WO2018035617A1 - Conjugués de support antibiotique pour le traitement d'infections rénales - Google Patents

Conjugués de support antibiotique pour le traitement d'infections rénales Download PDF

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WO2018035617A1
WO2018035617A1 PCT/CA2017/051004 CA2017051004W WO2018035617A1 WO 2018035617 A1 WO2018035617 A1 WO 2018035617A1 CA 2017051004 W CA2017051004 W CA 2017051004W WO 2018035617 A1 WO2018035617 A1 WO 2018035617A1
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compound
arg
formula
leu
asp
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PCT/CA2017/051004
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English (en)
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Roger Leger
Jerome ROSSERT
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Thrasos Therapeutics Inc.
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Publication of WO2018035617A1 publication Critical patent/WO2018035617A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • 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
    • A61K47/68—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 antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
    • A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
    • 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
    • A61K47/68—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 antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6889—Conjugates wherein the antibody being the modifying agent and wherein the linker, binder or spacer confers particular properties to the conjugates, e.g. peptidic enzyme-labile linkers or acid-labile linkers, providing for an acid-labile immuno conjugate wherein the drug may be released from its antibody conjugated part in an acidic, e.g. tumoural or environment
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/08—Linear peptides containing only normal peptide links having 12 to 20 amino acids

