WO2006132583A1 - Procede et moyens pour prevenir et inhiber la maladie respiratoire, l'atherosclerose et l'osteoporose provoquees par une infection aux chlamydia pneumoniae - Google Patents

Procede et moyens pour prevenir et inhiber la maladie respiratoire, l'atherosclerose et l'osteoporose provoquees par une infection aux chlamydia pneumoniae Download PDF

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Publication number
WO2006132583A1
WO2006132583A1 PCT/SE2006/000669 SE2006000669W WO2006132583A1 WO 2006132583 A1 WO2006132583 A1 WO 2006132583A1 SE 2006000669 W SE2006000669 W SE 2006000669W WO 2006132583 A1 WO2006132583 A1 WO 2006132583A1
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WO
WIPO (PCT)
Prior art keywords
type iii
atherosclerosis
iii secretion
heteroaryl
osteoporosis
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Application number
PCT/SE2006/000669
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English (en)
Inventor
Leslie Bailey
Åsa GYLFE
Sven Bergström
Mikael Elofsson
Hans Wolf-Watz
Peter NORDSTRÖM
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Innate Pharmaceuticals Ab
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.)
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Publication date
Application filed by Innate Pharmaceuticals Ab filed Critical Innate Pharmaceuticals Ab
Publication of WO2006132583A1 publication Critical patent/WO2006132583A1/fr

