WO2007065032A2 - Composes et methodes permettant d'inhiber une entree virale - Google Patents

Composes et methodes permettant d'inhiber une entree virale Download PDF

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WO2007065032A2
WO2007065032A2 PCT/US2006/046399 US2006046399W WO2007065032A2 WO 2007065032 A2 WO2007065032 A2 WO 2007065032A2 US 2006046399 W US2006046399 W US 2006046399W WO 2007065032 A2 WO2007065032 A2 WO 2007065032A2
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compound
hiv
inhibitor
pharmaceutical composition
compounds
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PCT/US2006/046399
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WO2007065032A3 (fr
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Jacquelyn Gervay-Hague
Christopher D. Meadows
Thomas W. North
Yen T. Duong
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The Regents Of The University Of California
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/095—Sulfur, selenium, or tellurium compounds, e.g. thiols
    • A61K31/10—Sulfides; Sulfoxides; Sulfones

Definitions

  • HIV-I human immunodeficiency virus type 1
  • Microbicides act by preventing HIV-I infection through blocking attachment, entry, or early steps of replication (Stone, Nat Rev Drug Discov 1:977-985(2002)).
  • these approved drugs target viral enzymes (reverse transcriptase (RT) and protease (PR)) only after the virus has successfully invaded a host cell.
  • RT reverse transcriptase
  • PR protease
  • T20 or enfuvirtide belongs to a new class of entry inhibitors that blocks fusion of the viral membrane to the target cell membrane. Even though this drug is an entry inhibitor, it requires a specific interaction with the host before it is able to block virus entry.
  • An ideal drug in preventing HIV-I infection would interact specifically with the virus particle and directly inactivate it, thereby rendering the particle non-infectious.
  • the HIV envelope glycoprotein is synthesized as a glycoprotein precursor (gpl ⁇ O), which is cleaved into the surface glycoprotein (gpl20) and the transmembrane protein (gp41). GpI 2 ⁇ and g ⁇ 41 remain noncovalently attached and are present as trimers in virions (Eckert and Kim, Annu Rev Biochem 70:777-810 (2001); Wyatt and Sodroski, Science 280:1884-1888 (1998)). This trimeric complex is located on the surface of HIV-I and is anchored to the viral envelope by the C-terminal domain of gp41. The entry process begins when gpl20 binds to the host receptor CD4.
  • gpl20 Upon interacting with CD4, gpl20 undergoes a conformational change, exposing a binding site for a chemokine coreceptor, either CCR5 (R5) or CXCR4 (X4) (Dimitrov, D. S., Cell 91:721-730 (1997)). Once the coreceptor is bound, it triggers the formation of a transient pre-hairpin intermediate structure in which the viral fusion protein gp41 inserts into the host membrane (Chan and Kim, Cell 93:681- 684(1998)).
  • a chemokine coreceptor either CCR5 (R5) or CXCR4 (X4)
  • fusion of the viral membrane with the cellular membrane is driven by the restructuring of gp41 from the intermediate pre-hairpin into a trimer of hairpins which allows the viral core to enter the host cell (Chan, et al., Cell 89:263-273 (1997); Chan and Kim, Cell 93:681-684(1998); and Weissenhorn, et al., Nature 387:426-430 (1997)).
  • the present invention provides a method for inhibiting viral entry into cells, the method comprising contacting the cells with a viral entry-inhibiting amount of a compound having the formula:
  • each Ar is an independently selected trihydroxyphenyl group; the double bonds adjacent to the sulfone groups are each independently in either a cis or trans orientation; or a pharmaceutically acceptable salt thereof.
  • the present invention provides a method of treating or inhibiting a HIV- viral infection, said method comprising administering to a subject in need of or at risk of such infection, a composition comprising a viral entry inhibiting amount of a compound of the formula:
  • each Ar 1 is a substituted or unsubstituted phenyl, pyridyl or indolyl ring and is other than 3,4,5-trihydroxyphenyl.
  • the present invention provides a pharmaceutical composition comprising an HIV viral entry inhibiting amount of a compound having the formula:
  • each Ar is an independently selected trihydroxyphenyl group; the double bonds adjacent to the sulfone groups are each independently in either a cis or trans orientation; or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable excipient.
  • the composition is formulated for topical use as a gel, cream or ointment.
  • compositions further comprise a compound of the formula:
  • each Ar 1 is a substituted or unsubstituted phenyl, pyridyl or indolyl ring and is other than 3,4,5-trihydroxyphenyl.
  • Figure 1 provides the structures of L-chicoric acid and neutral disulfone-containing analogs (Compound 1 and Compound 2).
  • Figure 2 provides representative data from time-of-addition studies. The data shown is a representative example from 5 independent experiments. The error bars represent variation in the number of foci from the six wells per time point.
  • Figure 3 illustrates the direct inactivation of HIV-I by Compound 2 in the absence of a cellular target.
  • A The chemical structure of Compound 2.
  • B The inhibitory effects of preincubating HIV-I particles with Compound 2 for 2 hours prior to the addition to HeLa H1-JC.37 cells. Infectivity was measured using the FIA.
  • C A similar preincubation experiment was performed with T20 as a negative control.
  • Figure 4 shows that Compound 2 does not bind to a cellular host factor to exert its antiviral activity.
  • HeLa H1-JC.37 cells were incubated with drug at various concentrations for 2 hours. The drug was removed and the cells were washed two times before HIV-I NL4- 3 was added.
