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WO2007053792A2 - Amelioration des proprietes pharmacocinetiques d'inhibiteurs de proteases et d'autres medicaments - Google Patents

Amelioration des proprietes pharmacocinetiques d'inhibiteurs de proteases et d'autres medicaments Download PDF

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Publication number
WO2007053792A2
WO2007053792A2 PCT/US2006/043400 US2006043400W WO2007053792A2 WO 2007053792 A2 WO2007053792 A2 WO 2007053792A2 US 2006043400 W US2006043400 W US 2006043400W WO 2007053792 A2 WO2007053792 A2 WO 2007053792A2
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Prior art keywords
pharmacokinetic
moiety
bifunctional compound
drug
protease inhibitor
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WO2007053792A3 (fr
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Mitchell W. Mutz
Jason E. Gestwicki
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Amplyx Pharmaceuticals Inc
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Amplyx Pharmaceuticals Inc
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Priority to US12/151,329 priority Critical patent/US20080306098A1/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/55—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound

Definitions

  • This invention relates generally to pharmacology and more specifically to the modification of known active agents to give them more desirable properties.
  • HIV protease inhibitors have always been major issues with HIV protease inhibitors due to the frequency of dosage and co-administration of other HIV therapeutics.
  • a reduction in dosage frequency would represent an improvement in quality of life for the patient and a lower chance of toxic side effects due to decreased production of secondary metabolites, especially in the liver.
  • recent HIV protease inhibitors require a reduced dosage burden compared with earlier drugs, there is still significant opportunity for improving PIs by reducing first pass clearance via cytochrome P450 enzymes and increasing the drug half-life in the circulation.
  • HIV protease inhibitors which have diminished half lives due to poor pharmacokinetics are amprenavir, lopinavir, indinavir and ritonavir, among others.
  • Previous methods to improve pharmacokinetics (PK) of HIV protease inhibitors include: medicinal chemistry-based analog synthesis, employing pro-drug strategies, improved fo ⁇ nulation, and co-administration with P450 and P-glycoprotein inhibitors. Regardless of the methods employed, these approaches share a desired outcome: improve pharmacokinetics to make treatment easier for patients.
  • a method for modulating at least one pharmacokinetic property of a protease inhibitor upon administration to a host is provided.
  • the pharmacokinetic modulating moiety binds to at least one intracellular protein.
  • the bifunctional compound has at least one modulated pharmacokinetic property upon administration to the host as compared to a free drug control that comprises the protease inhibitor.
  • a bifunctional compound comprising protease inhibitor functionality and a pharmacokinetic modulating moiety are provided.
  • a bifunctional compound is provided in a pharmaceutical formulation which is designed to have a controlled release mechanism in addition to that provided by the bifunctional compound.
  • the bifunctional compound may comprise a drug moiety that is a protease inhibitor or some other drug.
  • FIG. IA depicts the structure of FK506 linked to a modular linker and target binding moiety, for example a protease inhibitor. Due to the modular nature of the synthesis, the linker group and target-binding group have been altered.
  • FIG. IB illustrates how the steric bulk of an FKBP protein can confer protection from P450 enzymes.
  • the left side depicts the bimodal binding character of FK506 whereby it binds both FKBP and calcineurin.
  • the schematic on the right depicts how the calcineurin- binding mode can be eliminated by substituting a linker and target binding moiety. In this manner, FK506 can simultaneously target FKBP and bind a second protein.
  • FIG. 3 shows the structure of FK506 bound to curcumin.
  • (B) illustrates that FK506-curcumin is protected from CYP3a4, a P450 enzyme, in the presence of FKBP.
  • the left side illustrates an exemplary synthetic scheme for bifunctional compounds of the invention.
  • the right side shows the application of this scheme to amprenavir, lopinavir, and ritonavir.
  • FIG. 5 depicts useful linkers which have amine and (alkyl-protected) carboxyl moieties.
  • FIG. 6 sets out a synthetic scheme for the synthesis of an amprenavir-based SLF-
  • the amprenavir-like moiety is shown at the right in FIG. 6.
