH 3) (CF 3) -N H (CF 3), or N R 5 R 6; R 5 is hydrogen or C 1 -C 4 alkyl; R6 is hydrogen, C1-C4 alkyl or benzyl; p is 0, 1 or 2; and m is independently 2 or 3, or a pharmaceutically acceptable salt, prodrug or ester thereof. The most preferred compounds of formula 1 a are those wherein Z is CH 2; and R 4 is -NH 2, -N H (CF 3), or -N (CH 3) 2 or a pharmaceutically acceptable salt, prodrug or ester thereof. Other preferred compounds for use in the method of the present invention are compounds wherein W in formula I is -O-, Y is a substituted alkylene and X is an alkylene. These preferred compounds are represented by the formula Ib. wherein Z is - (CH2) P-; R 4 is -N R 5 R 6, -N H (CF) or -N (CH 3) (CF), R 5 and R 6 are independently H or C 1 -C alkyl; p is 0, 1 or 2; and m is independently 2 or 3, or a pharmaceutically acceptable salt, prodrug or ester thereof. The most preferred compounds of formula Ib are those wherein p is 1; and R5 and R6 are methyl. Because they contain a basic portion, the compounds of formulas I, la and Ib can exist as pharmaceutically acceptable acid addition salts. The acids commonly used to form the salts include inorganic acids such as hydrochloric, hydrobromic, hydroiodic, sulfuric and phosphoric acids, as well as organic acids such as para-toluenesulfonic, oxalic, para-bromophenylsulphonic, carbonic, succinic, citric, benzoic, acetic acids. and related inorganic and organic acids. Said pharmaceutically acceptable salts, therefore, include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, mono-hydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, format, isobutyrate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, 2-butyne-1,4-dioate, 3-hexin-2,5-dioate, benzoate, chlorobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, xylene sulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, hipurate, β-hydroxybutyrate, glycolate, maleate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate and the like. In particular, the hydrochloric and mesylate salts are used. In addition to pharmaceutically acceptable salts, other salts may also exist. They can serve as intermediates in the purification of the compounds, in the preparation of other salts or in the identification and characterization of the compounds and intermediates. The pharmaceutically acceptable salts of the compounds of the formulas I, la and Ib can also exist as several solvates, such as with water, methanol, ethanol, dimethylformamide, ethyl acetate and the like. Mixtures of said solvates can also be prepared. The source of said solvate can come from the crystallization solvent, it can be inherent in the preparation or crystallization solvent or adventitious with said solvent. It is recognized that various stereoisomeric forms of the compounds of formulas I, la and Ib may exist; for example, W may contain a chiral carbon atom in the substituted alkylene moiety. The compounds are normally prepared as racemates and conveniently can be used as such. Alternatively both individual enantiomers can be isolated or synthesized by conventional techniques if desired.

Said racemates and individual enantiomers and mixtures thereof are part of the compounds used in the methods of the present invention. The compounds used in this invention also encompass pharmaceutically acceptable drugs of the compounds of formulas I, la and Ib. A prodrug is a prodrug that can be chemically modified and may be biologically inactive at its site of action, but which can be degraded or modified by one or more enzymatic processes or other processes in vivo to the mother's bioactive form. This prodrug may probably have a different drug-kinetic profile than the mother form, allowing easier absorption through the mucosal epithelium, better salt formation or solubility and / or improved systemic stability (an increase in plasma half-life, by example). Typically, said chemical modifications include the following: 1) ester or amide derivatives that can be separated by esterases or lipases; 2) peptides that can be recognized by specific and non-specific proteases; or 3) derivatives that accumulate at a site of action through membrane selection of a prodrug form or a modified prodrug form; or any combination of 1 to 3, supra. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example in, H. Bundgaard, Design of Prodrugs, (1985).