  • Compound 2 (A) and T20 (B) a normal dose-response curve was observed when the drug and virus were both added after the cells were pretreated with drug, but there was almost no inhibition when the drug was removed and only virus was added to cells. Data are representative of 3 independent experiments.
  • Figure 5 illustrates probing the binding site of Compound 2 to ogpl40 with SPR competition studies.
  • Figure 6 provides a table of data for antiviral activity of Compound 2 against primary isolates and laboratory-adapted strains of HIV-I and agains SIVmac239.
  • EC 5 0 refers to the concentration of compound that inhibits 50% viral activity, including infective activity, as measured in an in vitro assay, including a focal infectivity assay (described in Pincus, et al. Biotechniques 10:336 (1991)).
  • HIV activity refers to the ability of HIV to complete its infectious life- cycle, including binding, fusing, entering and replicating in a cell, release and/or lysis from a cell, as well as its transmission to another cell or another host. Inhibition of HIV activity can be accomplished by interfering with one or more steps of the HIV infectious life-cycle. HIV activity can be decreased or obliterated. Compounds that decrease HIV activity, measurably decrease (e.g., by 10%, 15%, 30%, 50%) detectable indicators of HIV activity (e.g., viral titer, transmission to another cell, viral nucleic acid levels) in comparison to test samples or individuals that are not contacted with the compounds.
  • HIV activity refers to the ability of HIV to complete its infectious life- cycle, including binding, fusing, entering and replicating in a cell, release and/or lysis from a cell, as well as its transmission to another cell or another host. Inhibition of HIV activity can be accomplished by interfering with one or more steps of the HIV infectious life-cycle. HIV activity
  • Some compounds are "virucidal” or "a virucide.”
  • a virucidal compound prevents the completion of an HIV infectious life cycle upon contact with an HIV virion, thereby obliterating its HIV activity.
  • a virucidal compound decreases the frequency of transmission and can prevent transmission of an HIV virus from a first cell to a second cell, and from a first infected host to a second host.
  • HIV is intended all HTV types, subtypes, groups and clades.
  • HIV types include, without limitation, HIV-I and HIV -2.
  • HIV-I groups include, without limitation, Groups M (main) and O (outgroup).
  • Distinct HIV-I subtypes, or "clades,” within Group M include, without limitation, clades A, B, C, D, E, F, G, H, I, J and K.
  • Clades of HIV are described, for example, in Coffin, et al. y Retroviruses, Cold Spring Harbor Laboratory Press (1997) and in Spira, et ah, J. Antimicrob. Chemother. 51:229 (2003).
  • administering means oral administration, administration as a suppository, topical contact, intravenous, intraperitoneal, intramuscular, intralesional, intranasal or subcutaneous administration, or the implantation of a slow-release device e.g., a mini-osmotic pump, to a subject.
  • Administration is by any route including parenteral, and transmucosal (e.g., oral, nasal, vaginal, rectal, or transdermal).
  • Parenteral administration includes, e.g., intravenous, intramuscular, intra-arteriole, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial.
  • Other modes of delivery include, but are not limited to, the use of liposomal formulations, intravenous infusion, transdermal patches, etc.
  • alkyl by itself or as part of another substituent, means, unless otherwise stated, a straight or branched chain hydrocarbon radical, having the number of carbon atoms designated (i.e. C ⁇ s means one to five carbons).
  • alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, n-pentyl, and the like.
  • alkenyl refers to an unsaturated alkyl group having one or more double bonds.
  • alkynyl refers to an unsaturated alkyl group having one or more triple bonds.
  • Examples of such unsaturated alkyl groups include vinyl, 2-propenyl, crotyl, 2- isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(l,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and the higher homologs and isomers.
  • cycloalkyl refers to hydrocarbon rings having the indicated number of ring atoms (e.g., C 3-6 cycloalkyl) and being fully saturated or having no more than one double bond between ring vertices.
  • alkoxy alkyl groups and acyl groups (respectively) that are attached to the remainder of the molecule via an oxygen atom.
  • halo or halogen
  • substituents mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom.
  • terms such as “haloalkyl,” are meant to include monohaloalkyl and polyhaloalkyl.
  • C 1 - 4 haloalkyl is mean to include trifluoromethyl, 2,2,2-trifluoroethyl, 4- chlorobutyl, 3-bromopropyl, and the like.
  • aryl means, unless otherwise stated, a polyunsaturated, typically aromatic, hydrocarbon group which can be a single ring or multiple rings (up to three rings) which are fused together or linked covalently.
  • heteroaryl refers to aryl groups (or rings) that contain from one to five heteroatoms selected from N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quaternized.
  • a heteroaryl group can be attached to the remainder of the molecule through a heteroatom or through a carbon atom.
  • Non- limiting examples of aryl groups include phenyl, naphthyl and biphenyl, while non-limiting examples of heteroaryl groups include 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 1-pyrazolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2- oxazolyl, 4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4- thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2- pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl, purinyl, 2-benzimidazoIyl, benzopyrazolyl, 5- indolyl, 1 -isoquino
  • substituents for each of the " above noted aryl and heteroaryl ring systems are selected from the group of acceptable substituents described below.
  • the above terms e.g., "aryl” and “heteroaryl”
  • aryl and heteroaryl will include both substituted and unsubstituted forms of the indicated radical.
  • Preferred substituents for each type of radical are provided below.
  • aryl and heteroaryl will refer to substituted or unsubstituted versions as provided below.
