WO2019033122A1 - Traitement de maladies pulmonaires à l'aide d'agents pharmaceutiques qui éliminent des cellules sénescentes - Google Patents

Traitement de maladies pulmonaires à l'aide d'agents pharmaceutiques qui éliminent des cellules sénescentes Download PDF

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WO2019033122A1
WO2019033122A1 PCT/US2018/046567 US2018046567W WO2019033122A1 WO 2019033122 A1 WO2019033122 A1 WO 2019033122A1 US 2018046567 W US2018046567 W US 2018046567W WO 2019033122 A1 WO2019033122 A1 WO 2019033122A1
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compound
cells
tissue
senescent cells
lung
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PCT/US2018/046567
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English (en)
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Nick VLAHAKIS
Scott Armstrong
Jamie Dananberg
Ryan Hudson
Anne-Marie Beausoleil
Nathaniel David
Remi-Martin LABERGE
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Unity Biotechnology, Inc.
Buck Institute For Research On Aging
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Priority claimed from US15/675,171 external-priority patent/US20180000816A1/en
Application filed by Unity Biotechnology, Inc., Buck Institute For Research On Aging filed Critical Unity Biotechnology, Inc.
Priority to US16/636,299 priority Critical patent/US20200354336A9/en
Publication of WO2019033122A1 publication Critical patent/WO2019033122A1/fr

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    • 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
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/36—Oxygen or sulfur atoms
    • C07D207/40—2,5-Pyrrolidine-diones
    • C07D207/416—2,5-Pyrrolidine-diones with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to other ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
    • C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom

Definitions

  • the technology disclosed and claimed below relates generally to the field of lung disease leading to impaired respiration capacity.
  • This disclosure provides a family of compounds and techniques that can be used for treating pulmonary disease by eliminating senescent cells implicated in the underlying pathophysiology and symptomatology.
  • the goal of the compounds of the invention is to not just interrupt specific pathogenic pathways but specifically target senescent cells and in turn inhibit multiple pathogenic pathways.
  • the invention provided herein provides novel compounds for the treatment of respiratory disease (primary or secondary etiology), and extra-pulmonary effects arising from or associated with such lung diseases, through the elimination of senescent cells implicated in the pathophysiology of diseases of the pulmonary system.
  • respiratory disease primary or secondary etiology
  • extra-pulmonary effects arising from or associated with such lung diseases
  • senescent cells implicated in the pathophysiology of diseases of the pulmonary system.
  • This invention is based in part on the discovery that many pulmonary diseases and conditions associated with aging are mediated at least in part by cells bearing a senescent phenotype. Senescent cells accumulate with age, which is why conditions mediated by senescent cells occur more frequently in older adults. Senescent cells express factors that contribute to the pathophysiology of the age related and senescence-associated conditions. Different types of stress on pulmonary tissues may promote the emergence of senescent cells and the phenotype they express. Cell stressors include oxidative stress, metabolic stress, DNA damage (for example, because of environmental ultraviolet light exposure or genetic cause), oncogene activation, and telomere shortening (resulting, for example, from hyperproliferation) .
  • This invention is also based in part on new acyl sulfonamides that are Bel inhibitors.
  • Some of the Bel inhibitors in this family are particularly effective senolytic agents for lung diseases.
  • Contacting senescent cells in vitro or in vivo with the compounds and compositions of the invention selectively modulates or eliminates such cells.
  • These inhibitors can be used for administration to a diseased lung tissue in a subject having an age-related lung disease, thereby selectively eliminating senescent cells in or around the diseased lung tissue and relieving one or more symptoms or signs of the disease.
  • Selected compounds from the family can be formulated and marketed as chemotherapeutic agents.
  • FIG. 1 shows a general synthetic scheme for chemically synthesizing exemplary compounds according to this invention.
  • FIGS. 2A and 2B show immunohistochemical staining for pi 6 in human IPF lung tissue to demonstrate the presence of senescent cells.
  • FIG. 2A shows a macro-view of the IPF lung tissue having pi 6 positive staining.
  • FIG. 2B is an enlarged view of an area of the IPF lung tissue of FIG. 2A.
  • the senescent cells were predominately epithelial in origin and located in areas of fibrosis and at the leading edge of the disease. See Example 1.
  • FIG. 3 shows the quantification of pi 6 positive cells in all normal human lung tissues sampled as compared to all human IPF lung tissues sampled. Increased presence of pi 6 positive cells in human lung tissue with significant fibrotic area was indicative of a significant role in disease progression (****p ⁇ 0.0001 for group difference among means by one-way ANOVA). See Example 1.
  • FIGS. 4A, 4B and 4C show immunohistochemical staining for pl6 in human scleroderma lung tissue to demonstrate the presence of senescent cells.
  • FIG. 4A shows a macro-view of the human scleroderma lung tissue having pi 6 positive staining.
  • FIG. 4B is an enlarged view of an area of the scleroderma lung tissue of FIG. 4A.
  • FIG. 4C is a further enlarged view of an area of the scleroderma lung tissue of FIG. 4B.
  • the pi 6 positive senescent cells were fibrotic in origin and located in honeycomb areas of the lung. See Example 1.
  • FIG. 5 shows the quantification of pi 6 positive cells in normal human lung tissue as compared to human scleroderma lung tissue. Increased presence of pl6 positive cells in human lung tissue with significant fibrotic area was indicative of a significant role in disease progression
  • FIG. 6 shows a concentration-response curve demonstrating the selectivity of Compound 1 for senescent lung epithelial cells (SnC - solid lines) in contrast to non-senescent lung epithelial cells (NsC - dashed lines). See Example 2.
  • FIG. 7 shows a concentration-response curve, using one-way ANOVA, of relative pi 6 gene expression changes of 8%, 14% and 27% upon treatment with 0.1 mg/ml, 0.3 mg/ml and 1.0 mg/ml of Compound 1 , respectively, in mice challenged with bleomycin (+ ) to induce senescence in the lung. See Example 4.
  • FIG. 8 shows the ability of Compound 1 to eliminate pi 6 positive lung epithelial cells in mice challenged with bleomycin (+) to induce senescence in the lung. See Example 4.
  • enantiomerically enriched and stereoisomerically enriched denote that the compound of the invention comprises 75%, 80%, 85%, 90%, 95%, 98%, or 99% or more by weight of the enantiomer or the stereoisomer.
  • ex vivo refers to experimentation or manipulation done in or on living tissue in an artificial environment outside the organism.
  • pharmaceutically acceptable carrier or “pharmaceutically acceptable excipient” includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions.
  • pharmaceutically acceptable salt refers to salts that retain the biological effectiveness and properties of the compounds of this invention and, which are not biologically or otherwise undesirable.
  • the compounds of this invention are capable of forming acid and/or base salts by virtue of the presence of amino, phosphate, and/or carboxyl groups or groups similar thereto.
  • Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
  • Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, naphtoic acid, oleic acid, palmitic acid, pamoic (emboic) acid, stearic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, ascorbic acid, glucoheptonic acid, glucuronic acid, lactic acid, lactobioic acid, tartaric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like.
  • Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.
  • Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like; particularly preferred are the ammonium, potassium, sodium, calcium and magnesium salts.
  • Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, specifically such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, histidine, arginine, lysine, benethamine, N- methyl-glucamine, and ethanolamine.
  • Other acids include dodecylsufuric acid, naphthalene-l,5-disulfonic acid, naphthalene -2-sulfonic acid, and saccharin.
  • a "phosphorylated" form of a compound is a compound in which one or more -OH or - COOH groups have been substituted with a phosphate group which is either -OPO(OH) 2 or -alkyl- OPO(OH) 2 (where alkyl is C 1 6 alkyl), such that the phosphate group may be removed in vivo (for example, by enzymolysis).