The synthesis of various bis-indole-N-maleimide derivatives are described in Davis et al., Patent of E.U.A. No. 5,057,614 and the synthesis of preferred compounds suitable for use in this invention are described in the Patents of E.U.A. previously identified 5,552,396 and Faul et al. EP 0 657 41 1 A1, all of which are incorporated herein by reference. A preferred protein kinase inhibitor for use in the method of this invention is the compound described in Example 5g hydrochloride salt of ((S) -3,4- [N, N -'- 1, 1 '- ( (2"-ethoxy) -3" '(0) -4"' - (N, N-dimethylamino) -butane) -bis (3,3'-indolyl)] - 1 - (H) -pyrrole-2 , 5-dione of the above-mentioned U.S. Patent 5,552,396.This compound is a potent inhibitor of protein kinase C. It is selective for protein kinase C over other kinases and is highly isozyme-selective, ie it is selective for beta-1 and beta 2 isozymes. Other salts of this compound could also be favored, especially the mesylate salts A preferred mesylate salt can be prepared by reacting a compound of the formula II. with the methanesulfonic acid in a non-reactive organic solvent, preferably an organic / water mixture, and more preferably water-acetone. Other solvents such as methanol, acetone, ethyl acetate and mixtures thereof are also operable. The ratio of the solvent to water is not critical and is generally determined by the solubility of the reagents. The preferred solvent to water ratios are generally from 0.1: 1 to 100: 1 solvent to water by volume. Preferably, the ratio is 1: 1 to 20: 1 and more preferably 5: 1 to 10: 1. The optimum ratio depends on the selected solvent and preferably is a solvent ratio of acetone to water of 9: 1. The reaction usually involves approximately equimolar amounts of two reactants, although other ratios are operative, especially those in which methanesulfonic acid is in excess. The methanesulfonic acid addition rate is not critical to the reaction and can be added quickly (<5 minutes) or slowly for 6 or more hours. The reaction is carried out at temperatures ranging from 0 ° C to reflux. The reaction mixture is stirred until Complete the formation of the salt, as determined by the powder diffraction of x-rays and can take from 5 minutes to 12 hours. The salts of the present invention are preferably and easily prepared as a crystalline form. The trihydrate form of the salt can easily be converted to the monohydrate when dried or exposed to 20-60% relative humidity. The salt is substantially crystalline demonstrating a defined melting point, birefringency and a diffraction pattern of x-rays. Generally, the crystals have less than 10% amorphous solids and preferably less than 5% and still more preferably less than 1% amorphous solids. The mesylate salt is isolated by filtration or other separation techniques appreciated in the art, directly from the reaction mixture in yields ranging from 50% to 100%. Recrystallization and other purification techniques known in the art can be used to further purify the salt if desired. One skilled in the art will recognize that a therapeutically effective amount of the protein kinase C inhibitor of the present invention is sufficient to decrease the clinical symptomatology of CNS diseases associated with HIV infection or the amount sufficient to inhibit CNS disorders. induced by gp120. Within the ability of a person skilled in the art is to measure well the neurotoxicity of gp120 including, but not limited to, neuronal damage associated with CNS diseases. The amount administered varies among other things, depending on the concentration of the compound in the therapeutic formulation, and the patient's body weight. Usually, an amount of protein kinase C inhibitor that will be administered as a therapeutic agent for CNS disease associated with VI H will be determined on a case-by-case basis by the physician. As a guideline, the degree of infection, the resistance of the immune system, the body weight and the age of the patient will be considered when an appropriate dose is established. Generally, a suitable dose is one which results in a concentration of the protein kinase C inhibitor in the treatment site in the range of 0.5 mM to 200 μM and more usually 0.5 nM to 200 nM. It is expected that serum concentrations of 0.5 nM to 20 nM will be sufficient in most circumstances. To obtain these treatment conditions, a patient in need of treatment will probably be administered between approximately 0.001 mg per day per kg. of body weight and 50.0 mg per day per kg. Usually, no more than about 10.0 mg per day per kg will be necessary. of body weight of protein kinase C inhibitor. As noted above, the above amounts may vary on a case-by-case basis. The effectiveness of the compounds of the invention on CNS diseases related to VI H can be tested both in vitro and in vivo. See Toggas et al., Nature 367: 188-193, 1994; and Wyss-Coray and others, J. Clin. Invest. 