  • Two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -A-(CH 2 ) r -B-, wherein A and B are independently -CH 2 -, -O-, -NH-, -S-, -S(O)-, -S(O) 2 -, -S(O) 2 NR'- or a single bond, and r is an integer of from 1 to 3.
  • One of the single bonds of the new ring so formed may optionally be replaced with a double bond.
  • heteroatom is meant to include oxygen (O), nitrogen (N), sulfur (S) and silicon (Si).
  • pharmaceutically acceptable salts is meant to include salts of the active compounds which are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein. When compounds of the present invention contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent.
  • salts derived from pharmaceutically-acceptable inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc and the like.
  • Salts derived from pharmaceutically-acceptable organic bases include salts of primary, secondary and tertiary amines, including substituted amines, cyclic amines, naturally- occuring amines and the like, such as arginine, betaine, caffeine, choline, N 5 N'- dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylarninoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperadine, polyamine resins, procaine, purines,
  • acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent.
  • pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, malonic, benzoic, succinic, suberic, fumaric, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like.
  • salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like (see, for example, Berge, S. M., et al, "Pharmaceutical Salts", Journal of Pharmaceutical Science, 1977, 66, 1-19).
  • Certain specific compounds of the present invention contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.
  • the neutral forms of the compounds may be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner.
  • the parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for the purposes of the present invention.
  • the present invention provides compounds which are in a prodrug form.
  • Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the present invention. Additionally, prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds of the present invention when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent.
  • Certain compounds of the present invention can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present invention. Certain compounds of the present invention may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present invention and are intended to be within the scope of the present invention.
  • Certain compounds of the present invention possess asymmetric carbon atoms (optical centers) or double bonds; the racemates, diastereomers, geometric isomers, regioisomers and individual isomers (e.g., separate enantiomers) are all intended to be encompassed within the scope of the present invention.
  • the compounds of the present invention may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds.
  • the compounds may be radiolabeled with radioactive isotopes, such as for example tritium ( 3 H), iodine-125 ( 125 I) or carbon-14 (' C).
  • radioactive isotopes such as for example tritium ( 3 H), iodine-125 ( 125 I) or carbon-14 (' C).
  • AU isotopic variations of the compounds of the present invention, whether radioactive or not, are intended to be encompassed within the scope of the present invention.
  • the present invention derives from the surprising discovery that a small molecule inhibitor of HIV-I was able to directly inactivate HIV-I in the absence of a cellular target.
  • Compound 2 is active against X4, R5 and dual tropic laboratory-adapted and primary strains of HIV-L This compound also binds to the HIV-I envelope glycoprotein, and competition studies map the Compound 2 binding at or near the V3 loop of gpl20. Binding to this site interferes with the sCD4 interaction. With its ability to disable the virus particle, Compound 2 represents a new class of HIV entry inhibitors that can be used as a strategy in the prevention of HW-l/AIDS. Additionally, the compound can be used as part of a combination therapy directed to both the prevention of viral cell entry and the inhibition of, for example, integrase.
  • the present invention provides in one aspect, a method for inhibiting viral entry into cells.
  • cells are contacted with a viral entry- inhibiting amount of a compound having the formula:
  • each Ar is an independently selected trihydroxyphenyl group; the double bonds adjacent to the sulfone groups are each independently in either a cis or trans orientation; and pharmaceutically acceptable salts thereof.
  • the compound has the formula:
  • the viral entry is HIV viral entry.
  • the compound is provided in a topical formulation.
  • the compound is provided in a topical gel, cream or ointment formulation.
  • the compound is administered to a subject with a second agent selected from an HIV-IN inhibitor, and HIV-RT inhibitor, a second viral entry inhibitor and an HlV-protease inhibitor.
  • the second agent is a non-nucleoside reverse transcriptase inhibitor.
  • the second agent is Fuseon ® , a viral entry inhibitor.
  • the two agents are administered sequentially. In other embodiments, the two agents are administered simultaneously.
  • the present invention provides a method of treating or inhibiting a HlV-viral infection, the method comprising administering to a subject in need of or at risk of such infection, a composition comprising a viral entry inhibiting amount of a compound of the formula:
  • each Ar 1 is a substituted or unsubstituted phenyl, pyridyl or indolyl ring and is other than 3,4,5-trihydroxyphenyl.
  • the compounds can be administered separately and sequentially.
  • each of the Ar 1 groups is a substituted or unsubstituted phenyl
  • the substituted phenyl is a phenyl ring having from 1 to 5 substituents independently selected from the group consisting of hydroxy, C- 1 - 5 alkoxy, C 1 .
  • each of the Ar 1 groups is selected from:
  • the present invention provides a pharmaceutical composition comprising an HIV viral entry inhibiting amount of a compound having the formula:
  • each Ar is an independently selected trihydroxyphenyl group; the double bonds adjacent to the sulfone groups are each independently in either a cis or trans orientation; or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable excipient.
  • the composition is formulated for topical administration.
  • the compound is compound 2.
  • the topical compositions are preferably formulated as a topical gel, cream or ointment, but can also be provided as a paste, foam or spray.
  • the pharmaceutical composition further comprises a compound of the formula: wherein the dashed line indicates an optional double bond and each Ar 1 is a substituted or unsubstituted phenyl, pyridyl or indolyl ring and is other than 3,4,5-trihydroxyphenyl.