  • a non-phosphorylated or dephosphorylated form has no such phosphate group.
  • "Prodrug” refers to a derivative of an active agent that requires a transformation within the body to release the active agent. The transformation can be an enzymatic transformation. Prodrugs are frequently, although not necessarily, pharmacologically inactive until converted to the active agent.
  • a "senescent cell” is generally thought to be derived from a cell type that typically replicates, but as a result of aging or other event that causes a change in cell state, can no longer replicate. It remains metabolically active and commonly adopts a senescence associated secretory phenotype (SASP) that includes chemokines, cytokines and extracellular matrix and fibrosis modifying proteins and enzymes.
  • SASP senescence associated secretory phenotype
  • the nucleus of senescent cells is often characterized by senescence-associated heterochromatin foci and DNA segments with chromatin alterations reinforcing senescence.
  • senescent cells can be identified as expressing at least one marker selected from pl6, senescence-associated ⁇ -galactosidase, and lipofuscin; sometimes two or more of these markers, and other markers of SASP such a,s but not limited to, interleukin 6 (IL-6), and inflammatory, angiogenic and extracellular matrix modifying proteins.
  • pl6, senescence-associated ⁇ -galactosidase, and lipofuscin sometimes two or more of these markers, and other markers of SASP such a,s but not limited to, interleukin 6 (IL-6), and inflammatory, angiogenic and extracellular matrix modifying proteins.
  • IL-6 interleukin 6
  • a "senescence associated", "senescence related” or “age related” disease, disorder, or condition is a physiological condition that presents with one or more symptoms or signs, wherein a subject having the condition needs or would benefit from a lessening of such symptoms or signs.
  • the condition is senescence associated if it is caused or mediated in part by senescent cells, which may be induced by multiple etiologic factors including age, DNA damage, oxidative stress, genetic defects, etc. Lists of senescence associated disorders that can potentially be treated or managed using the methods and products taught in this disclosure include those discussed in this disclosure and the previous disclosures to which this application claims priority.
  • a compound of the invention is typically referred to as "senolytic” if it eliminates senescent cells, compared with replicative cells of the same tissue type, or quiescent cells lacking SASP markers.
  • compounds of the invention may effectively be used according to this invention if it decreases the release of pathological soluble factors or mediators as part of the senescence associated secretory phenotype that play a role in the initial presentation or ongoing pathology of a condition or inhibit its resolution.
  • the term "senolytic” is exemplary, with the
  • "Small molecule" Bel inhibitors according to this invention have molecular weights less than 20,000 daltons, and are often less than 10,000, 5,000, or 2,000 daltons. Small molecule inhibitors are not antibody molecules or oligonucleotides, and typically have no more than five hydrogen bond donors (the total number of nitrogen-hydrogen and oxygen-hydrogen bonds), and no more than 10 hydrogen bonds.
  • Successful "treatment" of a lung disease according to this invention may have any effect that is beneficial to the subject being treated. This includes decreasing severity, duration, or progression of a condition, or of any adverse signs or symptoms resulting therefrom.
  • senolytic agents can also be used to prevent or inhibit presentation of a condition for which a subject is susceptible, for example, because of an inherited susceptibility of because of medical history.
  • a “therapeutically effective amount” is an amount of a compound of the present disclosure that (i) treats the particular disease, condition, or disorder, (ii) attenuates, ameliorates, or eliminates one or more symptoms of the particular disease, condition, or disorder, (iii) prevents or delays the onset of one or more symptoms of the particular disease, condition, or disorder described herein, (iv) prevents or delays progression of the particular disease, condition or disorder, or (v) at least partially reverses damage caused by the condition prior to treatment.
  • all the compound structures referred to in the invention include conjugate acids and bases having the same structure, crystalline and amorphous forms of those compounds, pharmaceutically acceptable salts, and dissolved and solid forms thereof, including, for example, polymorphs, solvates, hydrates, unsolvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms of the compounds, as well as mixtures thereof.
  • other terms used in the specification have their ordinary meaning.
  • the half maximal inhibitory concentration is a measure of the potency of a compound in inhibiting a specific biological or biochemical function. Specifically, for compounds of the invention, IC 50 is the measure of the amount of a compound required to achieve 50% inhibition of the activity of the target Bel.
  • compounds of the invention have a demonstrated IC 50 for Bcl-xL of less than 10 nM, less than 5 nM, or less than 1 nM.
  • Compounds of the invention have a demonstrated IC 50 for Bcl-xL of between 1 nM to 10 nM, between 1 nM and 5 nM, between 5 nM to 10 nM, or between 0.1 nM to 1 nM.
  • Compounds of the invention have also demonstrated an IC 50 for Bcl-2 of less than 15 nM, less than 10 nM, less than 5 nM, or less than 1 nM.
  • Compounds of the invention have also demonstrated an IC 50 for Bcl-2 of between 1 nM to 10 nM, between 1 nM and 5 nM, between 5 nM to 10 nM, or between 0.1 nM to 1 nM.
  • Alkyl refers to monovalent saturated aliphatic hydrocarbyl groups having from 1 to 10 carbon atoms and preferably 1 to 6 carbon atoms. This term includes, by way of example, linear and branched hydrocarbyl groups such as methyl (-CH 3 ), ethyl (-CH 2 CH 3 , n-propyl (-CH 2 CH 2 CH 3 ), isopropyl (-CH(CH 3 ) 2 ), n-butyl (-CH 2 CH 2 CH 2 CH 3 ), isobutyl (-CH 2 CH(CH 3 ) 2 ), sec-butyl (-CH(CH 2 CH 3 )(CH) 3 ), t- butyl (-C(CH 3 ) 3 ), n-pentyl (-CH 2 CH 2 CH 2 CH 3 ), and neopentyl (-CH 2 C(CH 3 ) 3 ), etc.
  • an "alkyl” group can be substituted, where the term “substituted,” when used to modify a specified group or radical, means that one or more hydrogen atoms of the specified group or radical are each independently replaced with the same or different substituent groups as defined below.
  • Heteroalkyl refers to a saturated or unsaturated group having a single ring or multiple condensed rings, including fused bridged and spiro ring systems, and having from 3 to 20 ring atoms, including 1 to 10 hetero atoms. These ring atoms are selected from nitrogen, sulfur, or oxygen, where, in fused ring systems, one or more of the rings can be cycloalkyl, aryl, or heteroaryl. In certain
  • a "heteroalkyl” group can be substituted, as defined above.
  • Senescent cells are typically cells that no longer have replicative capacity, but remain in the tissue of origin, eliciting a senescence-associated secretory phenotype (SASP). Senescent cells are thought to derive from proliferative cells of a variety of tissue types, including cells that reside in and around the lung.
  • SASP factors include molecules that are angiogenic, inflammatory, proliferative, fibrotic, and extracellular matrix modifying molecules (Acosta et al., 2013). Some factors implicated in pulmonary pathologies are part of the constellation of factors produced by senescent cells. For this reason, elimination or control of senescent cells provides a means by which to treat lung disease, not only through the elimination of senescent cells but also through reduction of their associated SASP factors and impact on surrounding cells.
  • senescent cells are non-proliferative, eliminating senescent cells has the potential for a clinically beneficial effect that persists for an extended time between episodes of treatment.
  • Features of the condition mediated by senescent cells can resolve at least until senescent cells re-accumulate. Since senescent cells and the burden of their pathogenic effect are likely to accumulate slowly, as the nature of age related diseases is to evolve over a period of many years, the effects of a single treatment or treatment cycle may last for weeks, months, or years.