97: 789-798, 1996 for detailed description. Both references are incorporated herein by reference. The effects of the invention compounds of cultured viral cell phenotype over-expressing gp120 can be tested in vitro. A capacity of Compounds to inhibit the expression of the "activated astroglial cell phenotype" as exemplified by a reduction in the expression of fibrillar acidic protein (GFAP) could indicate a positive response of the compounds to attenuate CNS manifestations in patients infected by VI H. they can use transgenic mice that overexpress gp120 to test the effects of the compounds of the invention in vivo. Using histological analysis, compounds that induce a reduction in reactive gliosis and concomitant neurotoxicity in mice that overexpress gp120 could be highly predictive of a beneficial effect of the compounds for treating CNS diseases associated with LV infection. of the formula I and the preferred compounds of the formulas la and Ib are preferably formulated before administration. Suitable pharmaceutical formulations are prepared by known procedures using well-known and readily available ingredients. To form the compositions suitable for use in the method of the present invention, the active ingredient will usually be mixed with a vehicle, or diluted by a vehicle, or enclosed within a vehicle which may be in the form of a capsule, sac, paper or other container. When the vehicle serves as a diluent, it can be a solid, semi-solid or liquid material that acts as a vehicle, excipient or medium of the active ingredient. Thus, the compositions can take the form of tablets, pills, powders, troches, sacks, sealed capsules, elixirs, suspensions, emulsions, solutions, syrups, aerosol (as a solid or in a liquid medium), hard and soft hard gelatin capsules, suppositories, sterile injectable solutions and sterile packaged powders for oral or topical application. Some examples of suitable carriers, excipients and diluents include lactose, dextrose, sucrose, sorbitol, mannitol, starches, acacia gum, calcium phosphates, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water syrup , methyl cellulose, methyl and propyl benzoates, talc, magnesium stearate and mineral oil. The formulations may additionally include lubricating agents, wetting agents, emulsifying and suspending agents, preservatives, sweetening agents or flavoring agents. The compositions of the invention can be formulated so as to provide rapid, sustained or delayed release of the active ingredient after administration to the patient. The compositions are preferably formulated in a unit dosage form, each dose containing from about 0.05 mg to about 3 mg, more usually about 750 mg of the active ingredient. However, it will be understood that the therapeutic dose administered will be determined by the physician in view of the relevant circumstances which include the severity of the condition to be treated, the choice of compound to be administered and the chosen route of administration. Therefore, the above dose varies and is not intended to limit the scope of the invention in any way. The term "unit dose form" refers to physically described units suitable as unit doses for human subjects and other mammals, each unit containing one predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical carrier. In addition to the above formulations, most of which can be administered orally, the compounds used in the method of the present invention will also be administered topically. Topical formulations include ointments, creams and gels. Ointments are generally prepared using (1) an oil base, i.e., one consisting of fixed oils or hydrocarbons, such as white petrolatum or mineral oil, or (2) an absorbent base, i.e., one consisting of substance or anhydride substances that can absorb water, for example lanolin anhydride. Commonly, after the formation of the base, either oil or absorbent, the active ingredient (compound) is added to an amount that gives the desired concentration. The creams are oily / aqueous emulsions. They consist of an oil phase (internal phase), usually comprising fixed oils, hydrocarbons and the like, such as waxes, petrolatum, mineral oil and the like and an aqueous phase (continuous phase), which comprises water and water-soluble substances, such as salts added. The two phases are stabilized using an emulsifying agent, for example, an active surface agent, such as sodium lauryl sulfate, hydrophilic colloids, such as acacia colloidal clays, "veegum" and the like. When formulating the emulsion, the active ingredient (compound) is commonly added in an amount to achieve the desired concentration.