  • compositions wherein each of the Ar 1 groups is a substituted or unsubstituted phenyl, and the substituted phenyl is a phenyl ring having from 1 to 5 substituents independently selected from the group consisting of hydroxy, C 1 - 5 alkoxy, C 1 - 5 acyloxy, halogen, nitro, CO 2 H, SO 3 H, P(O)(OH) 2 , OSO 3 H and OP(O)(OH) 2 , or wherein two substituents on adjacent carbon atoms are combined to form a fused methylenedioxy or ethylenedioxy ring, and salts and esters thereof.
  • Particularly preferred are those compositions in which the Ar 1 groups are independently selected from:
  • a unique disulfone/diphosphonate reagent (3) was employed in the synthesis of the target compounds (Scheme 1, see Hadd, et al., Tetrahedron Lett., 2001, 42, 5137-5140).
  • HEW Horner-Emmons-Wadsworth
  • the invention provides methods of treating an HIV infection, methods of decreasing the frequency of transmission of an HTV infection, and methods of inhibiting HIV activity in a host, the methods comprising administering to a subject in need thereof an effective amount of one or more of the compounds described herein that inhibit HIV activity.
  • the invention provides methods of preventing an HIV infection, methods of preventing transmission of an HIV infection, and methods of obliterating HIV activity in a host, the methods comprising administering to a subject in need thereof an effective amount of one or more of the compounds described herein.
  • Selected compounds and compositions of the present invention are particularly suited for inhibiting or preventing HIV activity and for decreasing the frequency of or preventing HIV transmission of one or more HIV types and/or subtypes (clades), HIV mutants and HIV variants, and especially those that are unresponsive to currently administered anti-HIV therapies, for instance, currently used HAART therapies.
  • Preferred compounds can inhibit or prevent the HIV activity or transmission of at least two, three, four, five, six or more HIV subtypes or clades.
  • Preferred compounds are HIV virucides.
  • the compounds are administered therapeutically to an HIV infected individual. In some embodiments, the compounds are administered prophylactically to an uninfected individual.
  • the compounds are administered to a subject through any route of administration that allows contact with an HIV virion, and particularly with an HIV envelope protein.
  • the compounds are formulated for oral administration, but can also be administered parenterally, as appropriate.
  • the compounds can be administered by injection (intraveneously, intramuscularly, subcutaneously, intrathecally), or given transdermally, intraocularly, as an inhalant (pulmonary delivery) or intranasally.
  • the compounds are administered orally, intravenously or topically.
  • the compounds are administered topically. Accordingly, the invention further provides for a method for prophylactically or therapeutically decreasing the frequency of or preventing the transmission of an HIV infection, the method comprising topically administering to an individual a pharmaceutical composition comprising an effective amount of one or more of the compounds of the present invention.
  • Compounds formulated in topical pharmaceutical compositions can be prophylactically or therapeutically applied to an individual's skin or mucous membranes to decrease the frequency of or prevent the transmission of HIV infection.
  • the topical composition is preferably introduced into the vagina, at about the time of, and preferably prior to, sexual intercourse, but may also be administered to other topically accessible skin or mucous membrane.
  • Topical compositions can also be administered to the penis, the rectum or the mouth of an individual.
  • the manner of administration is preferably designed to obtain direct contact of the compositions of the invention with an HIV virion.
  • the compounds administered for topical delivery are virucidal.
  • An efficacious or effective amount of one or more compounds is determined by applying methods known to those in the art, generally by first administering a low dose or small amount of compound, and then incrementally increasing the administered dose until a desired effect of inhibited HIV activity is observed in the treated subject, with minimal or no toxic side effects.
  • Applicable methods for determining an appropriate dose and dosing schedule for administration of one or more of the compounds of the present invention are described, for example, in Goodman and Gilman 's The Pharmacological Basis of Therapeutics, 10 th Ed., Hardman, Limbird and Goodman-Gilman, Eds., McGraw-Hill (2001), and in Remington: The Science and Practice of Pharmacy, 21 st Ed., Gennaro, Ed., Lippencott Williams & Wilkins (2003). Further guidance is provided in Pharmaceutical Dosage Forms and Drug Delivery Systems, 7 th Ed., by Ansel, Allen and Popovich, Lippencott Williams & Wilkins (2000).
  • a desired effect of inhibited HIV activity in a host can be measured in any of a number of ways known to those in the art.
  • changes in HIV activity in a host are observed by measuring numbers of CD4 + T cells (CD4 + counts), HIV RNA plasma levels, usually from infected cells, such as CD4 + T cells, before and after treatment with a compound.
  • CD4 + counts CD4 + T cells
  • HIV RNA plasma levels usually from infected cells, such as CD4 + T cells
  • Usually several HIV activity measurements are taken at designated time periods subsequent to commencing administration of the compounds, for instance, bi-weekly, weekly, bi-monthly, monthly, every 2 nd or 3 rd month, semi-annually, annually, as is appropriate.
  • Preferred compounds decrease HIV activity in a host, for instance, by the measured indicators of increasing CD4 + counts or decreasing HIV RNA levels, by at least 5- 10%, more preferably by at least 15%, 20%, 25% or 30%, and most preferably by at least 35%, 40%, 45%, 50% or more.
  • the compounds are administered to enhance the efficacy of chemotherapeutics currently administered to HIV infected individuals.
  • the compounds can be administered in combination with one or more HIV reverse transcriptase inhibitors and/or HIV protease inhibitors.
  • compositions comprising the compounds of the present invention.
  • the pharmaceutical compositions of the present invention comprise one or more compounds that inhibit HIV activity, as described herein, or pharmaceutically acceptable salts thereof, together with one or more pharmaceutically acceptable carriers, diluents and/or excipients.