  • senolysis The specific clearance of senescent cells from tissue is referred to in this disclosure as senolysis.
  • Small molecule compounds capable of senolysis are referred to as senolytic agents, and clear senescent cells irrespective of mechanism of senescence induction, SASP profile or cell lineage.
  • SASP profile the mechanism of senescence induction
  • senescent cells in different parts of the lung respond to the same senolytic agents, several different lung diseases can be treated in the same patient at the same time.
  • a patient may present to the clinician with several concurrent active disease processes already under way: such as fibrosis and chronic obstructive lung disease.
  • It may be possible to administer a single senolytic agent in a treatment protocol that addresses the disease and its symptoms of each of the multiple conditions. Beyond the convenience of this approach, it has the added benefit of lowering the risk of side effects that may result from multiple drugs being given in combination to treat each of the conditions individually.
  • factors elicited by cells in one part of the lung may impact other parts of the lung such that treating senescence in two locations in the lung may have a beneficial effect on both lung diseases.
  • Senolytic medicines can be an important adjunct to other types of therapies, such as for example, standard of care, to relieve the symptoms that result from the condition(s).
  • the two modes of therapy can work synergistically to reduce the burden, frequency and side effects of either mode administered separately.
  • the Bel protein family (TC# 1.A.21) includes evolutionarily-conserved proteins that share Bcl-2 homology (BH) domains. Bel proteins are most notable for their ability to up- or down-regulate apoptosis, a form of programmed cell death, at the mitochondrion. The following explanation is provided to assist the user in understanding some of the scientific underpinnings of the compounds of this invention. These concepts are not needed to practice the invention, nor do they limit the use of the compounds and methods described here in any manner beyond that which is expressly stated or required. In the context of this invention, the Bel proteins of particular interest are those that downregulate apoptosis.
  • Anti-apoptotic Bel proteins contain BH1 and BH2 domains, some of them contain an additional N-terminal BH4 domain (Bcl-2, Bcl-x(L) and Bcl-w (Bcl-2L2), Inhibiting these proteins increases the rate or susceptibility of cells to apoptosis. Thus, an inhibitor of such proteins can be used to help eliminate cells in which the proteins are expressed.
  • ABT-737 (Navitoclax)
  • SMI small molecule inhibitors
  • ABT-737 is superior to previous BCL-2 inhibitors given its higher affinity for Bcl-2, Bcl-xL and Bcl-w.
  • In vitro studies showed that primary cells from patients with B-cell malignancies are sensitive to ABT-737.
  • ABT-737 is effective against some types of cancer cells but is subject to dose-limiting thrombocytopenia.
  • the compounds of the present disclosure have a structure that falls within the scope of the structure according to Formula (I) shown below.
  • X 1 is -CI
  • X 2 is -COOH or -S0 2 CH 3 ;
  • X 3 is -S0 2 CF 3 ; -S0 2 CH 3 ; or -N0 2 ;
  • X s is -F or -H
  • R 1 is -CH(CH 3 ) 2 ;
  • R 2 is -CH 3 ;
  • R 3 and R 4 are both -H
  • n 2;
  • R 6 is selected from -OR 7 , , and ;
  • R 7 is -H or -PO(OH) 2 ,
  • X 1 is -CI
  • R 1 is -CH(CH 3 ) 2
  • R 2 is -CH 3
  • R 3 is H, R is -H, and n is 2.
  • X 2 is -COOH or -S0 2 CH 3 .
  • X 2 can be -COOH, or X 2 can be -S0 2 CH 3 .
  • the dash symbol (“-") indicates the point of attachment of the moiety of interest to the remainder of the compound being described.
  • X 3 is -S0 2 CF 3 , -S0 2 CH 3 , or -N0 2 .
  • X 3 can be -S0 2 CF 3
  • X 3 can be -S0 2 CH 3
  • X 3 can be -N0 2 .
  • X s is -F or -H.
  • X s can be -F, or X s can be -H.
  • R 6 is
  • R 6 can be -OR 7 , or R 6 can be , or R 6 can be
  • a wavy line (“ ⁇ « ”) indicates the point of attachment or the bond where the moiety of interest is attached to the remainder of the compound being described.
  • R 7 is -H or -PO(OH) 2 .
  • R 7 can be -H, or R 7 can be
  • the -COOH group of X 2 may be phosphorylated as well as or instead of the hydroxyl group at the R 6 position, at the user's option.
  • Compounds of Formula (I) find use in methods of treating a pulmonary disease in a subject as described herein.
  • the pulmonary disease can be idiopathic pulmonary fibrosis (IPF), or the pulmonary disease can be chronic obstructive pulmonary disease (COPD).
  • IPF idiopathic pulmonary fibrosis
  • COPD chronic obstructive pulmonary disease
  • the compounds of the present disclosure have a structure that falls within the scope of the structure according to Formula (II) shown below.
  • X 1 is -CI
  • X 2 is -COOH or -S0 2 CH 3 ;
  • X 3 is -S0 2 CF 3 , -S0 2 CH 3 , or -N0 2 ;
  • X s is -F or -H
  • R 1 is -CH(CH 3 ) 2 ;
  • R 2 is -CH 3 ;
  • R 3 and R 4 are both -H
  • n 2;
  • R 6 is selected from -OH, -OR 7 , and ; and R 7 is -PO(OH) 2 ,
  • X 1 is -CI
  • R 1 is -CH(CH 3 ) 2
  • R 2 is -CH 3
  • R 3 is H
  • R 4 is -H
  • n is 2
  • R 7 is -PO(OH) 2 .
  • X 2 is -COOH or -S0 2 CH 3 .
  • X 2 can be -COOH, or X 2 can be -S0 2 CH 3 .
  • X 3 is -S0 2 CF 3 , -S0 2 CH 3 , or -N0 2 .
  • X 3 can be - S0 2 CF 3
  • X 3 can be -S0 2 CH 3
  • X 3 can be -N0 2 .
  • X s is -F or -H.
  • X s can be -F, or X s can be -H. ⁇ - ⁇ >— OR'
  • R 6 is selected from -OH, -OR 7 , .
  • R 6 can be -OH, or R 6 can be -OR 7 , or R 6 can be
  • the -COOH group of X 2 may be phosphorylated as well as or instead of the hydroxyl group at the R 6 position, at the user's option.
  • the compounds of the present disclosure have a structure that falls within the scope of the structure according to Formula (III) shown below.
  • R 1 and R 2 are independently Q to C 4 alkyl
  • R 3 , R 4 and R 5 are independently -H or -CH 3 ;
  • R 8 is -OH or -N(R 6 )(R 7 ), wherein R 6 and R 7 are independently alkyl or heteroalkyl, and are optionally cyclized;
  • X 1 is -F, -CI, -Br, or -OCH 3 ;
  • X 2 is -S0 2 R' or -C0 2 R', where R' is -H, -CH 3 , or -CH 2 CH 3 ;
  • X 3 is -S0 2 CF 3 ; -S0 2 CH 3 ; or -N0 2 ;
  • X s is -F, -Br, -CI, -H, or -OCH 3 .
  • R 1 and R 2 are independently Q to C 4 alkyl.
  • R 1 can be Ci to C 4 alkyl
  • R 2 can be Ci to C 4 alkyl.
  • R 3 , R 4 and R 5 are independently -H or -CH 3 .
  • R 3 can be -H or -CH 3 .
  • R 4 is -H or -CH 3 .
  • R 5 is -H or -CH 3 .
  • R 8 is -OH or -N(R 6 )(R 7 ), where R 6 and R 7 are independently alkyl or heteroalkyl, and are optionally cyclized.
  • R 8 can be -OH.