  • FIGS. 7A-7B depict a reaction schema for ritonavir and lopinavir respectively.
  • bifunctional compound refers to a non-naturally occurring compound that includes a pharmacokinetic modulating moiety and a drug moiety, where these two components may be covalently bonded to each other either directly or through a linking group.
  • drug refers to any active agent that affects any biological process. Bifunctional compounds may have more than two functionalities.
  • the pharmacokinetic modulating moiety may be a peptide or protein and may also be an enzyme or nucleic acid. Similarly, the drug moiety may also be peptide, protein, enzyme, or nucleic acid.
  • Active agents which are considered drugs for purposes of this application are agents that exhibit a pharmacological activity.
  • drugs include active agents that are used in the prevention, diagnosis, alleviation, treatment or cure of a disease condition.
  • pharmacologic activity is meant an activity that modulates or alters a biological process so as to result in a phenotypic change, e.g. cell death, cell proliferation etc.
  • pharmacokinetic property is meant a parameter the describes the disposition of an active agent in an organism or host. Representative pharmacokinetic properties include: drug half-life, hepatic first-pass metabolism, volume of distribution, degree of blood serum protein, e.g. albumin, binding, etc, degree of tissue targeting, cell type targeting..
  • half-life is meant the time for one-half of an administered drug to be eliminated through biological processes, e.g. metabolism, excretion, etc.
  • hepatic first-pass metabolism is meant the propensity of a drug to be metabolized upon first contact with the liver, i.e. during its first pass through the liver.
  • volume of distribution is meant the distribution and degree of retention of a drug throughout the various compartments of an organisms, e.g. intracellular and extracellular spaces, tissues and organs, etc.
  • efficacy refers to the effectiveness of a particular active agent for its intended purpose, i.e. the ability of a given active agent to cause its desired pharmacologic effect.
  • host refers to any mammal or mammalian cell culture or any bacterial culture.
  • HIV HIV
  • the invention may be employed on relative protease inhibitors such as found in other immunodeficiency viruses found in non- human species or human variants (HIV II, SIV, FIV, etc).
  • FK506 variants or analogs of FK506 are included, such as rapamycin, pimecrolimus, or synthetic ligands of FK506 binding proteins (SLFs) such as those disclosed in U.S. Patents Nos. 5,665,774, 5,622,970, 5,516,797, 5,614,547, and 5,403,833 or described by Holt et al., "Structure-Activity Studies of Synthetic FKBP Ligands M
  • a method for modulating at least one pharmacokinetic property of a protease inhibitor upon administration to a host is provided.
  • the pharmacokinetic modulating moiety binds to at least one intracellular protein.
  • the bifunctional compound has at least one modulated pharmacokinetic property upon administration to the host as compared to a free drug control that comprises the protease inhibitor.
  • Amyloid beta oligomers are believed to underlie the neuropathology of Alzheimer's disease. Therefore, methods to decrease amyloid aggregation are of therapeutic interest.
  • Amyloid ligands such as congo red or curcumin (above) can be synthetically coupled to FK506 or SLF. The resulting bifunctional compound binds both FKBP and amyloid beta. These molecules are potent inhibitors of amyloid aggregation and they block neurotoxicity. See Jason E.
  • Bifunctional compounds of the type employed in the present invention are generally described by the formula: X- L - Z wherein:
  • X is a drug moiety
  • L is a bond or linking group
  • a bifunctional compound is a non-naturally occurring or synthetic compound that is a conjugate of a drug or derivative thereof and a pharmacokinetic modulating moiety, where these two moieties are optionally joined by a linking group.
  • the pharmacokinetic modulating and drug moieties may be different, such that the bifunctional compound may be viewed as a heterodimeric compound produced by the joining of two different moieties.
  • the pharmacokinetic modulating moiety and the drug moiety are chosen such that the corresponding drug target and any binding partner of the pharmacokinetic modulating moiety, e.g., a pharmacokinetic modulating protein to which the pharmacokinetic modulating moiety binds, do not naturally associate with each other to produce a biological effect.