  • the pharmaceutical compositions are prepared according to methods known in the art based on the desired route of administration (e.g., oral, intravenous, intramuscular, subcutaneous, intravaginal, intrarectal, intranasal).
  • the pharmaceutical compositions can be formulated as, for example, a liquid, gel, semi-solid, solid, cream or ointment.
  • compositions can be aqueous, oil-based Jv emulsified or dry (e.g., a compressed powder).
  • the compound pharmaceutical compositions are prepared in a controlled and/or extended-release formulation (see, for example, U.S. Patent Nos. 6,235,712; 6,187,330; 6,180,608; 6,159,490 and 6,068,850, each of which is hereby incorporated herein by reference).
  • the compounds are encapsulated for delivery.
  • Preferred pharmaceutical compositions allow for delivery of an efficacious amount of the compounds to HIV virion repository sites in a host, and contact of the compound with an HIV virion.
  • the compounds are prepared in pharmaceutical compositions formulated for oral administration.
  • Formulations suitable for oral administration can consist of liquid solutions, such as an effective amount of one or more of the compounds dissolved in diluents, such as water, saline, or fruit juice; capsules, sachets or tablets, each containing a predetermined amount of the active ingredient, as solid, granules or freeze-dried cells; solutions or suspensions in an aqueous liquid; and oil-in-water emulsions or water-in-oil emulsions.
  • diluents such as water, saline, or fruit juice
  • capsules, sachets or tablets each containing a predetermined amount of the active ingredient, as solid, granules or freeze-dried cells
  • solutions or suspensions in an aqueous liquid and oil-in-water emulsions or water-in-oil emulsions.
  • Tablet forms can include one or more of lactose, mannitol, corn starch, potato starch, microcrystalline cellulose, acacia, gelatin, colloidal silicon dioxide, croscarmellose sodium, talc, magnesium stearate, stearic acid, and other excipients, colorants, diluents, buffering agents, moistening agents, preservatives, flavoring agents, and pharmacologically compatible carriers.
  • Suitable formulations for oral delivery can also be incorporated into synthetic and natural polymeric microspheres, or other means to protect the agents of the present invention from degradation within the gastrointestinal tract ⁇ see, for example, Wallace et ah, Science 260, 912-915, 1993).
  • the compounds are prepared in pharmaceutical compositions formulated for intravenous delivery.
  • Formulations suitable for parenteral administration include aqueous and non-aqueous, isotonic sterile injection solutions, which can contain anti-oxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient, and aqueous and non-aqueous sterile suspensions that can include suspending agents, solubilizers, thickening agents, stabilizers, and preservatives.
  • the formulations can be presented in unit-dose or multi-dose sealed containers, such as ampules and vials, and can be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, water, for injections, immediately prior to use.
  • sterile liquid carrier for example, water
  • Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules, and tablets of the kind previously described.
  • the compounds are prepared in pharmaceutical compositions formulated for topical administration, for instance, in a cream, a paste, a gel, a foam, an ointment, a spray, a lubricant, an emulsion or suspension.
  • the pharmaceutical compositions formulated for topical administration comprise one or more compounds.
  • the pharmaceutical compositions formulated for topical administration comprise one or more virucidal compounds that decrease the frequency or prevent the transmission of an HIV virus from a first infected individual to a second individual.
  • Topical microbicidal preparations suitable for formulating pharmaceutical compositions comprising the compounds of the present invention are described in Turpin, Expert Opin. Investig.
  • the compounds are included in about 0.1, 0.2, 0.5, 1.0 or 2.0 wt %, but can be included in as much as 5, 10, 15 or 20 wt % of the total formulation, or more.
  • the compounds are formulated with one or more pharmaceutically acceptable carriers.
  • the pharmaceutically acceptable carrier may additionally comprise organic solvents, emulsif ⁇ ers, gelling agents, moisturizers, stabilizers, other surfactants, wetting agents, preservatives, time release agents, and minor amounts of humectants, sequestering agents, dyes, perfumes, and other components commonly employed in pharmaceutical compositions for topical administration.
  • Solid dosage forms for topical administration include suppositories, powders, and granules.
  • the compositions may be admixed with at least one inert diluent such as sucrose, lactose, or starch, and may additionally comprise lubricating agents, buffering agents and other components well known to those skilled in the art.
  • Compound formulations suitable for vaginal administration can be presented as pessaries, tampons, creams, gels, pastes, foams, or spray formulas.
  • the active ingredient can be combined with a lubricant as a coating on a condom.
  • the active ingredient is applied to any contraceptive device, including, but not limited to, a condom, a diaphragm, a cervical cap, a vaginal ring and a sponge.
  • contraceptive device including, but not limited to, a condom, a diaphragm, a cervical cap, a vaginal ring and a sponge.
  • Formulations for rectal administration can be presented as a suppository with a suitable base comprising, for example, cocoa butter or a salicylate.
  • suitable base comprising, for example, cocoa butter or a salicylate.
  • oligonucleotide Substrates Preparation of Oligonucleotide Substrates.
  • the oligonucleotides 2 Hop, 5'- GTGTGGAAAATCTCTAGCAGT-S 1 and 21bot, 5 1 -ACTGCTAGAGATTTTCCACAC-3 l were purchased from Norris Cancer Center Microsequencing Core Facility (University of Southern California) and purified by UV shadowing on polyacrylamide gel.
  • 2 Hop was 5'-end labeled using T4 polynucleotide kinase (Epicentre, Madison, WI) and ⁇ [ 32 P]-ATP (Amersham Biosciences or ICN).