The gels comprise a base selected from an oleaginous base, water or an emulsion-suspension base. To the base is added a gelling agent that forms a matrix in the base, increasing its viscosity. Examples of gelling agents are hydroxypropyl cellulose, acrylic acid polymers and the like. Commonly, the active ingredient (compounds) is added to the formulation at the desired concentration at a point preceding the addition of the gelling agent. The amount of compound incorporated in a topical formulation is not critical; the concentration should be within a sufficient scale to allow easy application of the formulation to the area of affected tissue in an amount that will deliver the desired amount of the compound to the desired treatment site. The common amount of a topical formulation that will be applied to affected tissue will depend on the concentration of the compound in the formulation. Generally, the formulation will be applied to the affected tissue in an amount that gives from about 1 to about 500 μg of compound per cm2 of an affected tissue. Preferably, the applied amount of the compound will vary from about 30 to about 300 μg / cm2, more preferably, from about 50 to about 200 μg / cm2 and more preferably, from about 60 to about 100 μg / cm2. The following formulation examples are illustrative only and are not intended to limit the scope of the invention in any way.

Formulation 1 Hard gelatine capsules are prepared using the following ingredients: Amount (mg / capsule) Active Agent 5 Starch, dry 200 Magnesium stearate 10 Total 21 5 mg The above ingredients are mixed and filled into hard gelatin capsules in amounts of 460 mg.

Formulation 2 A tablet is prepared using the following ingredients: Amount ((rmg /? Capsul la) Active Agent 15 Cellulose, microcrystalline 10 Silicon dioxide, smoked 10 Stearic acid 5 Total 40 mg The components are mixed and compressed to form tablets each weighing 665 mg.

Formulation 3 Tablets are formed each containing 60 mg of active ingredient Quantity (mg / capsule) Active Agent 60 mg Starch 45 mg Microcrystalline cellulose 35 mg Polyvinylpyrrolidone (as a 10% solution in water) 4 mg Sodium carboxymethyl starch 4.5 mg Stearate of magnesium 0.5 mg Talcum 1 mg Total 1 50 mg The active ingredient, starch and cellulose are passed through a U.S. mesh screen. No. 45 and they mix thoroughly. The polyvinylpyrrolidone solution is mixed with the resulting powders which are then passed through a No. 14 mesh U.S sieve. The granules thus produced are dried at 50 ° C and passed through a U-sieve. S No. 18 mesh. Sodium carboxymethyl starch, magnesium stearate and talc, previously passed through a No. 60 mesh U.S sieve, is then added to the granules which, after mixing, compress to a tableting machine for tablets weighing each 1 50 mg.

The principles, preferred embodiments and modes of operation of the present invention have been described in the above specification. The invention which is intended to be protected in the present, however, should not be construed as limited in the particular forms described, since it should be considered as illustrative rather than restrictive. Variations and changes can be made by those skilled in the art without departing from the spirit of the invention.

Claims (9)