  • the bifunctional compounds are typically small. As such, the molecular weight of the bifunctional compound is generally at least about 100 D, usually at least about 400 D and more usually at least about 500 D.
  • the molecular weight may be less than about 800 D, about 1000 D, about 1200 D, or about 1500 D, and may be as great as 2000 D or greater, but usually does not exceed about 5000 D.
  • the preference for small molecules is based in part on the desire to facilitate oral administration of the bifunctional compound. Molecules that are orally administrable tend to be small.
  • the pharmacokinetic modulating moiety modulates a pharmacokinetic property, e.g. half-life, hepatic first-pass metabolism, volume of distribution, degree of albumin binding, etc., upon administration to a host as compared to free drug control.
  • modulated pharmacokinetic property is meant that the bifunctional compound exhibits a change with respect to at least one pharmacokinetic property as compared to a free drug control.
  • a bifunctional compound of the subject invention may exhibit a modulated, e.g. longer, half-life than its corresponding free drug control.
  • a bifunctional compound may exhibit a reduced propensity to be eliminated or metabolized upon its first pass through the liver as compared to a free drug control.
  • a given bifunctional compound may exhibit a different volume of distribution that its corresponding free drug control, e.g. a higher amount of the bifonctional compound may be found in the intracellular space as compared to a corresponding free drag control.
  • a given bifunctional compound may exhibit a modulated degree of albumin binding such that the drug moiety's activity is not as reduced, if at all, upon binding to albumin as compared to its corresponding free drug control.
  • the pharmacokinetic parameter of interest is typically assessed at a time at least 1 week, usually at least 3 days and more usually at least 1 day following administration, but preferably within about 6 hours and more preferably within about 1 hour following administration.
  • the linker L if not simply a bond, may be any of a variety of moieties chosen so that they do not have an adverse effect on the desired operation of the two functionalities of the molecule and also chosen to have an appropriate length and flexibility.
  • the linker may, for example, have the form F 1 — (CH 2 ) n — F 2 where F 1 and F 2 are suitable functionalities.
  • a linker of this sort comprising an alkylene group of sufficient length may allow, for example, for the free rotation of the drug moiety even when the pharmacokinetic modulating moiety is bound. Alternatively, a stiffer linker with less free rotation may be desired.
  • the hydrophobicity of the linker is also a relevant consideration.
  • the drug moiety X may, in certain embodiments of the invention, preferably be a protease inhibitor.
  • the drug moiety may be derived from a known protease inhibitor, which is preferably effective against HIV and/or against another prevalent virus such as hepatitis B.
  • the drug moiety preferably has a functionality which may readily and controllably be made to react with a linker precursor.
  • HIV protease inhibitors include, for example, atazanavir, saquinavir, ritonavir, indinavir, nelf ⁇ navir, amprenavir, fosamprenavir, mozenavir, TMCl 14 (darunavir), tipranavir, and lopinavir.
  • the known HIV protease inhibitors are generally susceptible to metabolism and subsequent deactivation by hepatic first-pass clearance mechanisms. Protease inhibition is an active area of research.
  • bifunctional compounds may usefully be made with any drug having a suitable moiety capable of reacting with linkers and which has a need for pharmacokinetic modulation.
  • drugs having a strong first-pass effect may be candidates for incorporation into a bifunctional compound.
  • the pharmacokinetic modulating moiety Z will be one which is capable of reversible attachment to a common protein, meaning one which is abundant in the body or in particular compartments of the body or particular tissue types.
  • Common proteins include, for example, FK506 binding proteins, cyclophilin, tubulin, actin, heat shock proteins, and albumin.
  • Common proteins are present in concentrations of at least 1 micromole, preferably at least 10 micromoles, more preferably at least 100 micromoles, and even more preferably 1 millimole in the body or in particular compartments or tissue types.
  • the pharmacokinetic modulating moiety should, like the drug, have a moiety which is capable of reacting with suitable linkers.
  • the binding of the pharmacokinetic modulating moiety Z to a common protein be such as to sterically hinder the activity of common metabolic enzymes such as CYP450 enzymes when the bifunctional compound is so bound.