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Classifications

    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/166—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/341—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide not condensed with another ring, e.g. ranitidine, furosemide, bufetolol, muscarine
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4406—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 3, e.g. zimeldine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the invention relates to a method and means for preventing and inhibiting respiratory disease and/or atherosclerosis and/or osteoporosis caused by Chlamydia pneumoniae infection.
  • Chlamydia pneumoniae was initially characterised in 1986 as TWAR and is now recognised as a common cause of respiratory infections. Severe cases of respiratory disease need to be treated in order to minimise secondary effects of the infection. Infections with C. pneumoniae are also associated with cardiovascular disease, supposedly by contributing to the pathogenesis of inflammatory diseases such as atherosclerosis.
  • Atherosclerotic heart disease is the leading cause of mortality in the Western hemisphere, and responsible for about 50% of all deaths.
  • the clinical manifestations of atherosclerosis range from coronary artery disease (CAD) to cerebrovascular disease.
  • CAD coronary artery disease
  • the hypothesis that inflammation contributes to the pathogenesis of atherosclerosis is over 100 years old, dating back to Virchow in 1859 and Osier in 1908. This theory was later proven by Russel Ross and others in the 1980s. Recent studies have demonstrated that various markers of systemic inflammation can predict future cardiovascular events including nonfatal and fatal myocardial infarction and stroke.
  • C. pneumoniae causes an intracellular infection and may be carried as a latent infection for months or even longer. It may be eradicated only with difficulty.
  • C. pneumoniae being an intracellular pathogen, is easily transported and invades tissues and organs distant to the primary infection site.
  • Chlamydiae spp. have been shown to possess a Type III secretory system; the effector molecules secreted through Type III pores deploy a set of host cell interactive proteins important for the virulence of the Chlamydiae, including C. pneumoniae and the sexually transmitted disease causing C. trachomatis (R Clifton et al . , PNAS 2004 101:10166-10171).
  • Chlamydia (Chlamydophila) pneumoniae and atherosclerosis came from a serologic study performed in Finland in 1988. Since this initial report, more that 700 papers have been published on the association of C. pneumoniae and atherosclerosis. Animal studies, including mouse and rabbit studies, have demonstrated that C. pneumoniae disseminates systemically after a respiratory infection and also appears to either induce or enhance the development of atherosclerosis, although these results have not been consistent. Osteoporosis and atherosclerosis have been linked to each other in a few recent studies. Thus, severely decreased bone mineral density (BMD) was found in a cohort of patients with serious atherosclerotic involvement of the carotid or femoral artery.
  • BMD bone mineral density
  • Rheumatoid arthritis is a inflammatory condition related to both atherosclerosis, as previously mentioned, and also to bone loss. The nature of this bone loss in arthritis was investigated in a rat model and showed that both systemic and local T-cell activation can lead to production of RANK-L and subsequent bone loss.
  • TNF- ⁇ cytokine tumour necrosis factor alpha
  • the present invention is based on the insight that the intracellular pathogen C. pneumoniae decreases the rate of bone densification in growing mice. While this hypothesis should not be considered binding in any way, the decreased calcification may be caused by an activation of CD3+ T-cells, expressing the osteoclast activator RANKL as well as the TH-I inflammatory pattern with increased levels of the proinflammatory cytokines IL-I and IL-6. Thus, it seems that cytokine production by the immune system could be the link between atherosclerosis and bone loss.
  • the biphasic life cycle of an infection by C. pneumoniae is illustrated in Fig. 1.
  • the infective bacteria enter the host cell and differentiate to reticular bodies (RB) by fusion with the endoplasmatic reticulum.
  • RB reticular bodies
  • the RBs grow by binary fission (pathway A) and finally differentiate back to RBs, which are released by exocytosis or host cell lysis.
  • a method and a means for preventing and/or inhibiting a condition selected from severe respiratory infection (such as pneumonia) , atherosclerosis, and osteoporosis comprising the administration to a person in need of pharmacologically effective amount of a Type III secretion blocker.
  • "Pharmacologically effective amount of a Type III secretion blocker” as used herein designates an amount capable of substantially reducing or even inhibiting the differentiation of cells infected with C. pneumoniae.
  • Substantially reducing the differentiation of cells infected with C. pneumoniae designates the reduction of the differentiation rate by 50 % or more, preferably by 80 % or more, more preferred by 90% or more, most preferred by 95 % or more.
  • the differentiation reducing effect of an extracellulary administered Type III secretion blocker of the invention switches the C. pneumoniae infection pathway of Fig. 1 from A to B, resulting in limited or delayed bacterial growth and division, and the formation of viable but noninfectious forms.
  • the Type III secretion blocker may be administered in combination with an agent facilitating its uptake in infected cells or as a pro-drug capable of being taken up by infected cells and of releasing the Type III secretion blocker in these cells.
  • pharmacologically effective amounts of Type III secretion blockers include amounts resulting in plasma concentrations of from 0.001 ⁇ g/ml to 10 ⁇ g/ml and more.