  • R 8 is - N(R 6 )(R 7 ).
  • R 6 can be alkyl or heteroalkyl
  • R 7 can be alkyl or heteroalkyl.
  • R 6 and R 7 together with the nitrogen to which they are attached are cyclized.
  • the resulting R 8 group can be a heterocyclyl.
  • the resulting R group can be , where m is an integer selected from 1, 2, and 3, and X 4 is -OH, -COOH, or -CH 2 OH.
  • the R 8 heterocyclyl is selected from a group such as, but not limited to, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, piperazinyl, morpholinyl, and the like.
  • the resulting R 8 group is piperidinyl.
  • the resulting R 8 group is morpholinyl.
  • the resulting R 8 group is optionally substituted with one or more substituent groups.
  • the optional substituent on the R 8 group can be -OH, - COOH, or -CH 2 OH.
  • X 1 is -F, -CI, -Br, or -OCH 3 .
  • X 1 can be -F, or X 1 can be -CI, or X 1 can be -Br, or X 1 can be -OCH 3 .
  • X 2 is -S0 2 R' or -C0 2 R', where R' is -H, -CH 3 , or -CH 2 CH 3 .
  • R' is -S0 2 R', or X 2 can be -C0 2 R' .
  • R' is -H, -CH 3 , or -CH 2 CH 3 .
  • R' can be -H, or R' can be -CH 3 , or R' can be -CH 2 CH 3 .
  • X 3 is -S0 2 CF 3 , -S0 2 CH 3 , or -N0 2 .
  • X 3 can be - S0 2 CF 3
  • X 3 can be -S0 2 CH 3
  • X 3 can be -N0 2 .
  • X s is -F, -Br, -CI, -H, or -OCH 3 .
  • X s can be -F, or X s can be -Br, or X s can be -CI, or X s can be -H, or X s can be -OCH 3 .
  • the compound of Formula (III) is phosphorylated.
  • compounds of Formula (III) can be phosphorylated on the R 8 group.
  • the compounds of Formula (III) also include salts or stereoisomers thereof.
  • Compounds of Formula (III) find use in methods of treating a pulmonary disease in a subject as described herein.
  • the pulmonary disease can be idiopathic pulmonary fibrosis (IPF), or the pulmonary disease can be chronic obstructive pulmonary disease (COPD).
  • IPF idiopathic pulmonary fibrosis
  • COPD chronic obstructive pulmonary disease
  • a suitable assay can be a homogeneous assay (an assay that does not require a separation step) for purposes of determining binding to the Bel isoforms, which is based on oxygen channeling that is marketed by PerkinElmer Inc., Waltham, Massachusetts: see Eglin et al., Current Chemical Genomics, 2008, 1, 2-10.
  • the test compound is combined with the target Bel protein and a peptide representing the corresponding cognate ligand, labeled with biotin.
  • the mixture is then combined with streptavidin bearing luminescent donor beads and luminescent acceptor beads, which proportionally reduces luminescence if the compound has inhibited the peptide from binding to the Bel protein.
  • compounds of the invention can be evaluated for an ability to kill senescent cells specifically, as described herein in Example 2.
  • Compounds can be screened for biological activity in an assay using senescent cells. Cultured cells are contacted with the compound, and the degree of cytotoxicity or inhibition of the cells is determined. The ability of the compound to kill or inhibit senescent cells can be compared with the effect of the compound on normal cells that are freely dividing at low density, and normal cells that are in a quiescent state at high density.
  • cultured cells such as, for example, human target tissue fibroblast IMR90 cell lines and HUVEC cells
  • the degree of cytotoxicity or inhibition of the cells is determined using, for example, a thermostable luciferase to enable reaction conditions that generate a stable luminescent signal while simultaneously inhibiting endogenous ATPase released during cell lysis.
  • the diseases can be classified according to the primary underlying pathophysiology. Diseases that fall within the same classification are amenable to applying senolytic medicine with the same principles and with similar objectives.
  • Pulmonary diseases suitable for treatment are discussed in more detail below, within the following classifications:
  • TYPE 1 Restrictive: result from diseases that cause a reduction in lung compliance and in turn reduction in lung vital capacity and total lung volume commonly a result of thickening of the lung interstitium exemplified by fibrotic diseases.
  • TYPE 2 Obstructive: result from diseases that cause air trapping in the lung and in turn a reduction in expiratory volume and increased total lung volume commonly a result of airway obstruction or destruction exemplified by diseases such as COPD and asthma.
  • TYPE 3 vascular: result from a disruption of the normal functioning of the blood vessels resulting from disorders affecting the cellular components of the vessel including but not limited to the endothelium. These disruptions may result in diseases characterized by vascular inflammation and increased vessel tone (e.g. ANCA-vasculitis and pulmonary hypertension) ultimately leading to dysfunction of the physiologic function of the lung and heart.
  • vascular inflammation e.g. ANCA-vasculitis and pulmonary hypertension
  • TYPE 4 Genetic: result from genetic abnormalities that result in lung disease that affects multiple anatomic components of the lung and extra-pulmonary organs. These include but are not limited to cystic fibrosis and alpha- 1 antitrypsin.
  • TYPE 5 Infections: result from pathogenic microorganisms, such as bacteria, viruses, parasites or fungi, may infect any anatomical location including the airways, alveoli and pleura. They may result in symptomatic (e.g. pneumonia) or asymptomatic latent disease (e.g. tuberculosis).
  • This classification is provided to assist in understanding and applying the invention to a particular patient and is not meant to limit application of this technology. Certain conditions may invoke several of these categories: for example, an inflammatory process may contribute to pathological processes having other underlying causes. Similarly, the SASP may trigger additional pathologic processes regardless of the primary insult.
  • Pulmonary diseases suitable for treatment with the compounds of the invention are:
  • compounds of Formula (I) as described herein find use in methods of treating a pulmonary disease in a subject as described herein.
  • compounds of Formula (II) as described herein find use in methods of treating a pulmonary disease in a subject as described herein.
  • compounds of Formula (III) as described herein find use in methods of treating a pulmonary disease in a subject as described herein.
  • Physiologic restriction of the lung result from diseases that cause a reduction in lung compliance and in turn reduction in lung vital capacity and total lung volume commonly a result of thickening of the lung interstitium exemplified by fibrotic diseases, such as, for example, idiopathic pulmonary fibrosis (IPF) and connective tissue disease-associated lung fibrosis such as systemic sclerosis (SSc).
  • fibrotic diseases such as, for example, idiopathic pulmonary fibrosis (IPF) and connective tissue disease-associated lung fibrosis such as systemic sclerosis (SSc).
  • IPF is a chronic and progressive fibrotic lung disease characterized by stiffening and scarring of the lung, which can lead to respiratory failure, pulmonary hypertension and increases the risk for lung cancer, and heart failure.
  • Fibrosis is associated with dysfunctional repair of the lung interstitium epithelium. Fibroblasts are activated, production of extracellular matrix proteins is increased, and transdifferentiation to contractile myofibroblasts contribute to wound contraction.
  • a provisional matrix plugs the injured epithelium and provides a scaffold for epithelial cell migration, involving an epithelial- mesenchymal transition (EMT). Blood loss associated with epithelial injury induces platelet activation, production of growth factors, and an acute inflammatory response.
  • EMT epithelial- mesenchymal transition
  • the epithelial barrier heals and the inflammatory response resolves.
  • the fibroblast response continues, resulting in unresolved wound healing. Formation of fibroblastic foci is a feature of the disease, reflecting locations of ongoing fibrogenesis.
  • the general approach and objectives of senolytic therapy for restrictive conditions are based on elimination of senescent cells from the area of the lung tissue that is central to the fibrogenic process. For example, based on Unity data in human IPF lung tissue, this includes the distal lung epithelium which has been demonstrated to express the senescence marker pl6.