  • common metabolic enzymes such as CYP450 enzymes
  • the effectiveness of this steric hindrance depends, among other factors, on the conformation of the common protein in the vicinity of the pharmacokinetic modulating moiety's binding site on the protein, as well as on the size and flexibility of the linker.
  • a suitable linker and pharmacokinetic modulating moiety may be made empirically or it may be made by means of molecular modeling of some sort if an adequate model of the interaction of candidate pharmacokinetic modulating moieties with the corresponding common proteins exists.
  • the attachment point and linker characteristics are preferably selected based on structural information such that the inhibitory potency of the protease inhibitor is preserved, giving the desired superior pharmacokinetic characteristics.
  • the pharmacokinetic modulating moiety operates by binding a protein, it may be referred to as a "presenter protein ligand” and the protein which it binds to may be referred to as a “presenter protein.”
  • the pharmacokinetic modulating moiety may be, for example, a derivative of FK506, which has high affinity for the FK506-binding protein (FKBP), as depicted for example in FIG. 1.
  • FKBP FK506-binding protein
  • FIG. 1 The abundance of FKBP (millimolar) in blood compartments, such as red blood cells and lymphocytes, makes it likely that a significant proportion of a dose of bifunctional compounds comprising FK506 would wind up bound in the blood.
  • a mechanism that tends to increase the portion of the protease dose that winds up in red blood cells and CD4+ lymphocytes will have a favorable effect on anti-HIV activity, as these sites are prime targets of HIV infection and viral load.
  • the steric bulk conferred by FKBP would hinder a protease inhibitor moiety from fitting into the binding pocket of CYP450 enzymes and so would prevent degradation via this class of enzymes.
  • FK506 may be preferable in some applications to avoid the possibility of side effects due to the possible interaction of the active FK506-FKBP complex with calcineurin.
  • FKBP binding molecules such as synthetic ligands for FKBP (SLFs) described by Holt et al., supra.
  • SLFs synthetic ligands for FKBP
  • This class of molecule is lower molecular weight than FK506, and that is generally advantageous for drug delivery and pharmacokinetics.
  • the diagrams will show examples of the use of FK506, though it should be understood that the same strategy can apply to other ligands of peptidyl prolyl isomerases such as the FKBP proteins.
  • FK506 tacrolimus
  • FK506 is an FDA-approved immunosuppressant. It has been determined that FK506 can be readily modified such that it loses all immunomodulatory activity but retains high affinity for FKBP.
  • FKBP is an abundant chaperone that is particularly prevalent ( ⁇ millimolar) in red blood cells (rbcs) and lymphocytes. The complex between FK506-FKBP gains affinity for calcineurin and inactivation of calcineurin blocks lymphocyte activation and causes immunosuppression.
  • FK506 This interesting mechanism of action is derived from FK506's chemical structure.
  • FK506 is bifunctional; it has two non-overlapping protein-binding faces. One side binds FKBP, while the other binds calcineurin. This property provides FK506 with remarkable specificity and potency.
  • FK506 has a long half-life in non-transplant patients (21 hrs) and excellent pharmacological profile. In part, this is because FK506 is unavailable to metabolic enzymes via its high affinity for FKBP, which favors distribution into protected cellular compartments (72-98% in the blood).
  • pharmacokinetic modulating moiety will likewise possess some favorable characteristics of inactive FK506, namely, good pharmacokinetics and blood cell distribution.
  • the pharmacokinetic modulating moiety will have a molecular weight less than about 2000 D, less than about 1600 D, less than about 1300 D 5 . less than about 1100 D, or less than about 900 D.
  • a method for synthesizing a bifunctional compound comprising protease inhibitor functionality and the ability to bind to a common protein.