  • the agents decreasing bacterial virulence are amides of the general formula I
  • A is substituted or unsubstituted aryl or heteroaryl
  • A is substituted aryl or heteroaryl, it is preferred to be mono- or disubstituted by one or more of halogen, nitro, hydroxy, alkoxy, Ci-C 6 alkyl, Ci-C 6 alkenyl, halogen being preferably selected from Cl, Br, I and, independently, alkoxy preferably being acetoxy.
  • Y is selected from aryl and heteroaryl substituted with one or several of halogen, Ci-C 6 alkyl, Ci-Cg alkenyl, halogen being preferably selected from F, Cl, Br.
  • agents decreasing bacterial virulence are amides of the general formula I
  • A is substituted or unsubstituted aryl, heteroaryl, substituted or unsubstituted aryloxy or carbamyl;
  • A is substituted aryl or heteroaryl, it is preferred to be mono- or disubstituted by one or more of halogen, nitro, hydroxy, alkoxy, Ci-Cg alkyl, Ci-Cg alkenyl. It is preferred for Y to be selected from aryl and heteroaryl substituted with one or several of halogen, Ci-Cg alkyl, Ci-Cg alkenyl.
  • a pharmaceutical composition comprising a pharmacologically effective amount of a Type III secretion blocker or a prodrug thereof and an acceptable pharmaceutical excipient.
  • a pharmaceutical composition capable of providing pharmacologically effective plasma concentrations of the Type III blocker, in particular plasma concentrations ranging from 0.001 ⁇ g/ml to 10 ⁇ g/ml and more, can be used.
  • Oral and parenteral administration is preferred but does not exclude other ways of administration.
  • the pharmaceutical composition of the invention may furthermore comprise an adjuvant supporting the uptake of the Type III secretion blocker by infected cells or the attachment to such cells.
  • Fig. 1 is a rough scheme illustrating the life cycle of
  • FIG. 2 is a culture of HEP-2 cells infected with C. pneumoniae
  • Fig. 3 is the culture of Fig. 2, containing 10 ⁇ M of 7;
  • Fig. 4 illustrates the uptake of C. pneumoniae by cultured HEP-2 cells at various concentrations of 7 in the culture medium.
  • Figs. 5 - 10 are preferred Type III secretion blockers of the invention.
  • EXAMPLE 1 Indication of atherosclerosis in mice infected with C. pneumoniae. Infection mice of strain C57/BL/6 (apo (a) /apoBH double transgenic mice; three males) with C. pneumoniae resulted in significantly increased plasma levels of lipoprotein (a) (Lp (a) ) compared with the average level in non- infected controls. The clinical significance of inherited high Lp (a) levels in man in respect of atherosclerosis is well established.
  • EXAMPLE 2 Rate decrease of bone calcification in growing mice .
  • the bone density in growing mice (Balb/c; three males) infected with C. pneumoniae was compared with that of non- infected controls .
  • the infected significantly reduced rate was observed for the infected group.
  • EXAMPLE 3 Inhibition of RG differentiation by the compound 7.
  • a culture of non-infected HPE-2 cells served as a negative control.
  • a monoclonal antibody against C. pneumoniae conjugated with fluorescein isothiocyanate (FITC) was used to visualize EB and RB bodies. The results are shown in Figs 2, 3, and 4.
  • Fig. 2 shows the culture with no 7 added; the chlamydial elementary bodies appear in classical inclusions.
  • Fig. 1 shows the culture with no 7 added; the chlamydial elementary bodies appear in classical inclusions.
  • FIG. 3 shows the culture with 10 ⁇ M of 7 added; the chlamydial elementary bodies are exclusively located outside of the cells.
  • Fig. 4 illustrates the dose effect of 7 obtained by counting the number of inclusions; zero inclusion corresponds to full blocking of RG differentiation. Similar results were obtained in experiments with Chlamydia trachomatis .
  • EXAMPLE 4 Inhibition or prevention of respiratory disease.
  • a person infected with C. pneumoniae is given an amount of a compound of the invention such as, for instance, 7, that is effective to inhibit bacterial propagation, over an appropriate period of time, such as from three days to two weeks.
  • Administration is continued until C. pneumoniae is no longer detectable in serum or biopsy samples.
  • the person seemingly free from infection is controlled at chosen intervals, such as every third or sixth month, for possible relapse, whereupon the treatment is repeated.
  • Administration is preferably orally or parenterally; it will vary according to the bioavailability of the Type III secretion blocker or prodrug used.
  • EXAMPLE 5 Inhibition or prevention of atherosclerosis.
  • a person infected with C. pneumoniae is given an amount of a compound of the invention such as, for instance, 7, that is effective to inhibit bacterial propagation, over an appropriate period of time, such as from three days to two weeks.
  • Administration is continued until C. pneumoniae is no longer detectable in serum or biopsy samples .
  • the person seemingly free from infection is controlled at chosen intervals, such as every third or sixth month, for possible relapse, whereupon the treatment is repeated.
  • Administration is preferably orally or parenterally; it will vary according to the bioavailability of the Type III secretion blocker or prodrug used.
  • EXAMPLE 6 Inhibition or prevention of osteoporosis.
  • a person infected with C. pneumoniae is given an amount of a compound of the invention such as, for instance, 7, that is effective to inhibit bacterial propagation, over an appropriate period of time, such as from three days to two weeks and even up to one year and more.
  • Administration is continued until C. pneumoniae is no longer detectable in serum or biopsy samples ,
  • the person seemingly free from infection is controlled at chosen intervals, such as every third or sixth month, for possible relapse, whereupon the treatment is repeated.
  • Administration is preferably orally or parenterally; it will vary according to the bioavailability of the Type III secretion blocker or prodrug used.