  • the kinase was heat-inactivated and 21bot was added in 1.5-molar excess.
  • the mixture was heated at 95 °C, allowed to cool slowly to room temperature, and run through a spin 25 mini-column (USA Scientific) to separate annealed double-stranded oligonucleotide from unincorporated material.
  • % I JOOXfJ - .(D - C)Z(N- C)]
  • C, N, and D are the fractions of 21-mer substrate converted to 19-mer (3 '-processing product) or strand transfer products for DNA alone, DNA plus IN, and IN plus drug, respectively.
  • the IC 5O values were determined by plotting the logarithm of drug concentration versus percent inhibition to obtain concentration that produced 50% inhibition.
  • the compounds in Table 1 were first tested against the purified enzyme to determine if functional groups other than hydroxy, acetoxy, and/or methoxy could elicit activity against either 3 '-processing or strand transfer (Table 2).
  • Compound 5 demonstrated moderate activity against both functions
  • 11 showed moderate activity against strand transfer only
  • Focal Infectivity Assay Drug-susceptibility of HTV-I to inhibitors was determined with a focal infectivity assay (FIA) as previously described (see Murry, et al., J. Virol. 2003, 77, 1120-1130; and Giuffre, et al., Antimicrob. Agents Chemother. 2003, 47, 1756-1759). Immunostaining was performed using the monoclonal antibody 22-6 13 at a 1/800 dilution. Foci were counted under a dissecting microscope at.30 to IOOX magnification. Data for drug-susceptibility assays were plotted as a percentage of control foci (no drug) versus inhibitor concentrations. The concentrations required to inhibit focus formation by 50% (EC 5 0) were obtained from a best-fit line of the linear portions of those plots. EC5 0 values for each drug were determined from at least three separate experiments with six determinations per experiment.
  • FFA focal infectivity assay
  • Cytotoxicity Toxicity was determined with the Promega CellTiter 96 Aqueous One Solution Cell Proliferation Assay (MTS assay) using the manufacturer's recommended conditions. Data for cell proliferation assays were plotted as a percentage of control (no drug) versus inhibitor concentrations. The concentrations required to inhibit cell proliferation by 50% (IC 5 0) were obtained from a best-fit line of the linear portions of those plots. IC5 0 values for each drug were determined from at least two separate experiments.
  • a EC50 values are the mean ⁇ SE from three separate determinations.
  • b IC 50 values are the average of two experiments.
  • FIA focal infectivity assay
  • HeLa-CD4 cells expressing human CCR5 these cells naturally express CXCR4, see lenegger, et al., AIDS Research and Human Retroviruses 2001, 17, 243-251 and are permissive for infection by T-cell tropic and macrophage tropic isolates of HIV-I.
  • Compound 7 is the hydrogenated analog of 1.
  • the data from the purified enzyme assays of 1 and 7 strongly correlate with antiviral activity: Both assays show that 7 is approximately half as active as 1.
  • Compound 21 is a protected analog of 2, but unlike 2 it is only active in the FIA.
  • compounds 12, 14, and 20 do not possess IN activity but are rather potent antiviral compounds. The source of this activity apparently stems from cytoxocity (vide supra).
  • T20 and 3TC were generously provided by Dr. Raymond F. Schinazi (Emory University, Atlanta, GA).
  • HeLa H1-JC.37 cells were used for the focal infectivity assay (FIA) (Platt, et al., J Virol 72:2855-2864 (199S)). These cells, which naturally express CXCR4, have been engineered to stably express both CD4 and CCR5, making them permissive to all R5, X4 and dual tropic strains of HIV-I tested. In addition, they are permissive to SIV infection (Kuhmann, et al., J Virol 71 :8642-8656 (1997)).
  • the cells were maintained in Dulbecco modified Eagle medium (DMEM; GIBCO, Invitrogen, Carlsbad, CA), supplemented with 10 % fetal bovine serum (FBS) (Omega Scientific, Tarzana, CA) that had been heat inactivated for 30 minutes at 56°C, 100 U of penicillin per ml, 100 ⁇ g of streptomycin per ml, and 2 mM L-glutamine (GIBCO). All cultures were maintained at 37 0 C with a humidified 5% CO 2 atmosphere.
  • DMEM Dulbecco modified Eagle medium
  • FBS fetal bovine serum
  • All cultures were maintained at 37 0 C with a humidified 5% CO 2 atmosphere.
  • CEMx 174 cells were obtained from Dr. Peter Cresswell through the AIDS Research and Reference Reagent Program, Division of AIDS, NIAID, NHH. They were maintained in RPMI 1640 medium (GIBCO) supplemented with 10% FBS, penicillin, streptomycin, and L- glutamine at concentrations described above. HIV-I NL4-3, 89.6, and HXBc2, and SIV stocks were grown in CEMxl74 cells. HIV-I 89.6, Ba-L, SF162 and all the primary isolates were obtained from the AIDS Research and Reference Reagent Program. HIV-I HXBc2 was
  • NL4-3 and SIVmac239 were produced by transfecting CEMxI 74 cells using electroporation.
  • the plasmid pNL4-3 and the two SIVmac239 half clones were kindly provided by Dr. Paul Luciw (University of California, Davis, Davis, CA) (Luciw, et al., Proc Natl Acad Sd USA 92:7490-7494 (1995)).
  • PBMCs Human peripheral blood mononuclear cells
  • the cells were aliquoted into 24-well plates and maintained in RPMI 1640 medium supplemented with 20% FBS, 5% human IL-2, 100 U of penicillin per ml, 100 ⁇ g of streptomycin per ml, and 2 mM L-glutamine (GIBCO).