  • the synthesis of the bifunctional compound starts with a choice of suitable pharmacokinetic modulating and drug moieties. It is desirable to identify on each of these moieties a suitable attachment point which will not result in a loss of biological function for either one. This is preferably done based on the existing knowledge of what modifications result or do not result in a biological function. On that basis, it may reliably be conjectured that certain attachment points on the pharmacokinetic and drug moieties do not affect biological function. Thus, for example, in FK506 there is a carboxylic acid function which is suitable as an attachment point. Likewise, in FIG. 4 one sees secondary amine functions on three protease inhibitors which are believed not to significantly affect biological function.
  • a general synthetic strategy is to locate a secondary amine on the drug moiety at which the drag moiety can be split (so that the secondary amine does not form part of any cycle in the drug moiety).
  • the secondary amine is chosen such that, from experimental or other considerations, it is believed that the drag will retain its efficacy if only the portion of the drag moiety to one side of the secondary amine is present.
  • the portion of the drag moiety to that side of the secondary amine is then synthesized by any appropriate technique, with the secondary amine in the synthesized molecule being protected during synthesis by an appropriate protecting moiety such as Boc.
  • the protecting moiety is then removed, leaving a primary amine which may react with a carboxyl group through a variety of known chemistries for making a peptide bond (see, e.g., J. Mann et al., Natural Products: Their Chemistry and Biological Significance (1994), chapter 3).
  • a bifunctional compound comprising a protease inhibitor moiety with antiviral activity is formulated, for example in the form of a tablet, capsule, parenteral formulation, to make a pharmaceutical preparation
  • the pharmaceutical preparation may be employed in a method of treating a patient having a viral infection against which the protease inhibitor moiety is effective.
  • the pharmaceutical preparation may be administered to a patient infected with the HIV virus.
  • a bifunctional compound is formulated as part of a controlled release formulation in which an additional controlled release mechanism besides the effect of the pharmacokinetic modulating moiety is employed to achieve desirable release characteristics.
  • the bifunctional compound is as above, comprising a drug moiety, a linker, and a pharmacokinetic modulating moiety.
  • a drug moiety may be a protease inhibitor or a different type of drug.
  • bifunctional compounds have the advantage that they can favorably improve the pharmacokinetic characteristics of existing or new drugs.
  • bifunctional compounds used in conventional dosage formulations may not provide enough of an advantage over the mono-functional drug molecules to overcome the additional expense of regulatory approval, drug manufacture, and cost incurred to make the more complex bifunctional compound.
  • the bifunctional strategy can greatly expand the number of drugs which can be used in a controlled release formulation.
  • a controlled release formulation of the bifunctional compound can provide enough additional value that may overcome the disadvantage of the extra cost of obtaining regulatory approval for and manufacturing bifunctional drugs compared to mono-functional drugs.
  • Controlled drug delivery includes slow erosion, erosion core, pellets in capsules, pellets in tablets, leaching, ion-exchange resins, complexation, microencapsulation, flotation-diffusion, and osmotic pumps.
  • the drugs that are candidates for bifunctionalization and then the application of other controlled release technologies will generally be those in which other controlled release technologies by themselves do not produce a satisfactory release profile, and bifunctionalization is both possible (e.g., there are suitable linkage points in the drug which do not affect function) and yet does not produce a release profile which is fully adequate.
  • Drugs which are candidates for bifunctionalization followed by application of other controlled release technologies may belong to a wide variety of therapeutic categories including, but not limited to: analeptic agents; analgesic agents; anesthetic agents; antiarthritic agents; respiratory drugs, including antiasthmatic agents; anticancer agents, including antineoplastic drugs; anticholinergics; anticonvulsants; antidepressants; antidiabetic agents; antidiarrheals; antihelminthics; antihistamines; antihyperlipidemic agents; antihypertensive agents; anti-infective agents such as antibiotics and antiviral agents; antiinflammatory agents; antimigraine preparations; antinauseants; antiparkinsonism drugs; antipruritics; antipsychotics; antipyretics; antispasmodics; antitubercular agents; antiulcer agents; antiviral agents; anxiolytics; appetite suppressants; attention deficit disorder (ADD) and attention deficit hyperactivity disorder (ADHD) drugs; cardiovascular preparation
  • Exemplary drugs presently known to have high first-pass metabolism include HIV protease inhibitors as discussed above, paclitaxel, methotrexate, vinblastine, verapamil, morphine, lidocaine, acebutolol, isoproterenol, and desipramine.