1. REVIVAL DICTION IS 1. A method for treating central nervous system disease associated with human immunodeficiency virus which comprises administering to a patient in need of such treatment a therapeutically effective amount of a protein kinase C isozyme β inhibitor.
2. 2. The method of claim 1, wherein the inhibitor of the protein isozyme β of protein kinase c is a bis-indolylmaleimide or a macrocyclic bis-indolylmaleimide.
3. 3. The method of claim 1 wherein the inhibitor is isozyme-selective and wherein the isozyme selectivity is selected from the group consisting of beta-1 and beta-2 isozymes.
4. 4. The method of claim 3, wherein the protein kinase C inhibitor has the following formula: wherein: W is -O-, -S-, -SO-, -S02-, -CO-, C2-C6 alkylene, substituted alkylene, C2-C6 alkenylene, -aryl, -aryl (CH2) mO- , -heterocycle-, heterocycle- (CH2) m-, fused bicyclic-, bicyclic-fused- (CH2) mO, -NR3-, -ÑOR3-, -CON H-, or -N HCO-; X and Y are independently C1-C4 alkylene, substituted alkylene, or together X, Y, and W combine to form - (CH2) n-AA-; R1 are hydrogen or up to four optional substituents independently selected from halo, C? -C4 alkyl, hydroxy, C? -C alkoxy, haioalkyl, nitro, -NR4R5, or -N HCO (d-C4 alkyl); R2 is hydrogen, CH3CO-, -N H2 or hydroxy; R3 is hydrogen, - (CH) maryl, C1-C4 alkyl, -COO (C1-C4 alkyl), -CONR4Rs, - (C = NH) NH2, -SO (C1-C4 alkyl), -S02 ( NR4R5) or -S02 (C? -C alkyl); R4 and R5 are independently hydrogen, d-04 alkyl, phenyl, benzyl or is combined with nitrogen which are attached to form a saturated or unsaturated 5 or 6 membered ring; AA is an amino acid residue; m is independently 0, 1, 2, or 3; and n is independently 2, 3, 4, or 5, or a pharmaceutically acceptable salt, prodrug or ester thereof. The method of claim 4, wherein the protein kinase C inhibitor has the following formula. wherein Z is - (CH2) P- or - (CH2) p-0- (CH2) p-; R 4 is hydroxy, -SH, C 1 -C 4 alkyl, (CH 2) maryl, -N H (aryl), -N (CH 3) (CF 3) -N H (CF 3), or NRSR 6; Rs is hydrogen or C?-C 4 alkyl; R6 is hydrogen, C1-C4 alkyl or benzyl; p is 0, 1 or 2; and m is independently 2 or 3, or a pharmaceutically acceptable salt, prodrug or ester thereof. 6. The method of claim 4, wherein the protein kinase C inhibitor has the following formula: H wherein Z is - (CH2) P-; R 4 is -NR 5 R 6, -N H (CF) or -N (CH 3) (CF), R 5 and R 6 are independently H or d-C 4 alkyl; p is 0, 1 or 2; and m is independently 2 or 3, or a pharmaceutically acceptable salt, prodrug or ester thereof. 7. The method of claim 4, wherein the protein kinase C inhibitor comprises (S) -3,4- [N, N'-1, 1 '- ((2"-ethoxy) -3'" (0). ) -4 '"- (N, N-dimethylamino) -butane) -bis- (3,3'-indolyl)] - 1 (H) -pyrrole-2, 5-dione or its pharmaceutically acceptable acid salt. A method of claim 7, wherein the pharmaceutically acceptable acid salt is selected from the hydrochloride salt and the mesylate salt 9. A method for inhibiting the central nervous system disease induced by gp120 comprising administering to a patient such a treatment requires a therapeutically effective amount of an inhibitor of the protein kinase C β isozyme 1. The method of claim 9, wherein the inhibitor is isozyme-selective and wherein the isozyme selectivity is selected from the group it consists of beta-1 and beta-2 isozymes 12. The method of claim 1, wherein the protein kinase C inhibitor has the following formula: wherein: W is -O-, -S-, -SO-, -S02-, -CO-, C2-C6 alkylene, substituted alkylene, C2-C6 alkenylene, -aryl, -aryl (CH2) mO- , -heterocycle-, heterocycle- (CH2) m-, fused bicyclic-, -bicyclic fused- (CH2) mO, -N R3-, -ÑOR3-, -CON H-, or -NHCO-; X and Y are independently C1-C4 alkylene, substituted alkylene, or together X, Y, and W combine to form - (CH2) n-AA-; R1 are hydrogen or up to four optional substituents independently selected from halo, C1-C4 alkyl, hydroxy, C1-C4 alkoxy, haloalkyl, nitro, -NR4R5, or -N HCO (d-C4 alkyl); R2 is hydrogen, CH3CO-, -N H2 or hydroxy; R3 is hydrogen, - (CH2) maryl, C1-C4 alkyl, -COO (C1-C4 alkyl), -CON R4R5, - (C = NH) N H2, -SO (d-C4 alkyl), - S02 (NR4R5) or -S02 (d-C4 alkyl); R 4 and R 5 are independently hydrogen, C 1 -C 4 alkyl, phenyl, benzyl or is combined with nitrogen which are attached to form a saturated or unsaturated 5 or 6 membered ring; AA is an amino acid residue; m is independently 0, 1, 2, or 3; and n is independently 2, 3, 4, or 5, or a pharmaceutically acceptable salt, prodrug or ester thereof. 13. A method of claim 12, wherein the protein kinase C inhibitor has the following formula: wherein Z is - (CH2) P- or - (CH2) p-0- (CH2) p-; R4 is hydroxy, -SH, d-C4 alkyl, (CH2) maryl, -N H (aryl), -N (CH3) (CF3) -N H (CF3), or N RSR6; Rs is hydrogen or C?-C 4 alkyl; R6 is hydrogen, C1-C4 alkyl or benzyl; p is 0, 1 or 2; and m is independently 2 or 3, or a pharmaceutically acceptable salt, prodrug or ester thereof. 14. A method of claim 12, wherein the protein kinase C inhibitor has the following formula: wherein Z is - (CH2) P-; R 4 is -N R 5 R 6, -NH (CF) or -N (CH 3) (CF), R 5 and R 6 are independently H or C 1 -C 4 alkyl; p is 0, 1 or 2; and m is independently 2 or 3, or a pharmaceutically acceptable salt, prodrug or ester thereof. The method of claim 12, wherein the protein kinase C inhibitor comprises (S) -3,4- [N, N'-1, 1 '- ((2"-ethoxy) -3'" (0) -4 '"- (N, N-dimethylamino) -butane) -bis- (3,3'-indolyl)] - 1 (H) -pyrrole-2,5-dione or its pharmaceutically acceptable acid salt. 16. A method of claim 15, wherein the pharmaceutically acceptable acid salt is selected from the hydrochloride salt and the mesylate salt.