WO2009005839A2 - Composés et procédés d'utilisation - Google Patents

Composés et procédés d'utilisation Download PDF

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Publication number
WO2009005839A2
WO2009005839A2 PCT/US2008/008299 US2008008299W WO2009005839A2 WO 2009005839 A2 WO2009005839 A2 WO 2009005839A2 US 2008008299 W US2008008299 W US 2008008299W WO 2009005839 A2 WO2009005839 A2 WO 2009005839A2
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WO
WIPO (PCT)
Prior art keywords
compound
binding
mmol
receptor
steroid hormone
Prior art date
Application number
PCT/US2008/008299
Other languages
English (en)
Other versions
WO2009005839A3 (fr
Inventor
Nima Sharifi
William L. Farrar
Prabhakar Risbood
David George Ian Kingston
Jun Qi
Original Assignee
The Government Of The U.S.A. As Represented By The Secretary Of The Dept. Of Health & Human Service
Virginia Tech Intellectual Properties, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by The Government Of The U.S.A. As Represented By The Secretary Of The Dept. Of Health & Human Service, Virginia Tech Intellectual Properties, Inc. filed Critical The Government Of The U.S.A. As Represented By The Secretary Of The Dept. Of Health & Human Service
Publication of WO2009005839A2 publication Critical patent/WO2009005839A2/fr
Publication of WO2009005839A3 publication Critical patent/WO2009005839A3/fr

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Classifications

    • 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
    • A61K47/554—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 a steroid plant sterol, glycyrrhetic acid, enoxolone or bile acid
    • 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
    • A61K47/56—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 macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/59—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 macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
    • A61K47/60—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 macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • FIG. 2 depicts a synthesis scheme for a novel compound disclosed herein.
  • FIG. 3 represents a possible mode of CCN binding to the androgen receptor after molecular dynamics equilibration in which binding occurs along channel I, which is the path between helices 3, 6, 7, and 1 1.
  • FIG. 6 are Western blots of nuclear and cytoplasmic LNCaP extracts shown after 1 1 hours of exposure to vehicle (Veh), 0.1 ⁇ M nilutamide (Nilut), 0.1 ⁇ M colchicine (Colch) or 0.1 ⁇ M CCN (CCN). Ponceau S stained membrane is shown for protein loading control. Colchicine and CCN increase cytoplasmic AR protein levels without a detectable change in nuclear AR.
  • FIG. 7 is a graph depicting cell toxicity data.
  • Alkyl refers to a branched or unbranched saturated hydrocarbon group of 1 to 24 carbon atoms, such as methyl, ethyl, H-propyl, isopropyl, w-butyl, isobutyl, f-butyl, pentyl, hexyl, heptyl, octyl, decyl, tetradecyl, hexadecyl, eicosyl, tetracosyl and the like.
  • a "lower alkyl” group is a saturated branched or unbranched hydrocarbon having from 1 to 10 carbon atoms.
  • Illustrative specific estrogenic agents include 2-methoxyestradiol (also known as l,3,5(10)-estratriene-3,17 ⁇ diol 2 methyl ether); 17 ⁇ -estradiol (also known as estra-1, 3,5(10)-triene-3, 17 ⁇ -diol); and SERMs such as clomiphene; cycladiene; tamoxifen; nafoxidine; nitromifene citrate (N-55,945-27); 13-ethyl- 17.alpha.-ethynl-17.beta.-hydroxygona-4-9-l 1-trie- n-3-one (R2323); diphenol hydrochrysene; erythro-MEA; allenolic acid; cyclofenyl; chlorotrianisene; ethamoxytriphetol; triparanol; CI- 626; CI-680; MER-25; U-1 1 ,555A; U-1 1,10OA;
  • the actual dosage of the compound will vary according to factors such as the disease indication and particular status of the subject (for example, the subject's age, size, fitness, extent of symptoms, susceptibility factors, and the like), time and route of administration, other drugs or treatments being administered concurrently, as well as the specific pharmacology of the compound for eliciting the desired activity or biological response in the subject. Dosage regimens can be adjusted to provide an optimum prophylactic or therapeutic response. A therapeutically effective amount is also one in which any toxic or detrimental side effects of the compound and/or other biologically active agent is outweighed in clinical terms by therapeutically beneficial effects.
  • CCN was also examined for its ability to inhibit the binding of [ 3 H]colchicine to tubulin, in comparison with thiocolchicine and combretastatin A-4. Inhibitory effects on tubulin assembly and on colchicine binding were equivalent to those of thiocolchicine (Table 2). In comparison with combretastatin A-4, CCN was a more effective inhibitor of assembly, but it was less potent as an inhibitor of [ 3 H]colchicine binding. This potent inhibition of colchicine binding by combretastatin A-4 derives entirely from its rapid binding to tubulin, in comparison with the slower binding of colchicinoids (30). Given the increased activity of CCN over colchicine and the fact that some steroid receptor ligands have tubulin binding activity (31), it was verified that cyanonilutamide had no effect on tubulin assembly (data not shown).