Definitions

  • Antibiotics arc typically the first line of treatment for kidney infections.
  • many antibiotics and their metabolites are excreted via the kidney due to its glomerular filtration, tubular secretion, or in some cases both.
  • renal impairment such as e.g., acute kidney injury or myeloma cast nephropathy
  • the clearance of the antibiotic becomes of great clinical importance because of the altered excretions from the kidney. Sec e.g., medical investigation 1999; 33 (2): 43-46. Altered clearance can also impede the pharmacokinetics- absorption, distribution (including protein binding), and metabolism of the administered antibiotic. Finding alternative and more effective treatments for kidney infections, particularly in patients having renal impairment, is therefore of great importance.
  • compositions comprising the compounds of Formula I as well as the use of the disclosed compounds and compositions for treating bacterial infections (e.g., for treating kidney infections caused by bacteria in subjects with renal impairment).
  • FIG. 1 illustrates the plasma pharmacokinetics following intravenous bolus injection of a portion of the compound of Formula I in rat.
  • FIG. 2 illustrates the plasma pharmacokinetics following 2 hour intravenous infusion of a portion of the compound of Formula I in rat.
  • FIG. 3 compares the plasma pharmacokinetics of two portions of the compound of Formula I after intraperitoneal injection in rat, where a.) shows a plot of peptide vs time at various concentrations; b.) shows a plot of steady state concentration (Css) as a function of. dose; and c.) shows a plot of the Area Under the Cure (AUC) as a function of dose.
  • FIG. 4 illustrates the urine recovery of a portion of the compound of Formula I
  • J 1 is Aha or Arg
  • X 1 to X 7 arc each independently a natural or non-natural amino acid
  • s, t, w, and v are each independently 0 or I ;
  • J and y arc each independently Lys or Arg; J 4 , if present is Lys or Arg;
  • RM if present, is a group capable of degrading in such a manner such that A T is displaced from the remaining portion of Formula I;
  • a r is an antibody.
  • amino acid refers to an organic compound containing an amine (-NH 2 ) and a carboxylic acid (-COOH) functional group, usually along with a side-chain specific to each amino acid.
  • Amino acids can be classified according to the core structural functional groups' locations as alpha- (a-), beta- ( ⁇ -), gamma- ( ⁇ -) or delta- (5-) amino acids; other categories relate to polarity, pH level, and side-chain group type (aliphatic, acyclic, aromatic, containing hydroxyl or sulfur, etc.).
  • amino acid includes
  • Natural amino acid is used interchangeably with protcinogenic amino acid and refers to the 20 standard amino acids encoded by the universal genetic code along with sclenocystcinc and pyrrolysinc.
  • the 20 standard amino acids encoded by the universal genetic code include glycine, alanine, valine, leucine, isoleucinc, proline, phenylalanine, tyrosine, tryptophan, serine, threonine, cysteine, methionine, asparaginc, glutaminc, aspartate, glutamate, lysine, arginine, and histidine.
  • isoleucine is interchangeable with three letter abbreviation lie or the one letter abbreviation I
  • proline is interchangeable with three letter abbreviation Pro or the one letter abbreviation P
  • phenylalanine is interchangeable with three letter abbreviation Phe or the one letter abbreviation F
  • tyrosine is interchangeable with three letter abbreviation Tyr or the one letter abbreviation Y
  • tryptophan is interchangeable with three letter abbreviation Trp or the one letter abbreviation W
  • serine is interchangeable with three letter abbreviation Ser or the one letter abbreviation S
  • threonine is interchangeable with three letter abbreviation Thr or the one letter abbreviation T
  • cysteine is interchangeable with three letter abbreviation Cys or the one letter abbreviation C
  • methionine is interchangeable with three letter abbreviation Met or the one letter abbreviation M, asparagin
  • the term "natural amino acid" or proteinogenic amino acid refers only to the 20 standard amino acids encoded by the universal genetic code, i.e., G, A, V, L, 1, P, F, Y, W, S, T, C, M, N, Q, D, E, , R, and H.
  • Non-natural amino acid refers to a noti- proteinogenic amino acid that is not found in proteins (e.g., carnitine, gamma-ammob tyrk acid, and D-forms of natural amino acids except glycine) or not produced directly and in isolation by standard cellular machinery (e.g., hydroxyprol ine and selenomethionine).
  • ⁇ -amino acids ⁇ 3 and ⁇ 2
  • homo-amino acids ⁇ 3 and ⁇ 2
  • homo-amino acids alanine derivatives
  • alicyclic amino acids arginine derivatives, asparaginc derivatives, aspartic acid derivatives, cysteine derivatives, 2,4-diaminobutyric acid
  • glycine derivatives isoleucine derivatives, leucine derivatives, lysine derivatives (such as 6-aminohexanoic acid abbreviated herein as Aha), methionine derivatives, norleucine (nL) and norlcucine derivatives, phenylalanine derivatives, phcnylglycine derivatives, proline and pyruvic acid derivatives, pyroglutaminc derivatives, serine derivatives, threonine derivatives, tryptophan derivatives, norvaline derivatives, 2,3-diaminopropionic acid, ornithine derivatives
  • non-natural amino acid refers only to D-fomis of the 20 standard amino acids encoded by the universal genetic code. These forms include D-Ala, D-Val, D-Lcu, D-lIc, D-Pro, D-Phc, D-Tyr, D-Trp, D-Ser, D-Thr, D-Cys, D-Met, D-Asn, D-Gln, D-Asp, D-GIu, D-Lys, D- Arg, and D-His.
  • a "D-amino acid" or D-form of an amino acid means that the indicated amino acid is present as the D-enantiomcr.
  • Shorthand notation for the D-cnantiomcr of an amino acid can be represented by an asterisk ⁇ *).
  • I* or I*lc, wherein * represents a D-atnino acid refers to the D-enantiomer of lie (isoleucine).
  • alkyl refers to a monovalent saturated, straight- or branched-chain hydrocarbon radical, having unless otherwise specified (such as C