  • HIV protease inhibitors as discussed above, paclitaxel, methotrexate, vinblastine, verapamil, morphine, lidocaine, acebutolol, isoproterenol, and desipramine.
  • the formation of bifunctional compounds is particularly appropriate for these drugs.
  • the general method for testing PI-FK506 conjugates is to synthesize the bifunctional compound and test whether the bifunctional version maintains activity against HIV protease. Then, the P450 susceptibility of the bifunctional compound was tested in a series of fluorescence-based assays.
  • FKBP sources such as recombinant protein, red blood cells or lymphocytes.
  • the desired outcome is prolonged drug lifetime in the presence of an FKBP source combined with potent anti-HIV protease activity.
  • the synthetic schemes and methods for determining drug lifetime in the presence of P450s will be discussed.
  • the FDA-approved PIs amprenavir, lopinavir and ritonavir are models for generating FK506-coupled derivatives. These drugs are chosen based on their known defects in pharmacological characteristics. Like all FDA-approved PIs, these compounds are based on peptide substrate sequences. Therefore, we developed a modular amide-based approach to the synthesis of bifunctional compounds (see below). Specifically, an amine in the P2 region (shaded boxes, FIG. 4) is targeted for attachment to a pendant carboxylate on FK506. This region is selected based on structure activity relationships that show the P2 site as a region in which modifications are permitted without affecting biological activity. This approach is amenable to high throughput, solid-phase synthesis if large-scale diversification becomes necessary. These conjugates between FK506 and a Pi-derivative are expected to have better activity than the FDA-approved drug on which they are based.
  • linker bearing an amine on one end and a protected carboxylate on the other can be readily installed as shown in FIG. 6.
  • This capability is designed to allow facile synthesis of analogs with a variety of linker properties (length, flexibility, solubility, etc). For example, longer linkers can be installed if a shorter linker reduces protease inhibition.
  • An amyloid ligand, curcumin is known to be a good substrate for CYP3a4 (a common P450 enzyme).
  • CYP3a4 a common P450 enzyme
  • FK506 conjugates between curcumin and FK506 would also be substrates for the enzyme.
  • CYP3a4 assay This assay, marketed by Invitrogen (Carlsbad, CA), under the name VIVID probes, relies on cytochrome-mediated production of a fluorescent marker from a model substrate. When a compound, such as curcumin, binds to the P450, it displaces the substrate and reduces the rate of production of the fluorescent product.
  • FKBP protects the curcumin conjugates from degradation by sterically hindering CYP3a4 binding. In the presence of cellular FKBP sources, this effect would be predicted to be increased because the compartmentalization of the conjugate further reduces availability to P450 enzymes.
  • FIG. 6 depicts the overall synthesis. Briefly, a commercially available Phe-derived epoxide is opened with a valine isostere. The resulting compound is coupled to Boc-protected aminobenzenesulfonyl chloride. Deprotection of the Boc groups is followed by coupling to an activated acid derivative of SLF using l-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC) and N-hydroxylsuccinimide (NHS) (10 equivalents EDC to 1 equivalent NHS).
  • EDC l-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride
  • NHS N-hydroxylsuccinimide
  • the coupling takes place in dimethylformamide (DMF) at room temperature over four hours. Relative nucleophilicity of the two amines is used to direct amide formation; the benzyl amino group is believed to have diffuse electron density and lowered reactivity.
  • DMF dimethylformamide
  • the linkers shown in FIG. 5 may be coupled to FK506 or SLF via EDC-mediated amide formation followed by deprotection of the newly installed carboxylate. This acid is then used for conjugation to the amprenavir-based molecule as above.
  • the linker can be readily altered to enhance solubility or other physical characteristics of the bifunctional compound.
  • the amprenavir conjugate of this example may also be regarded as a TMCl 14 conjugate, because TMCl 14 shares with amprenavir the structure to the right of the attachment point used in this example.