  • the recombinant human IL-2 was obtained from Dr.
  • the cells were incubated for 4 days at 37°C and a humidified 5% CO 2 atmosphere. Cells were fixed and immunostained according to previously described methods (Meadows, et al., ibid; and Murry, et al., J Virol 77: 1120-1130 (2003)). Data were plotted as a percentage of control foci (no drug) versus inhibitor concentration. Within each experiment, each value represents the mean of at least five replicate wells. Concentrations required to inhibit focus formation by 50% (EC50S) were obtained directly from the linear portion of these plots by using a computer-generated regression line. Results from three or more independent experiments were used to derive the EC50 values plus or minus standard error.
  • E50S Concentrations required to inhibit focus formation by 50%
  • the virus solution (100 ⁇ l per well) was added to a 96-well microtiter plate seeded with HeLa H1-JC.37 as described for the FIA. For each drug concentration, there were 5 replicate wells. The virus was allowed to adsorb for 2 hours at 37 0 C 3 followed by the addition of 100 ⁇ l of growth medium and FBS to bring the FBS concentration to 10%. The standard procedure for the FIA was followed for immuno staining the cells, quantification of foci, and data analysis (see above).
  • the virus solution was removed and the cells were washed two times with media using centrifugation to remove unadsorbed virus. Finally, the cells were resuspended in media containing 10% FBS and aliquoted into a 96-well microtiter plate at 225 ⁇ l per well. Following 4 days of incubation at 37°C, 200 ⁇ l per well of supernatant was removed and added to p24 ELISA plates. The ⁇ 24 ELISA was used to measure virus replication (Higgins, et al., J CHn Microbiol 24:424-430(1986)), and data were analyzed as described for the FIA (see above).
  • HeLa H1-JC.37 cells (4.5 x 10 3 cells per well) were seeded into 96-well microtiter plates and incubated overnight at 37°C. The medium was removed and 100 ⁇ l per well of DMEM containing 0.1 % FBS and the desired drug concentration was added and incubated for 2 hours. Compound 2 and T20 concentrations in this experiment were the same as in the drug-virus preincubation experiment (see above). The medium with drug was then removed and the cells were washed twice with DMEM plus 0.1% FBS. 100 ⁇ l per well of medium containing 0.1% FBS and 20-60 ffu/well of HIV-I NL4-3 was added and incubated for 2 hours.
  • a positive control was also included in which drug was added along with virus to the HeLa cells as is performed in the normal drug susceptibility FIA.
  • the volume was then brought up to 200 ⁇ l and 10% FBS and the plates were incubated for 4 days at 37°C in a humidified 5% CO 2 atmosphere: The FIA protocol was then followed for immunostaining, quantification of foci, and data analysis.
  • Residual reactive groups were deactivated with a 7 min injection of 1 M ethanolamine hydrochloride, pH 8.5 (20 ⁇ l/min). The surface was then conditioned by three 15 ⁇ l injections of 146 mM phosphoric acid (H3PO 4 ) at 100 ⁇ l/min to remove any noncovalently bound antibody.
  • H3PO 4 phosphoric acid
  • the immobilized goat anti-human Ig was used to capture all the monoclonal antibodies (mAbs). Several of these mAbs were provided as crude supernatant or contained other additives that would have made direct immobilization of the mAbs difficult (Canziani, et al., Anal Biochem 325:301-307 (2004)).
  • the antibodies used in the competition studies were 5F3 (gp41 - aa 526-543), F240 (gp41 - aa 592-606), bl2 (gpl20 - CD4 binding site), F425 B4e8 (gpl20 - base of V3 loop), 48d (gpl20 - CD4i epitope), and 17b (gpl20 - CD4i epitope).
  • the mAbs were diluted to 10 ⁇ g/ml in running buffer and injected for 1 min at 20 ⁇ l/min over Fc2 or Fc4.
  • the antigen 50 nM ogpl40 (Srivastava, et al., J Virol 77:11244-11259 (2003)), was preincubated with 0, 1, 5, or 10 ⁇ M Compound 2 for 30 min then injected over all Fes for 1 min at 20 ⁇ l/min.
  • the I min analyte injection consisted of 50 nM ogpl40 preincubated with Compound 2 and 150 nM sCD4.
  • Antigen binding data were analyzed by aligning all the sensorgrams, including the buffer response, on the x axis and zeroing on the y axis. Systematic noise and other artifacts that occurred in all 4 flow cells were removed by subtracting the antigen responses with the response from the reference flow cell, FcI . Antigen data were then double referenced by subtracting the buffer injection (Myszka, ibid). To be able to compare the responses from different injection cycles, the antigen responses were normalized for the differences in the amount of antibody captured on the surface (Canziani, et al., Anal Biochem 325:301-307 (2004)). Normalization was performed by dividing the antigen response data by the mAb capture level within the injection cycle. The antibody capture level was determined by the baseline level immediately prior to the antigen injection (Canziani, et al., ibid).
  • Ogpl40 contains gpl20 (with a partial deletion in the V2 loop) and the ectodomain of gp41, was employed. Ogpl40 was used in these studies, rather than the monomelic gpl20, because it represents a more biologically relevant target.
  • the protein has been shown to resemble the native glycoprotein on the virus surface through antibody- binding and structure characterization (Srivastava, et al., J Virol 77:11244-11259 (2003)).