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Epidemiology (AREA)
  • Botany (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Peptides Or Proteins (AREA)

Abstract

La présente invention concerne des composés comprenant une structure représentée par la formule (I) : X - L - Z, X étant un fragment se liant à un récepteur d'hormone stéroïdienne ; Z, (i) un fragment qui se lie à un élément extranucléaire ; ou (ii) un fragment bloquant qui rompt l'interaction entre le récepteur d'hormone stéroïdienne et un coactivateur de récepteur d'hormone stéroïdienne ; et L, un groupe de liaison lié par covalence à X et Z. Le groupe de liaison est physiologiquement non clivable et a une longueur et une rigidité structurales suffisantes pour permettre au composé de se lier au récepteur d'hormone stéroïdienne et (i) à l'élément extranucléaire ou (ii) au fragment bloquant.
PCT/US2008/008299 2007-07-03 2008-07-02 Composés et procédés d'utilisation WO2009005839A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US95835107P 2007-07-03 2007-07-03
US60/958,351 2007-07-03

Publications (2)

Publication Number Publication Date
WO2009005839A2 true WO2009005839A2 (fr) 2009-01-08
WO2009005839A3 WO2009005839A3 (fr) 2009-10-29

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104974147A (zh) * 2014-04-02 2015-10-14 中国医学科学院药物研究所 紫杉醇、多西紫杉醇衍生物及组合物和其抗肿瘤应用
US11826430B2 (en) 2019-05-14 2023-11-28 Nuvation Bio Inc. Anti-cancer nuclear hormone receptor-targeting compounds
US11834458B2 (en) 2021-03-23 2023-12-05 Nuvation Bio Inc. Anti-cancer nuclear hormone receptor-targeting compounds
US11952349B2 (en) 2019-11-13 2024-04-09 Nuvation Bio Inc. Anti-cancer nuclear hormone receptor-targeting compounds
US12006314B2 (en) 2021-05-03 2024-06-11 Nuvation Bio Inc. Anti-cancer nuclear hormone receptor-targeting compounds

Non-Patent Citations (13)