  • alkyl radicals include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, sec-pentyl, iso-pcntyl, tcrt-butyl, n-pentyl, neopentyl, n-hexyl, sec-hexyl, and the like.
  • Optional substitucnts for an alkyl group include groups that result in the formation of stable or chemically feasible compounds.
  • stable refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.
  • optional substitucnts arc selected from halo (CI, Br, I, Fl), -0 ⁇ Ci-Cio)alkyl, OH, NH,, N H(C,-Cio)alkyl, and N
  • Pharmaceutically acceptable salts are art-recognized and include e.g., relatively non-toxic inorganic and organic acid addition salts, or inorganic or organic base addition salts that arc suitable for human consumption.
  • Examples of such salts include, but are not limited to, sodium, potassium, calcium, magnesium, acetate, benzoate, bicarbonate, carbonate, citrate, dihydrochloi ide, gluconate, glutamate, hydrochloride, and tartrate.
  • pharmaceutically acceptable carrier refers to a non- toxic carrier, ad juvant, or vehicle that does not adversely affect the pharmacological activity of the peptide with which it is formulated, and which is also safe for human use.
  • Pharmaceutical ly acceptable carriers that may be used include, but are not limited to, ion exchangers, alumina, aluminum stearatc, magnesium stcaratc, lecithin, scrum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, dicalcium phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicatc, polyvinyl pyrrolidonc, polyvinylpyrrolidonc-vinyl acetate, ccllulosc-bascd substances (e.g., microcrystallinc cellulose, hydroxypropyl
  • mcthylccllulosc hydroxypropyl mcthylccllulosc acetate succinate, hydroxypropyl mcthylccllulosc Phthalatc), starch, lactose monohydratc, mannitol, trehalose sodium lauryl sulfate, and crosscarmcllose sodium, polyethylene glycol, sodium
  • carboxymethylccllulose polyacrylatcs, polymcthacrylatc, waxes, polycthylcnc- polyoxypropylene-block polymers, polyethylene glycol and wool fat.
  • subject and patient may be used interchangeably, and mean a mammal in need of treatment, e.g., companion animals (e.g., dogs, cats, and the like), farm animals (e.g., cows, pigs, horses, sheep, goats and the like) and laboratory animals (e.g., rats, mice, guinea pigs and the like).
  • companion animals e.g., dogs, cats, and the like
  • farm animals e.g., cows, pigs, horses, sheep, goats and the like
  • laboratory animals e.g., rats, mice, guinea pigs and the like.
  • the subject is a human in need of treatment.
  • treatment refers to reversing, alleviating, or inhibiting the progress of a disease or disorder, or one or more symptoms thereof, as described herein.
  • treatment may be administered after one or more symptoms have developed, i.e., therapeutic treatment.
  • treatment may be administered in the absence of symptoms.
  • treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and/or in light of genetic or other susceptibility factors), i. e., prophylactic treatment. Treatment may also be continued after symptoms have resolved, for example to prevent or delay their recurrence.
  • an "effective amount” or “therapeutical ly effective amount” is a quantity sufficient to achieve a desired therapeutic and/or prophylactic effect, for example, an amount which results in the prevention of or a decrease in the symptoms associated with a condition that is being treated, e.g., the conditions described herein.
  • X fl in the compound of Formula I is not Glu, Thr, Asn, or Asp; and X 7 is not Glu or Asp, wherein the remaining variables in Formula 1 are as described above.
  • 1 in the compound of Formula I is selected from Arg, Lys, His, Pro, Cys, Thr, Ser, Gin, Glu, Leu, He, Met, Ala, Val, Gly, n-Leu, Met, Asp, and lie, wherein the remaining variables in Formula I arc as described above for Formula I or the second embodiment.
  • X 1 in the compound of Formula I is selected from Arg, Gin, Glu, Leu, n-Leu, Met, Asp, and He, wherein the remaining variables in Fonnula I are as described above for Formula I or the second embodiment.
  • X 1 in the compound of Formula I is selected from Gin, Leu, and n-Lcu, wherein the remaining variables in Fonnula I arc as described above for Formula I or the second embodiment.
  • X 2 in the compound of Formula I is selected from a natural amino acid, wherein the remaining variables in Fonnula I arc as described above for Fonnula I or the second or third embodiment.
  • X 2 in the compound of Formula I is selected from Ser, Thr, Cys, Met, Asn, Lys, Gin, His, Arg, Glu, and Asp, wherein the remaining variables in Fonnula I arc as described above for Formula I or the second or third embodiment.
  • X 2 in the compound of Formula I is selected from Ser, Gin, His, Arg, Glu, and Asp, wherein the remaining variables in Formula I arc as described above for Fonnula I or the second or third embodiment.
  • X ⁇ in the compound of Formula I is selected from Gin and His, wherein the remain ing variables in Formula I are as described above for Formula 1 or the second or third embodiment.
  • X 3 in the compound of Formula I is selected from a natural amino acid, wherein the remaining variables in Formula I are as described above for Formula I or the second, third, or forth embodiment.
  • X ? in the compound of Formula I is selected from Tyr, Trp, Phc, Scr, Thr, Cys, Met, Asn, Ala, Lys, His, Glu, Arg, and Asp, wherein the remaining variables in Formula I arc as described above for Formula I or the second, third, or forth embodiment.
  • ⁇ in the compound of Formula I is selected from Tyr, Scr, Ala, Glu, Arg, and Asp, wherein the remaining variables in Formula I arc as described above for Formula I or the second, third, or forth embodiment.
  • X :t is selected from Tyr, Scr, Arg, and Asp, wherein the remaining variables in Formula I arc as described above for Formula I or the second, third, or forth embodiment.