  • fibrotic diseases include but are not limited to, those exposed to environmental or occupational pollutants, such as asbestosis and silicosis, those who have a connective tissue diseases such as RA, SLE, scleroderma, sarcoidosis, those who take certain medications, including, for example, amiodarone, bleomycin, busufan, methotrexate, and nitrofurantoin; those subject to radiation therapy to the chest; and those whose family member have pulmonary fibrosis.
  • environmental or occupational pollutants such as asbestosis and silicosis
  • connective tissue diseases such as RA, SLE, scleroderma, sarcoidosis
  • those who take certain medications including, for example, amiodarone, bleomycin, busufan, methotrexate, and nitrofurantoin
  • those subject to radiation therapy to the chest and those whose family member have pulmonary fibrosis.
  • Physiologic obstruction of the lung result from diseases that cause air trapping in the lung and in turn a reduction in expiratory volume and increased total lung volume commonly a result of airway obstruction or destruction exemplified by diseases such as, for example, chronic obstructive pulmonary diseases (COPD) and asthma.
  • COPD chronic obstructive pulmonary diseases
  • COPD is a lung disease defined by persistently poor airflow resulting from the breakdown of lung tissue, emphysema, and the dysfunction of the small airways, obstructive bronchiolitis.
  • Primary symptoms of COPD include shortness of breath, wheezing, chest tightness, chronic cough, and excess sputum production.
  • Elastase from cigarette smoke-activated neutrophils and macrophages can disintegrate the extracellular matrix of alveolar structures, resulting in enlarged air spaces and loss of respiratory capacity.
  • COPD can be caused by, for example, tobacco smoke, cigarette smoke, cigar smoke, secondhand smoke, pipe smoke, occupational exposure, exposure to dust, smoke, fumes, and pollution, occurring over decades thereby implicating aging as a risk factor for developing COPD.
  • the processes that cause lung damage include, for example, oxidative stress produced by the high concentrations of free radicals in tobacco smoke, cytokine release due to the inflammatory response to irritants in the airway, and impairment of anti-protease enzymes by tobacco smoke and free radicals, allowing proteases to damage the lungs.
  • Genetic susceptibility can also contribute to the disease. In about 1% percent of people with COPD, the disease results from a genetic disorder that causes low level production of alpha- 1 -antitrypsin in the liver. Alpha- 1 -antitrypsin is normally secreted into the bloodstream to help protect the lungs.
  • Symptoms of COPD can include any one of shortness of breath, wheezing, chest tightness, having to clear one's throat first thing in the morning because of excess mucus in the lungs, a chronic cough that produces sputum that can be clear, white, yellow or greenish, cyanosis, frequent respiratory infections, lack of energy, and unintended weight loss.
  • Subjects with COPD can also experience exacerbations, during which symptoms worsen and persist for days or longer.
  • Symptoms of pulmonary fibrosis include, for example, shortness of breath, particularly during exercise; dry, hacking cough; fast, shallow breathing; gradual, unintended weight loss; fatigue; aching joints and muscles; and clubbing of the fingers or toes.
  • TYPE 3 Vascular
  • vascular inflammation characterized by vascular inflammation, increased vessel tone (vasoconstriction) and restricted blood flow ultimately leading to damage and physiologic dysfunction of the lung and heart. It also includes local deficiencies that arise in a given part of a body resulting from issues affecting blood flow but not the vessel itself, such as vasoconstriction, thrombosis, or embolism.
  • vascular pulmonary diseases include, but are not limited to, pulmonary hypertension and vasculitis such as Wegener's granulomatosis.
  • senolytic therapy for ischemic or vascular conditions are based on elimination of senescent cells from the vasculature and decrease the associated SASP factor impact on surrounding cells or area of the lung tissue that is central to the effects of vascular dysfunction.
  • the senolytic agent can be delivered either systemically or directly in the vasculature.
  • Pulmonary hypertension is a pathophysiological disorder that may involve multiple clinical conditions and can complicate many pulmonary and cardiovascular diseases. It is defined physiologically by the resulting hemodynamic change of a mean pulmonary artery pressure (mPAP) at rest greater than 25 mmHg.
  • mPAP mean pulmonary artery pressure
  • the clinical pathogenic categories of PH are described based on broad etiologies: pulmonary arteries (including pulmonary veno-occlusion and pulmonary capillary
  • the overall treatment goal in patients with PH is to maintain good exercise capacity, good quality of life, good Right Ventricular function and a low mortality risk. Specifically, this means bringing and/or keeping the patient in WHO-FC II whenever possible.
  • Genetic respiratory conditions are characterized as a disease that is caused by a mutation, deletion, or insertion in an individual's DNA sequence. Genetic disorders can be grouped into three main categories: (1) Single gene disorders: disorders caused by defects in one particular gene, often with simple and predictable inheritance patterns such as dominant, recessive and x-linked; (2) Chromosome disorders: disorders resulting from changes in the number or structure of the chromosomes; and (3) Multifactorial disorders (complex diseases): disorders caused by changes in multiple genes, often in a complex interaction with environmental and lifestyle factors such as diet or cigarette smoke. Examples of genetic pulmonary diseases include cystic fibrosis (CF) and alpha-1 antitrypsin deficiency (A1AT).
  • CF cystic fibrosis
  • A1AT alpha-1 antitrypsin deficiency
  • CF is a monogenic autosomal recessive disease that is caused by mutations in CFTR, located on chromosome 7.
  • the CFTR protein is an ion channel that regulates transport of chloride ions (C1-) in epithelial cells in the airways, as well as in the pancreas, liver, intestine and skin.
  • C1- chloride ions
  • the various CFTR mutations cause different CFTR protein defects, which impair transport of chloride and sodium across epithelial surfaces, leading to thick viscous secretions (e.g. mucus or phlegm).
  • CFTR modulators and potentiators are drugs that modify the function of CFTR to improve lung function and reduce symptoms and pulmonary exacerbations.
  • Genetic disorders of the pulmonary system can affect all anatomic layers and are associated with cellular defects that may lead to an accelerated aging phenotype, caused or mediated at least in part by senescent cells.
  • An inheritable susceptibility to certain lung diseases suggests that the accumulation of disease-mediating senescent cells may directly or indirectly be influenced by genetic components, which again may lead to earlier presentation.
  • Genetic disorders demonstrate a multifactorial cascade with senescent cells and SASP production contributing to ongoing cell dysfunction and degeneration/death.
  • senolytic therapy because senescent cells and their associated SASP factors mediate associated contributions to ongoing cell dysfunction, cell loss, and disease progression via blockage of the angiogenic, inflammatory, fibrotic, and extracellular matrix- modifying proteins present in the pathophysiology.
  • SASP factors mediate associated contributions to ongoing cell dysfunction, cell loss, and disease progression via blockage of the angiogenic, inflammatory, fibrotic, and extracellular matrix- modifying proteins present in the pathophysiology.
  • TYPE 5 Infectious Pulmonary Diseases
  • diseases caused by pathogenic microorganisms such as bacteria, viruses, parasites or fungi; the diseases can be spread, directly or indirectly, from one person to another.
  • Infectious pulmonary diseases can be caused by numerous infectious agents, including but not limited to
  • Streptococcus Myocobacteria, Pneumocystis, Blastomyces, Paragonimus and human immunodeficiency virus (HIV).
  • HIV human immunodeficiency virus
  • Infectious agents may contribute to the induction of senescence and a multifactorial cascade with senescent cells and SASP production contributing to ongoing cell dysfunction. Once present, senescent cells may in turn impact the ability to fight infection.