  • ogpl40 also contains the ectodomain of gp41 which has proven to be important as a target for entry inhibition (Bianchi, et al., Proc Natl Acad Sci USA 102:12903-12908 (2005); and Chan and Kim, Cell 93:681-684 (1998)).
  • CM5 chip Biacore
  • Compound 2 Binds at or Near the Base of the V3 Loop of gpl20 and Blocks CD4 Attachment.
  • Ogpl40 preincubated with 0, 1, 5 and 10 ⁇ M of Compound 2 was then injected over the surface and binding to each mAb was measured simultaneously.
  • the binding levels observed for each mAb were equal to ogpl40 alone ( Figure 5, A and B), indicating that gp41 is not the target of Compound 2.
  • Compound 2 was most potent against both a B clade dual tropic virus (92TH014) and a C clade R5 tropic virus (98TZO13) with an EC50 value of 190 nM.
  • the activity against SIVmac239 indicates that Compound 2 may be interfering with a conserved region involved in the interaction between these viruses and their target cells.
  • Entry inhibitors are attractive candidates for prophylactic microbicide development to prevent the sexual transmission of HIV-I .
  • Inhibitors that block the early stages of the replication cycle attachment, coreceptor and fusion inhibitors
  • Anti-HIV agents that have moved into Phase III clinical trials for the development of HIV-I microbicides are detergents (Savvy) or other substances (PRO 2000) that do not specifically target the virus .
  • microbicide candidates target virus replication (tenofovir), bind to gp41 (2F5), or target host-cell structures, such as CD4 (TNX- 355) or CCR5 (PSC-RANTES) (Lederman, et al., Nat Rev Immunol 6:371-382 (2006)).
  • CD4 TNX- 355
  • PSC-RANTES CCR5
  • inhibitor concentrations need to be orders of magnitude higher than the observed EC 50 values obtained in vitro to completely protect against HIV-I infection (Veazey, et al., Nature 438:99-102 (2005)).
  • Compound 2 is a novel small molecule inhibitor that directly inactivates HIV-I in the absence of a cellular target. It is able to inactivate virus in HeLa cells, CEMxI 74 cells and PBMCs. Its specificity to gpl20 is demonstrated by the direct binding of Compound 2 to ogpl40 and its ability to inhibit R5, X4 and dual tropic HIV-I strains, indicating that its mechanism of action is independent of coreceptor usage. Furthermore, there was no direct binding observed between Compound 2 and sCD4 in SPR studies and pretreatment of drug with cells prior to infection of HIV-I showed no virus inhibition. The ability of Compound 2 to bind to gpl20 and inactivate virus further demonstrates that gpl20 is a viable target for small molecule inhibitors to block HIV-I entry.
  • V3 loop has been characterized as a hypervariable region, much of the V3 loop, including the tip and the crown, are highly conserved (Stanfield, et al., J. Virol. 80:6093-6105 (2006)). Studies to structurally define the interaction between Compound 2 and gpl20 are underway, including selections of resistant variants.
  • microbicide should meet the following requirements: (i) be highly potent against HIV-I, (ii) act directly on the virus and inactivate it without the need for metabolic activation, (iii) be effective against a range of HIV-I strains, (iv) have minimal cytotoxic effects, and (v) be relatively inexpensive to manufacture. Cost-effectiveness favors the development of small molecule inhibitors, such as Compound 2.
  • BMS-378806 can inactivate the virus without the presence of the host-cell receptor, though its use as a microbicide in combination with two other compounds, CMPD 167 and C52L, was protective when applied vaginally in the rhesus macaque/SHTV model (Veazey, et al., Nature 438:99-102 (2005)).
  • This experiment showed that small molecule entry inhibitors have the potential to be effective at inhibiting HIV when applied topically to the vaginal surface, especially when used in conjunction with other compounds.
  • Compound 2 is a prototype for a new class of small molecule entry inhibitors that can disarm HIV-I by direct inactivation through a specific interaction with gpl20 without the presence of cellular target. These characteristics make this compound particularly useful as a topical microbicide.

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Abstract

Cette invention concerne une série de composés contenant des disulfones géminaux qui conviennent pour le traitement du VIH. Un inhibiteur de stade précoce agit comme co-récepteur de petites molécules/inhibiteur indépendant d'entrée virale et peut s'utiliser dans le cadre d'une thérapie combinatoire avec d'autres anti-viraux, dont ceux décrits ici.
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015130947A1 (fr) * 2014-02-26 2015-09-03 Howard University Utilisation de dérivés benzène-sulfonamides comme inhibiteurs de l'intégrase du vih

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040167096A1 (en) * 2003-02-19 2004-08-26 Yung-Chi Cheng Anti-viral nucleoside analogs and methods for treating viral infections, especially HIV infections
US6812365B2 (en) * 1999-06-14 2004-11-02 The Arizona Disease Control Research Commission Disulfone reagents and methods of preparing and using same

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6812365B2 (en) * 1999-06-14 2004-11-02 The Arizona Disease Control Research Commission Disulfone reagents and methods of preparing and using same
US20040167096A1 (en) * 2003-02-19 2004-08-26 Yung-Chi Cheng Anti-viral nucleoside analogs and methods for treating viral infections, especially HIV infections

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015130947A1 (fr) * 2014-02-26 2015-09-03 Howard University Utilisation de dérivés benzène-sulfonamides comme inhibiteurs de l'intégrase du vih
US10301258B2 (en) 2014-02-26 2019-05-28 Howard University Benzende sulfonamide derivatives as HIV integrase inhibitors

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