  • X J in the compound of Formula I is selected from a natural amino acid, wherein the remaining variables in Formula I arc as described above for Fomiula I or the second, third, fourth, or fifth embodiment.
  • X J in the compound of Fomiula I is selected froni Gly, Ala, Val, Leu, lie, Pro, Phc, Tyr, Trp, Asp, Glu, Lys, Arg, and His, wherein the remaining variables in Formula I are as described above for Formula I or the second, third, fourth, or fifth embodiment.
  • X 4 in the compound of Formula I is selected from Leu, Asp, Gly, Tyr, Glu, and Arg, wherein the remaining variables in Formula I arc as described above for Formula I or the second, third, fourth, or fifth embodiment.
  • X 4 in the compound of Formula I is selected from Leu, Asp, Tyr, and Arg, wherein the remaining variables in Formula I are as described above for Formula I or the second, third, fourth, or fifth embodiment.
  • X 5 in the compound of Formula I is selected from a natural amino acid, wherein the remaining variables in Formula I are as described above for Formula I or the second, third, fourth, fifth, or sixth embodiment.
  • X s in the compound of Formula I is selected from Ser, Thr, Cys, Met, Asn, G in, Asp, Glu, Lys, Arg, and His, wherein the remaining variables in Formula I arc as described above for Formula 1 or the second, third, fourth, fifth, or sixth embodiment.
  • X 3 in the compound of Formula I is selected from Tyr, Ser, Arg, Glu, and Asp, wherein the remaining variables in Formula I are as described above for Formula I or the second, third, fourth, fifth, or sixth embodiment.
  • X ( ' in the compound of Formula I is selected from Gly, Ala, Val, Leu, He, Pro, Phe, Tyr, Tip, Ser, Cys, Met, Gin, Lys, Arg, and His, wherein the remaining variables in Formula I are as described above for Formula I or the second, third, fourth, fifth, sixth, or seventh embodiment.
  • X ft in the compound of Formula I is selected from He, Leu, Pro, Val, Ala, Gly, His, Lys, and Arg, wherein the remaining variables in Formula I are as described above for Formula I or the second, third, fourth, fifth, sixth, or seventh embodiment.
  • X f) in the compound of Formula I is selected from He, Leu, and Arg, wherein the remaining variables in Formula I arc as described above for Fonnula I or the second, third, fourth, fifth, sixth, or seventh embodiment.
  • X Cl in the compound of Fonnula I is selected from l ie and Leu, wherein the remaining variables in Formula I arc as described above for Formula I or the second, third, fourth, fifth, sixth, or seventh embodiment.
  • X 7 in the compound of Formula I is selected from Gly, Ala, Val, Leu, He, Pro, Phe, Tyr, Trp, Ser, Thr, Cys, Met, Asn, Gin, Lys, Arg, and His, wherein the remaining variables in Formula I are as described above for Formula 1 or the second, third, fourth, fifth, sixth, seventh, or eighth embodiment.
  • X 7 in the compound of Formula 1 is selected from Tyr, Phe, His, Lys, Arg, and Trp, wherein the remaining variables in Fonnula I arc as described above for Formula I or the second, third, fourth, fifth, sixth, seventh, or eighth embodiment.
  • X 7 in the compound of Formula I is selected from Tyr, Arg, and Trp, wherein the remaining variables in Formula I are as described above for Formula I or the second, third, fourth, fifth, sixth, seventh, or eighth embodiment.
  • X 7 in the compound of Formula I is Tyr, wherein the remaining variables in Formula I arc as described above for Formula I or the second, third, fourth, fifth, sixth, seventh, or eighth embodiment.
  • s and t are each 0 in the compound of Fonnula 1, wherein the remaining variables in Formula I arc as described above for Formula 1 or the second, third, fourth, fifth, sixth, seventh, eighth, or ninth embodiment.
  • s and t are each 1 in the compound of Formula I, wherein the remain ing variables in Formula I are as described above for Formula 1 or the second, third, fourth, fifth, sixth, seventh, eighth, ninth, or tenth embodiment.
  • J 1 in the compound of Formula I is Aha, wherein the remaining variables in Formula I are as described above for Formula I or the second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, or eleventh embodiment.
  • the compounds of Formula I comprise a release group R M .
  • This release group is defined as a defined as a group capable of degrading in such a manner such that A r is displaced from the remaining portion of Formula I.
  • the selection (and presence) of this release group will depend whether the antibiotic (AT) target is intracellular or if the carrier portion represented by
  • release group R M is likely not required. In other words, v is likely 0 in these instances.
  • release group RM is also likely not required. Examples of the latter include, but are not limited to, polymyxin and colistin.
  • v is 0 and the remaining variables for Formula I are as described above for Formula I or the second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, or twelfth embodiment.
  • release group R ⁇ i is required.
  • v is 1 in these instances.
  • segments that arc sensitive to enzymes found in the urine and produced by proximal tubular cells can be used as release group RM- Sec e.g., Bioconjugatc Chcm. 2013, Vol. 24, 29 1 -299. Hydro!yzable release groups can also be used.
  • a release group R M that is tailored to react with the bacterial specific enzyme can used (i.e., v is 1 ).
  • the bacterial specific enzyme reacts release group RM and subsequent with such that antibiotic A r is released into the target medium essentially unmodified is advantageous.
  • the bacterial enzyme reacts with release group R M instead of antibiotic Ay, and antibiotic Ay is subsequently released into the target medium.
  • Exemplary release groups of this nature include, but are not limited to those which target beta-l ctamase.
  • release group RM is:
  • An antibiotic AT in Formula I is an antibiotic that when bound to the remaining features of Formula I (-( v -fLH -j'CysX'x'x'X ⁇ 'x'Pro 'ThrCysJ'j' ' 5 )!), elicits an improvement in activity, a decrease in toxicity, an increase in kidney clearance, an increase in urine concentration, or a lower systemic distribution when compared to administration of the A alone, i.e., without being bound to the remaining features of Formula 1.