  • Senescent cells have an impaired ability to control viral replication (Kim et al., Enhanced Viral Replication by Cellular Replicative Senescence., Immune Network., 2016 Oct;16(5):286-295), which is in line with the known increased susceptibility to infection that occurs with age. Senescence and the ability to respond to infectious agents are a category of lung disease that can be significantly impacted by senolytic therapy. Elimination of senescent cells and their associated SASP factors can ameliorate damage to the cellular microenvironment.
  • the pharmaceutical senolytic compositions of the invention are formulated for administration by inhalation.
  • Suitable pharmaceutical compositions for administration by inhalation will typically be in the form of an aerosol or a powder.
  • Compounds of the invention may be directly administered as an aerosol to a site of pulmonary pathology as described above.
  • the aerosol may also be delivered to the pulmonary compartment for absorption into the pulmonary vasculature for therapy or prophylaxis of extra-pulmonary pathologies such as fibrosis for example, or pulmonary or intra-nasal delivery for extra-pulmonary or extra-nasal cavity diseases.
  • the pharmaceutical compositions of the invention will typically comprise the active ingredient and a suitable propellant, such as, for example, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • the pharmaceutical composition may be in the form of a capsule or cartridge (made, for example, from gelatin) comprising a compound of the invention and a powder suitable for use in a powder inhaler.
  • Suitable powder bases include, by way of example, lactose or starch.
  • compositions of the invention may be administered using well-known delivery devices, such as a metered-dose inhaler, a dry powder inhaler, a nebulizer, a vaporizer, or a similar delivery device.
  • delivery devices such as a metered-dose inhaler, a dry powder inhaler, a nebulizer, a vaporizer, or a similar delivery device.
  • MDI Meter Dose Inhaler
  • a propellant driven inhaler releases a metered dose of medicine upon each actuation.
  • the medicine is formulated as a suspension or solution of a drug substance in a suitable propellant such as a halogenated hydrocarbon.
  • pMDIs are described in, for example, Newman, S. P., Aerosols and the Lung, Clarke et al., eds., pp. 197-224 (Butterworths, London, England, 1984).
  • DPI Dry Powder Inhaler
  • nebulizers suitable to provide delivery of a medicament as described herein may be used in the various embodiments and methods described herein.
  • nebulizers include, e.g., jet nebulizers, ultrasonic nebulizers, pulsating membrane nebulizers, nebulizers with a vibrating mesh or plate with multiple apertures, and nebulizers comprising a vibration generator and an aqueous chamber (e.g., Pari eFlow®).
  • any known vaporizer suitable to provide delivery of a medicament as described herein may be used in the various embodiments and methods described herein.
  • a vaporizer may be used to vaporize a pharmaceutical composition as described herein, such that the vaporized components of the pharmaceutical composition can be inhaled by a user.
  • the vaporizer applies sufficient heat to the pharmaceutical composition to vaporize one or more components of the pharmaceutical composition, such as the active agent or drug substance.
  • the pharmaceutical composition for use in a vaporizer may be provided in solid form or liquid form prior to vaporization.
  • a pulmonary preparation can be prepared by mixing a senolytic agent with a
  • Ingredients acceptable in a pulmonary formulation are excipients or carriers that cause little to no pulmonary irritation, provide suitable preservation if needed, and deliver one or more agents in a suitable volume.
  • a base or carrier include water; an aqueous solvent such as a polar solvent; a polyalcohol; a vegetable oil; and an oily base.
  • the base or carrier for an intrapulmonary injection include water for injection and physiological saline.
  • a senolytic agent may be combined with acceptable excipients for use in and around the lung, such as a surfactant, preservatives, co-solvents, a flavor or cooling agent, an antiseptic, a bactericide or antibacterial agent, a pH adjusting agent, a tonicity agent, a chelating agent, a buffering agent, a stabilizer, an antioxidant, viscosity enhancers, penetration enhancers, sodium chloride and a thickening agent.
  • acceptable excipients for use in and around the lung, such as a surfactant, preservatives, co-solvents, a flavor or cooling agent, an antiseptic, a bactericide or antibacterial agent, a pH adjusting agent, a tonicity agent, a chelating agent, a buffering agent, a stabilizer, an antioxidant, viscosity enhancers, penetration enhancers, sodium chloride and a thickening agent.
  • a composition for intrapulmonary injection may contain one or more of a solubilizing agent, a suspending agent, a tonicity agent, a buffering agent, a soothing agent, a stabilizer, and an antiseptic.
  • the pulmonary composition carrier and excipients can be combined to form an aqueous, sterile pulmonary suspension, solution, or viscous or semi-viscous gels or other types of solid or semisolid composition such as an ointment.
  • excipients and additives that can be used include surfactants (for example, polyoxyethylene and block copolymers); buffers and pH adjusting agents (for example, hydrochloric acid, sodium hydroxide, phosphate, citrate, and sodium cyanide); tonicity agents (for example, sodium bisulfite, sodium sulfite, glycerin, and propylene glycol); chelating agents (for example, ascorbic acid, sodium edetate, and citric acid); flavors; coloring agents; antiseptics; bactericides; antibacterial agents; and the like.
  • surfactants for example, polyoxyethylene and block copolymers
  • buffers and pH adjusting agents for example, hydrochloric acid, sodium hydroxide, phosphate, citrate, and sodium cyanide
  • tonicity agents for example, sodium bisulfite, sodium sulfite, glycerin, and propylene glycol
  • chelating agents for example, ascorbic acid, sodium edetate, and citric
  • Pulmonary solution formulations may be prepared by dissolving the agent in a
  • the pulmonary solution may include an acceptable surfactant to assist in dissolving the agent.
  • Viscosity building compounds such as hydroxymethyl cellulose, hydroxy ethyl cellulose, methylcellulose, polyvinylpyrrolidone may be added to improve the retention of the compound.
  • Sterile pulmonary gel formulations may be prepared by suspending the agent in a hydrophilic base prepared from the combination of, for example, CARBOPOL®-940. VISCOAT® (Alcon Laboratories, Inc., Fort Worth, Tex.) may be used for intrapulmonary injection.
  • Other compositions of the present invention may contain penetration enhancing materials such as
  • CREMOPHOR® Sigma Aldrich, St. Louis, Mo.
  • TWEEN® 80 polyoxyethylene sorbitan monolaureate, Sigma Aldrich
  • kits that enclose one or more unit doses of one or more of the agents or compositions described in this disclosure.
  • Such kits typically comprise a pharmaceutical preparation in one or more containers.
  • the preparatoins may be provided as one or more unit doses (either combined or separate).
  • the kit may contain a device such as a syringe for administration of the agent or composition in or around the lung of a subject in need thereof.
  • the product may also contain or be accompanied by an informational package insert describing the use and attendant benefits of the drugs in treating the senescent cell associated lung disease, and optionally an appliance or device for delivery of the composition.
  • a unit dose refers to a physically discrete unit suitable as a single dosage for a subject in need thereof, where each unit dose contains a predetermined quantity of a compound of the invention in an amount sufficient to produce the desired therapeutic effect.
  • the compound may be provided in the usit dose in association with a pharmaceutically acceptable diluent, carrier and/or vehicle.
  • the amount of the compound in each unit dose may depend on the particular compound employed and the effect to be achieved, and the pharmacodynamics associated with the compound in the user.
  • Senolytic agents for treating pulmonary diseases and conditions can be combined with other pharmaceutical agents that are approved for clinical use. Since the removal of senescent cells works by a different mechanism from current therapies, the two agents can operate synergistically or additively to minimize the administration schedule and improve outcomes. The senolytic agent will remove senolytic cells in the lung that are promoting persistence and progression of disease -related pathophysiology.