Abstract

L'invention concerne un procédé pour traiter une infection respiratoire, l'athérosclérose ou l'ostéoporose chez un patient, provoquées par une infection par une bactérie Gram-négative possédant une sécrétion de Type III, notamment par Chlamydia pneumoniae; le procédé consiste à administrer la composition pharmaceutique comprenant une quantité pharmacologiquement efficace d'un bloquant de sécrétion de Type III et d'un excipient pharmaceutiquement efficace. L'invention concerne aussi un procédé pour fabriquer un médicament destiné à s'utiliser avec ce procédé de traitement.
PCT/SE2006/000669 2005-06-07 2006-06-06 Procede et moyens pour prevenir et inhiber la maladie respiratoire, l'atherosclerose et l'osteoporose provoquees par une infection aux chlamydia pneumoniae WO2006132583A1 (fr)

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SE0501281 2005-06-07
SE0501281-0 2005-06-07

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20120232105A1 (en) * 2011-03-11 2012-09-13 National Defense Medical Center Pharmaceutical composition for inhibiting osteoclast growth
JP2014501763A (ja) * 2010-12-22 2014-01-23 ザ トラスティーズ オブ コロンビア ユニヴァーシティ イン ザ シティ オブ ニューヨーク ヒストンアセチル基転移酵素モジュレーターおよびその使用
WO2017009344A1 (fr) 2015-07-13 2017-01-19 Centre National De La Recherche Scientifique (Cnrs) Composes inhibiteurs de pseudomonas aeruginosa
US10640457B2 (en) 2009-12-10 2020-05-05 The Trustees Of Columbia University In The City Of New York Histone acetyltransferase activators and uses thereof
CN114105870A (zh) * 2021-11-26 2022-03-01 四川省医学科学院·四川省人民医院 一种抗肿瘤化合物、应用以及含有该化合物组合物

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WO2003075910A1 (fr) * 2002-03-08 2003-09-18 Protemix Corporation Limited Prevention et/ou traitement d'une maladie vasculaire, d'une cardiomyopathie et/ou d'une defaillance cardiaque associee
WO2003088748A1 (fr) * 2002-04-15 2003-10-30 Beth Israel Deaconess Medical Center Utilisation d'heme-oxygenase-1 et produits de degradation d'heme
WO2004022775A1 (fr) * 2002-09-04 2004-03-18 Innate Pharmaceuticals Ab Methode et sonde d'identification d'agents modificateurs de la virulence bacterienne, agents ainsi identifies et leur utilisation
WO2004084907A2 (fr) * 2003-03-28 2004-10-07 Procorde Gmbh Inhibiteurs specifiques de l'activation de nf-kb et methode de traitement de processus inflammatoires dans des maladies cardio-vasculaires
WO2004105769A1 (fr) * 2003-05-28 2004-12-09 Universite De Liege Composition pharmaceutique destinee au traitement et/ou a la prevention de l'atherosclerose d'origine infectieuse
WO2005037257A2 (fr) * 2003-10-15 2005-04-28 Imtm Gmbh Nouveaux inhibiteurs d'alanyl-aminopeptidases destines a exercer une influence fonctionnelle sur diverses cellules et a constituer un traitement immunologique de maladies inflammatoires, neuronales et autres
WO2005037779A2 (fr) * 2003-10-15 2005-04-28 Imtm Gmbh Nouveaux inhibiteurs de dipeptidylpeptidases iv destines a influencer le fonctionnement de diverses cellules et a traiter des maladies immunologiques, inflammatoires, neuronales et autres
WO2005082882A1 (fr) * 2004-01-30 2005-09-09 Clinigenetics Composes de type hydrazide et leur utilisation dans des compositions pharmaceutiques pour le traitement des maladies cardiovasculaires