  • antibiotics include, but are not limited to beta-lactam antibiotics, fluoroquinolone antibiotics, aminoglycosides, and others such as e.g., polymyxin, colistin, tigccyclinc, inocyclinc, and cosycyclinc.
  • the compounds of Fomiula I A is selected from bcta-Iactam antibiotics such as meropenem, imipenem, biapenem, doripenem, meropenem, ertapenem, piperacillin, mezlocill in, temocillin, ticarcillin, carbcnicillin, ceftazidime, cefotaxime, cefaloridine, ceftriaxone, cefteram, cefpimizole, cefminox, cefalonium, and aztreonam; fluoroquinolone antibiotics such as ulifloxacin, trovafloxacin, sitailoxacon, moxifloxacin, gemifloxacin, gatifloxacin, clinafloxacin, tosufloxacin, pazufloxacin, pazufloxacin, norfloxacin, and ciprofloxacin; amino
  • the present disclosure provides a method of treating a subject ⁇ e.g., a human) suffering from a bacterial infection, comprising administering to the subject a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof.
  • the compound of Formula I is such that it is an effective binding inhibitor of light chains to uromodulin.
  • a provided composition is formulated for administration to a subject in need of such composition.
  • the bacterial infection is a kidney infection.
  • the subject being treated is also suffering from renal impairment (e.g.. acute kidney injury or myeloma cast nephropathy).
  • compositions can be administered to humans and other animals by other methods such as e.g. , orally, rectally, parcntcrally, intracisternally, intraperitoncally, topically (as by powders, creams, ointments, or drops), bucally, as an oral or nasal spray, or the like.
  • the disclosed compounds may be administered parcntcrally (e.g., intravenous).
  • the present disclosure also provides a method of treating a subject (e.g., a human) suffering from a bacterial, comprising administering to the subject a therapeutically effective amount of composition comprising a compound of the Formula I, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
  • a therapeutically effective amount of composition comprising a compound of the Formula I, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
  • the amount of compound of Formula I in a provided composition is such that it is an effective binding inhibitor of light chains to uromodulin.
  • the bacterial infection is a kidney infection.
  • the subject being treated is also suffering from renal impairment (e.g., acute kidney injury or myeloma cast nephropathy).
  • a specific dosage for any particular subject will depend upon a variety of factors, including age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, the judgment of the treating physician, and the severity of the particular disease being treated.
  • the amount of a provided compound in the composition will also depend upon the particular compound in the composition. 1 .
  • the amount of provided compounds that may be combined with carrier materials to produce a composition in a single dosage form will vary depending upon the patient to be treated and the particular mode of administration.
  • Standard solid phase techniques can be employed to synthesize the disclosed compounds.
  • Fmoc (fluorenylmethyloxycarbonyl) chemistry can occurr on PEG-base Rink Amide resin, 0.45 mmol/g loading.
  • Fmoc amino acid can include t-Bu (t-butyl) on Asp, Ser, Tyr and D-Tyr; Trt (trityl) on Asn and Cys; Boc (tcrt-butyloxycarbonyl) on Lys; Pbf (2,2,4,6,7-pcntamcthyldihydrobcnzofuranc) on Arg, Fmoc on K* (i.e., Fmoc-Lys(Fmoc)-OH can be used to coupled to the rcsin).
  • Fmoc on K* i.e., Fmoc-Lys(Fmoc)-OH can be used to coupled to the rcsin).
  • Peptidyl resin was extensively washed with DCM (dicloromethane) and methanol to remove the trace of DMF and dried at RT overnight.
  • Peptidyl rcsin was cleavaged with the mixture of TFA/TIS/EDT/HiO (trifluoracctic acid/triethylsilane/1 ,2- ethanedithiol/water) (92.5/2.5/2.5/2.5, v/v/v/v) for 2.5-3 h under nitrogen bubbling.
  • Peptides were collected by precipitation in cold diethyl cthcr/Hcxanc ( 1 / 1 , v/v). 4. Purification of Linear Peptide
  • Crude liner peptide was purified using Phcnomenex Gemini C- prep column. 21 .5mm x 250mm. The peptide was then dried by lyophilization..
  • Enzyme-l inked immunosorbent assays were performed independently on the portion of the compounds of Formula I having the structure
  • Binding inhibition, stability, and solubility data was obtained independently on the portion of the compounds of Formula I having the structure These results are shown in Table 4.
  • MLO> represents the lowest [C50 at which uromodulin binding to 90% of the light ch tested was inhibited.
  • KBB is kidney brush border enzyme.
  • FIG. 1 The plasma pharmacokinetics of SEQ I D No. 27 was evaluated following intravenous (IV) bolus injection (FIG. 1 ) and 2 hour IV infusion (FIG. 2) in rats.
  • FIG. 3 plasma pharmacokinetics of SEQ ID No. 27 following intraperitoneal injection of SEQ ID No. 27 when compared with SEQ ID No. 4 in rat.
  • This data establishes that the portion of the compounds of Formula I having the structure j' CysX' in particular SEQ ID No. 27, has high efficacy and very good dose-exposure proportionally over a broad range of doses.
  • the clearance rate of SEQ ID No. 27 was essentially equal to the glomerular filtration rate, e.g., after infusion of 10 mg/kg of SEQ ID No. 27 for 2 hours to 6 rats, the percentage of intact peptide recovered in the urine was 100% ⁇ 22% (mean ⁇ SD). See FIG. 4.
  • the peptide is reacted with a compound of formula 100, where Acti and Ac are each independently carboxylic acid leaving groups such as halogen or sulfinate ester, to form an intermeidate of the formula 101.
  • Antibody A T comprising a thiol or amine, is then reacted with 101 to form products 102 or 103.