  • the methods of this invention for treating or reducing the likelihood of a pulmonary disease or condition can also be used for treating a subject who is aging and has loss of pulmonary function, or degeneration of pulmonary tissue.
  • the respiratory system can undergo various anatomical, physiological and immunological changes with age.
  • the structural changes include chest wall and thoracic spine deformities that can impair the total respiratory system compliance resulting in increased effort to breathe.
  • the respiratory system undergoes structural, physiological, and immunological changes with age. An increased proportion of neutrophils and lower percentage of macrophages can be found in
  • bronchoalveolar lavage BAL
  • Persistent low grade inflammation in the lower respiratory tract can cause proteolytic and oxidant-mediated injury to the lung matrix resulting in loss of alveolar unit and impaired gas exchange across the alveolar membrane seen with aging.
  • Sustained inflammation of the lower respiratory tract can predispose older adults to increased susceptibility to toxic environmental exposure and accelerated lung function decline.
  • Oxidative stress exacerbates inflammation during aging. Alterations in redox balance and increased oxidative stress during aging precipitate the expression of cytokines, chemokines, and adhesion molecules, and enzymes.
  • Constitutive activation and recruitment of macrophages, T cells, and mast cells foster release of proteases leading to extracellular matrix degradation, cell death, remodeling, and other events that can cause tissue and organ damage during chronic inflammation.
  • the effects of the treatment can be determined using techniques that evaluate mechanical functioning of the lung, for example, techniques that measure lung capacitance, elastance, and airway hypersensitivity can be performed.
  • any one of numerous measurements can be obtained, for example, expiratory reserve volume (ERV), forced vital capacity (FVC), forced expiratory volume (FEV) (e.g., FEV in one second, FEV1), FEV1/FEV ratio, forced expiratory flow 25% to 75%, and maximum voluntary ventilation (MVV), peak expiratory flow (PEF), slow vital capacity (SVC).
  • Total lung volumes include total lung capacity (TLC), vital capacity (VC), residual volume (RV), and functional residual capacity (FRC).
  • Sp02 Peripheral capillary oxygen saturation
  • normal oxygen levels are typically between 95% and 100%.
  • An Sp02 level below 90% suggests the subject has hypoxemia. Values below 80% are considered critical and require intervention to maintain brain and cardiac function and avoid cardiac or respiratory arrest.
  • Senescent cells accumulate with age, which is why conditions mediated by senescent cells occur more frequently in older adults.
  • different types of stress on pulmonary tissues may promote the emergence of senescent cells and the phenotype they express.
  • Cell stressors include oxidative stress, metabolic stress, DNA damage (for example, as a result of environmental ultraviolet light exposure or genetic disorder), oncogene activation, and telomere shortening (resulting, for example, from hyperproliferation).
  • Pulmonary tissues that are subject to such stressors may have a higher prevalence of senescent cells, which in turn may lead to presentation of certain lung diseases at an earlier age, or in a more severe form.
  • An inheritable susceptibility to certain lung diseases suggests that the accumulation of disease-mediating senescent cells may directly or indirectly be influenced by genetic components, which can lead to earlier presentation.
  • the therapeutic regimen will depend on the location of the senescent cells, and the pathophysiology of the disease.
  • one or more doses of a compound or pharmaceutical composition of the invention are administered to a subject in need thereof.
  • the frequency of administration of the compound or pharmaceutical composition can vary depending on any of a variety of factors, e.g., severity of the symptoms, condition of the subject, etc.
  • the compound or pharmaceutical composition is administered once per month, twice per month, three times per month, every other week (qow), once per week (qw), twice per week (biw), three times per week (tiw), four times per week, five times per week, six times per week, every other day (qod), daily (qd), twice a day (qid), or three times a day (tid), or the like.
  • Compounds that may be useful for clearing senescent cells in or around the lung for purposes of treating pulmonary diseases according to this invention include Bcl-2 inhibitors, Bcl-xL inhibitors, MDM2 inhibitors, and Akt inhibitors. See U.S. Patent Nos. 8,691,184, 9,096,625, and 9,403,856; published applications WO 2015/017159, WO 2015/116740, WO 2016/127135, WO
  • X 1 is -CI
  • X 2 is -COOH or -S0 2 CH 3 ;
  • X 3 is -S0 2 CF 3 , -S0 2 CH 3 , or -N0 2 ;
  • X s is -F or -H
  • R 1 is -CH(CH 3 ) 2 ;
  • R 2 is -CH 3 ; R 3 and R 4 are both -H;
  • n 2;
  • R 6 is selected from -OH, -OR 7 ,
  • R 7 is -PO(OH) 2
  • Clause 7 The compound of any of Clauses 1 to 6, wherein X s is -F.
  • Clause 8 The compound of any of Clauses 1 to 6, wherein X s is -H.
  • Clause 9 The compound of any of Clauses 1 to 8, wherein X 6 is -OH.
  • Clause 10 The compound of any of Clauses 1 to 8, wherein X 6 is -OR 7 .
  • Clause 14 The compound of any of Clauses 1 to 13, wherein the carboxyl group in X 2 is phosphorylated.
  • Clause 15 The compound of Clause 1, wherein the compound is selected from the group consisting of:
  • Clause 16 The compound of any preceding Clause, which has pro-apoptotic activity.
  • Clause 17 The compound of any preceding Clause, which specifically kills senescent cells compared with non-senescent cells, said senescent cells being defined as non-cancerous cells that express pl6.
  • Clause 18 The compound of any preceding Clause, which specifically kills cancer cells compared with non-cancer cells of the same tissue type.
  • Clause 19 The compound of any preceding Clause, which has an IC 50 for Bcl-xL of 1 nM or less.
  • Clause 20 The compound of any preceding Clause, which has an IC 50 for Bcl-2 of 10 nM or less.
  • Clause 21 The compound of any preceding Clause, which has an IC 50 for Bcl-xL of 1 nM or less and an IC 50 for Bcl-2 of 10 nM or less.
  • Clause 22 A pharmaceutical composition comprising a compound according to any preceding Clause in a pharmaceutically compatible excipient.
  • Clause 23 A method of selectively removing senescent cells and/or cancer cells from a mixed cell population or tissue, comprising contacting a cell, a cell population or a tissue with a compound according to any of Clauses 1 to 21 or a pharmaceutical composition according to Clause 22.
  • Clause 24 A method of treating a senescence related condition in a tissue in a subject, wherein the senescence related condition is characterized as being caused or mediated at least in part by senescent cells, or is characterized as having an overabundance of senescent cells in or around the tissue, in comparison with unaffected tissue, the method comprising:
  • a unit dose of a pharmaceutical composition comprising:
  • the pharmaceutical composition contains a formulation of the compound configured for administration to a target tissue in a subject that manifests the senescence associated condition
  • the formulation and the amount of the compound in the unit dose configure the unit dose to be effective in selectively removing senescent cells in or around the tissue in the subject, thereby decreasing the severity of one or more signs or symptoms of the condition without causing adverse effects in the subject when administered to the tissue as a single dose.
  • Clause 26 The unit dose of Clause 25, packaged with an informational insert describing the use and attendant benefits of the drugs in treating the senescent cell associated condition.
  • Clause 27 A compound according to any of Clauses 1 to 21 or a pharmaceutical composition according to claim 24 for use in selectively eliminating senescent cells from a tissue or mixed cell population or for use in treating a senescence-related condition.
  • Clause 28 Use of a compound according to any of Clauses 1 to 21 in the manufacture of a medicament for treating a senescence-related condition.