  • Example 2 To analyze efficacy of the conjugates of Example 2 against HIV protease, a commercial biochemical assay was used.
  • the AnaSpec (www.anaspec.com) 71126 HIV-I protease assay was used according to the manufacturer's direction, except that 1 ⁇ M recombinant FKBP was used in some wells.
  • the assay uses a quenched fluorophore substrate. Proteolytic cleavage of the substrate reverses the quench and releases a fluorescent substrate.
  • Experiments were performed in 96-well black Costar plates in real time using a Molecular Devices M5 plate reader. In all cases, fluorescence corrections were made for all drugs and proteins. Linear portions of the curve were used to predict drug lifetime and relative Ki values.
  • the AnaSpec assay kit shows amprenavir bifunctional retains inhibitory activity against HIV protease. It is twice as effective as the monofunctional TMCl 14, showing that linker choice has resulted in optimized activity of bifunctional relative to monofunctional.
  • a commercial Invitrogen P2856 assay was used to test for degradation via CYP3a4 in accordance with the manufacturer's directions.

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Abstract

L'invention concerne une méthode de modulation d'au moins une propriété pharmacocinétique d'un inhibiteur de protéase lors de son administration à un hôte. La méthode consiste à administrer à l'hôte une quantité efficace d'un composé bifonctionnel inférieur à environ 5000 daltons, comprenant l'inhibiteur de protéase ou un dérivé actif de celui-ci et un fragment de modulation pharmacocinétique. Le fragment de modulation pharmacocinétique est lié à au moins une protéine intracellulaire. Le composé bifonctionnel présente au moins une propriété pharmacocinétique modulée lors de son administration à l'hôte par rapport à un témoin de médicament libre comprenant l'inhibiteur de protéase.
PCT/US2006/043400 2005-11-05 2006-11-06 Amelioration des proprietes pharmacocinetiques d'inhibiteurs de proteases et d'autres medicaments Ceased WO2007053792A2 (fr)

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Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010077317A3 (fr) * 2008-12-17 2010-10-28 Amplyx Pharmaceuticals, Inc. Inhibiteurs des protéases
US9597343B2 (en) 2012-04-16 2017-03-21 Synta Pharmaceuticals Corp. Targeted therapeutics
US9956293B2 (en) 2014-03-18 2018-05-01 Madrigal Pharmaceuticals, Inc. Targeted therapeutics
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US9597343B2 (en) 2012-04-16 2017-03-21 Synta Pharmaceuticals Corp. Targeted therapeutics
US10722525B2 (en) 2012-04-16 2020-07-28 Madrigal Pharmaceuticals, Inc. Targeted therapeutics
US10828315B2 (en) 2013-09-10 2020-11-10 Madrigal Pharmaceuticals, Inc. Targeted therapeutics
US10376598B2 (en) 2013-10-28 2019-08-13 Madrigal Pharmaceuticals, Inc. Targeted therapeutics
US10117944B2 (en) 2014-01-29 2018-11-06 Madrigal Pharmaceuticals, Inc. Targeted therapeutics
US10675360B2 (en) 2014-03-03 2020-06-09 Madrigal Pharmaceuticals, Inc. Targeted therapeutics
US10232049B2 (en) 2014-03-03 2019-03-19 Madrigal Pharmaceuticals, Inc. Targeted therapeutics
US9956293B2 (en) 2014-03-18 2018-05-01 Madrigal Pharmaceuticals, Inc. Targeted therapeutics
US11377447B2 (en) 2017-06-20 2022-07-05 Madrigal Pharmaceuticals, Inc. Targeted therapeutics
US11491145B2 (en) 2017-06-20 2022-11-08 Madrigal Pharmaceuticals, Inc. Combination therapies comprising targeted therapeutics
CN114591442A (zh) * 2022-03-01 2022-06-07 中国科学院深圳先进技术研究院 一种受光调控的蛋白酶工具及其配套底物
CN114591442B (zh) * 2022-03-01 2024-04-19 中国科学院深圳先进技术研究院 一种受光调控的蛋白酶工具及其配套底物

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