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  • Urology & Nephrology (AREA)
  • Oncology (AREA)
  • Communicable Diseases (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Peptides Or Proteins (AREA)

Abstract

L'invention concerne des composés de formule I : AT(RM)V-(LR)W-R3CysX1X2X3X4X5X6ProX7ThrCysR2XR3(R4)S(R5)1, (1) ; des sels pharmaceutiquement acceptables de ceux-ci, et des compositions pharmaceutiques de ceux-ci. L'invention concerne également l'utilisation de ces composés pour le traitement des infections bactériennes.
PCT/CA2017/051004 2016-08-26 2017-08-25 Conjugués de support antibiotique pour le traitement d'infections rénales WO2018035617A1 (fr)

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US201662380073P 2016-08-26 2016-08-26
US62/380,073 2016-08-26

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11021514B2 (en) 2016-06-01 2021-06-01 Athira Pharma, Inc. Compounds

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9611297B1 (en) * 2016-08-26 2017-04-04 Thrasos Therapeutics Inc. Compositions and methods for the treatment of cast nephropathy and related conditions

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9611297B1 (en) * 2016-08-26 2017-04-04 Thrasos Therapeutics Inc. Compositions and methods for the treatment of cast nephropathy and related conditions

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11021514B2 (en) 2016-06-01 2021-06-01 Athira Pharma, Inc. Compounds

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