* Cited by examiner, † Cited by third party
Title
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COGAN PETER S ET AL: "Studies of targeting and intracellular trafficking of an anti-androgen doxorubicin-formaldehyde conjugate in PC-3 prostate cancer cells bearing androgen receptor-GFP chimera." JOURNAL OF MEDICINAL CHEMISTRY 4 NOV 2004, vol. 47, no. 23, 4 November 2004 (2004-11-04), pages 5690-5699, XP002543188 ISSN: 0022-2623 *
DEVRAJ R ET AL: "Design, synthesis, and biological evaluation of ellipticine-estradiol conjugates" JOURNAL OF MEDICINAL CHEMISTRY 1996 US, vol. 39, no. 17, 1996, pages 3367-3374, XP002543190 ISSN: 0022-2623 *
HAN GUI-ZHEN ET AL: "Synergism between the anticancer actions of 2-methoxyestradiol and microtubule-disrupting agents in human breast cancer" CANCER RESEARCH, vol. 65, no. 2, 15 January 2005 (2005-01-15), pages 387-393, XP002543191 ISSN: 0008-5472 *
HODL C ET AL: "A Novel, High-Affinity, Fluorescent Progesterone Receptor Antagonist. Synthesis and in Vitro Studies" BIOCONJUGATE CHEMISTRY 200403 US, vol. 15, no. 2, March 2004 (2004-03), pages 359-365, XP002543185 ISSN: 1043-1802 *
HOFFMANN J ET AL: "Steroidhormone receptors as targets for the therapy of breast and prostate cancer-recent advances, mechanisms of resistance, and new approaches" JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY, ELSEVIER SCIENCE LTD., OXFORD, GB, vol. 93, no. 2-5, 1 February 2005 (2005-02-01), pages 191-200, XP025298405 ISSN: 0960-0760 [retrieved on 2005-02-01] *
LIU C ET AL: "Design, synthesis and bioactivities of steroid-linked Taxol analogues as potential targeted drugs for prostate and breast cancer" JOURNAL OF NATURAL PRODUCTS, AMERICAN CHEMICAL SOCIETY, US, vol. 67, no. 2, 1 January 2004 (2004-01-01), pages 152-159, XP002995410 ISSN: 0163-3864 *
MEISINGSET K K ET AL: "INTRA CELLULAR BINDING OF FLUORESCEIN IN LYMPHOCYTES" CYTOMETRY, vol. 1, no. 4, 1981, pages 272-278, XP002543186 ISSN: 0196-4763 *
RICKERT E L ET AL: "Synthesis and characterization of bioactive tamoxifen-conjugated polymers" BIOMACROMOLECULES NOVEMBER 2007 AMERICAN CHEMICAL SOCIETY US, vol. 8, no. 11, November 2007 (2007-11), pages 3608-3612, XP002543192 *
SHARIFI NIMA ET AL: "A bifunctional colchicinoid that binds to the androgen receptor" MOLECULAR CANCER THERAPEUTICS, vol. 6, no. 8, August 2007 (2007-08), pages 2328-2336, XP002543194 ISSN: 1535-7163 *
SINGH PRATAP ET AL: "Rational design of novel antiandrogens for neutralizing androgen receptor function in hormone refractory prostate cancer" PROSTATE, vol. 68, no. 14, October 2008 (2008-10), pages 1570-1581, XP002543193 ISSN: 0270-4137 *
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TAPLIN MARY-ELLEN: "Androgen receptor: role and novel therapeutic prospects in prostate cancer." EXPERT REVIEW OF ANTICANCER THERAPY SEP 2008, vol. 8, no. 9, September 2008 (2008-09), pages 1495-1508, XP008110773 ISSN: 1744-8328 *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104974147A (zh) * 2014-04-02 2015-10-14 中国医学科学院药物研究所 紫杉醇、多西紫杉醇衍生物及组合物和其抗肿瘤应用
CN104974147B (zh) * 2014-04-02 2019-02-01 中国医学科学院药物研究所 紫杉醇、多西紫杉醇衍生物及组合物和其抗肿瘤应用
US11826430B2 (en) 2019-05-14 2023-11-28 Nuvation Bio Inc. Anti-cancer nuclear hormone receptor-targeting compounds
US11952349B2 (en) 2019-11-13 2024-04-09 Nuvation Bio Inc. Anti-cancer nuclear hormone receptor-targeting compounds
US11834458B2 (en) 2021-03-23 2023-12-05 Nuvation Bio Inc. Anti-cancer nuclear hormone receptor-targeting compounds
US12006314B2 (en) 2021-05-03 2024-06-11 Nuvation Bio Inc. Anti-cancer nuclear hormone receptor-targeting compounds

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