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003075910A1 (fr) * 2002-03-08 2003-09-18 Protemix Corporation Limited Prevention et/ou traitement d'une maladie vasculaire, d'une cardiomyopathie et/ou d'une defaillance cardiaque associee
WO2003088748A1 (fr) * 2002-04-15 2003-10-30 Beth Israel Deaconess Medical Center Utilisation d'heme-oxygenase-1 et produits de degradation d'heme
WO2004022775A1 (fr) * 2002-09-04 2004-03-18 Innate Pharmaceuticals Ab Methode et sonde d'identification d'agents modificateurs de la virulence bacterienne, agents ainsi identifies et leur utilisation
WO2004084907A2 (fr) * 2003-03-28 2004-10-07 Procorde Gmbh Inhibiteurs specifiques de l'activation de nf-kb et methode de traitement de processus inflammatoires dans des maladies cardio-vasculaires
WO2004105769A1 (fr) * 2003-05-28 2004-12-09 Universite De Liege Composition pharmaceutique destinee au traitement et/ou a la prevention de l'atherosclerose d'origine infectieuse
WO2005037257A2 (fr) * 2003-10-15 2005-04-28 Imtm Gmbh Nouveaux inhibiteurs d'alanyl-aminopeptidases destines a exercer une influence fonctionnelle sur diverses cellules et a constituer un traitement immunologique de maladies inflammatoires, neuronales et autres
WO2005037779A2 (fr) * 2003-10-15 2005-04-28 Imtm Gmbh Nouveaux inhibiteurs de dipeptidylpeptidases iv destines a influencer le fonctionnement de diverses cellules et a traiter des maladies immunologiques, inflammatoires, neuronales et autres
WO2005082882A1 (fr) * 2004-01-30 2005-09-09 Clinigenetics Composes de type hydrazide et leur utilisation dans des compositions pharmaceutiques pour le traitement des maladies cardiovasculaires

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10640457B2 (en) 2009-12-10 2020-05-05 The Trustees Of Columbia University In The City Of New York Histone acetyltransferase activators and uses thereof
US11034647B2 (en) 2009-12-10 2021-06-15 The Trustees Of Columbia University In The City Of New York Histone acetyltransferase activators and uses thereof
JP2014501763A (ja) * 2010-12-22 2014-01-23 ザ トラスティーズ オブ コロンビア ユニヴァーシティ イン ザ シティ オブ ニューヨーク ヒストンアセチル基転移酵素モジュレーターおよびその使用
US9969677B2 (en) 2010-12-22 2018-05-15 The Trustees Of Columbia University In The City Of New York Histone acetyltransferase modulators and uses thereof
US20120232105A1 (en) * 2011-03-11 2012-09-13 National Defense Medical Center Pharmaceutical composition for inhibiting osteoclast growth
US8772344B2 (en) * 2011-03-11 2014-07-08 National Defense Medical Center Pharmaceutical composition for inhibiting osteoclast growth
WO2017009344A1 (fr) 2015-07-13 2017-01-19 Centre National De La Recherche Scientifique (Cnrs) Composes inhibiteurs de pseudomonas aeruginosa
US10908153B2 (en) 2015-07-13 2021-02-02 Centre National De La Recherche Scientifique (Cnrs) Pseudomonas aeruginosa inhibitor compounds
CN114105870A (zh) * 2021-11-26 2022-03-01 四川省医学科学院·四川省人民医院 一种抗肿瘤化合物、应用以及含有该化合物组合物

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