  • Clause 29 The method, unit dose, or use of any of Clauses 24 to 28, wherein the condition is osteoarthritis.
  • Clause 30 The method, unit dose, or use of any of Clauses 24 to 28, wherein the condition is an ophthalmic condition.
  • Clause 31 The method, unit dose, or use of any of Clauses 24 to 28, wherein the condition is a pulmonary disease.
  • Clause 32 A method of treating cancer, comprising administering to a tissue of a subject in need thereof an amount of a compound according to any of Clauses 1 to 21 or a pharmaceutical composition according to Clause 22 effective to selectively remove cancer cells from the tissue.
  • Clause 33 A compound according to any of Clauses 1 to 21 or a pharmaceutical composition according to claim 22 for use in selectively eliminating cancer cells from a tissue or mixed cell population or for use in treating cancer.
  • Clause 34 A method of treating a pulmonary disease in a subject, comprising administering to the subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising:
  • X 1 is -CI
  • X 2 is -COOH or -S0 2 CH 3 ;
  • X 3 is -SO 2 CF 3 ; -SO 2 CH 3 ; or -N0 2 ;
  • X s is -F or -H
  • R 1 is -CH(CH 3 ) 2 ;
  • R 2 is -CH 3 ;
  • R 3 and R 4 are both -H
  • n 2;
  • R 6 is selected from -OR 7 , , and I
  • R 7 is -H or -PO(OH) 2 ,
  • Clause 35 The method of Clause 34, wherein X 2 is -COOH.
  • Clause 36 The method of Clause 34, wherein X 2 is -S0 2 CH 3 .
  • Clause 37 The method of Clause 34, wherein X 3 is -S0 2 CF 3 .
  • Clause 38 The method of Clause 34, wherein X 3 is -S0 2 CH 3 .
  • Clause 39 The method of Clause 34, wherein X 3 is -N0 2 .
  • Clause 40 The method of any of Clauses 34 to 39, wherein X s is -F.
  • Clause 41 The method of any of Clauses 34 to 39, wherein X s is -H.
  • Clause 42 The method of any of Clauses 34 to 39, wherein R 6 is -OR 7
  • Clause 44 The method of any of Clauses 34 to 39,
  • Clause 45 The method of any of Clauses 34 to 44, wherein R 7 is -H.
  • Clause 46 The method of any of Clauses 34 to 44, wherein R 7 is -PO(OH) 2 .
  • Clause 47 The method of any of Clauses 34 to 46, wherein the carboxyl group in X 2 is phosphorylated.
  • Clause 48 The method of Clause 34, wherein the compound is selected from the group consisting of:
  • Clause 49 The method of Clause 34, wherein the pulmonary disease is idiopathic pulmonary fibrosis (IPF).
  • IPF idiopathic pulmonary fibrosis
  • Clause 50 The method of Clause 34, wherein the pulmonary disease is chronic obstructive pulmonary disease (COPD).
  • COPD chronic obstructive pulmonary disease
  • Clause 51 The method of Clause 48, wherein the pulmonary disease is idiopathic pulmonary fibrosis (IPF).
  • IPF idiopathic pulmonary fibrosis
  • Clause 52 The method of Clause 48, wherein the pulmonary disease is chronic obstructive pulmonary disease (COPD).
  • COPD chronic obstructive pulmonary disease
  • Clause 53 The method of Clause 34, wherein the administration of the pharmaceutical composition is by inhalation as an aerosol.
  • Clause 54 The method of Clause 48, wherein the administration of the pharmaceutical composition is by inhalation as an aerosol.
  • Clause 55 The method of Clause 34, wherein the pulmonary disease is a restrictive pulmonary disease.
  • Clause 56 The method of Clause 55, wherein the restrictive pulmonary disease is idiopathic pulmonary fibrosis (IPF) or systemic sclerosis (SSc).
  • IPF idiopathic pulmonary fibrosis
  • SSc systemic sclerosis
  • Clause 57 The method of Clause 34, wherein the pulmonary disease is an obstructive pulmonary disease.
  • Clause 58 The method of Clause 57, wherein the obstructive pulmonary disease is chronic obstructive pulmonary diseases (COPD) or asthma.
  • COPD chronic obstructive pulmonary diseases
  • Clause 59 The method of Clause 34, wherein the pulmonary disease is a vascular pulmonary disease.
  • Clause 60 The method of Clause 59, wherein the vascular pulmonary disease is pulmonary hypertension or vasculitis.
  • Clause 61 The method of Clause 34, wherein the pulmonary disease is a genetic pulmonary disease.
  • Clause 62 The method of Clause 61, wherein the genetic pulmonary disease is cystic fibrosis (CF) or alpha- 1 antitrypsin deficiency (A1AT).
  • CF cystic fibrosis
  • A1AT alpha- 1 antitrypsin deficiency
  • Clause 63 The method of Clause 34, wherein the pulmonary disease is an infectious pulmonary disease.
  • Clause 64 The method of Clause 63, wherein the infectious pulmonary disease is pneumonia or tuberculosis.
  • Clause 65 A method of treating a pulmonary disease in a subject, comprising administering to the subject in need thereof a therapeutically effective amount of a compound of Formula (III) or a phosphorylated for
  • R 1 and R 2 are independently Q to C 4 alkyl
  • R 3 , R 4 and R 5 are independently -H or -CH 3 ;
  • R 8 is -OH or -N(R 6 )(R 7 ), wherein R 6 and R 7 are independently alkyl or heteroalkyl, and are optionally cyclized;
  • X 1 is -F, -CI, -Br, or -OCH 3 ;
  • X 2 is -S0 2 R' or -C0 2 R', where R' is -H, -CH 3 , or -CH 2 CH 3 ; X 3 is -SO 2 CF 3 ; -SO 2 CH 3 ; or -N0 2 ; and
  • X s is -F, -Br, -CI, -H, or -OCH 3 .
  • R 1 and R 2 are independently d to C 4 alkyl
  • R 3 and R 4 are independently -H or -CH 3 ;
  • X 1 is -F, -CI, -Br, or -OCH 3 ;
  • X 2 is -S0 2 R' or -C0 2 R ⁇ where R' is -H, -CH 3 , or -CH 2 CH 3 ;
  • X 3 is -S0 2 CF 3 , -S0 2 CH 3 , or -N0 2 ;
  • X 4 is -OH, -COOH or -CH 2 OH
  • X s is -F, -CI, or -H
  • n 1, 2, or 3.
  • X 3 is -S0 2 CF 3 or -N0 2 ;
  • R 8 is -N(R 6 )(R 7 ), wher em R 6 and R 7 are independently alkyl or heteroalkyl, and are optionally cyclized.
  • X 3 is -S0 2 CF 3 or -N0 2 ;
  • R 8 is , wherein X 4 is -OH or -COOH.
  • Senescent cells associated with areas of active disease in lung tissue was tested in human idiopathic pulmonary fibrosis (IPF) tissues and human scleroderma tissues taken from afflicted human patients.
  • Human IPF tissues were procured from the University of Michigan, courtesy of Dr. Eric White.
  • Human scleroderma tissues were procured from the Medical University of South Carolina, courtesy of Dr. Carol Browstick.
  • the samples included both upper and lower lung lobe sections from 9 normal, 12 human IPF patients and 7 human scleroderma patients.
  • DAB tetrahydrochloride hydrate
  • FIGS. 2A and 2B Immunohistochemistry staining for pi 6 in human IPF lung tissue demonstrated the presence of senescent cells, see FIGS. 2A and 2B. These cells were predominantly epithelial in origin and located in areas of fibrosis and at the leading edge of the disease, which indicated accessibility by inhalation therapeutics.
  • SAEC Primary human small airway epithelial cells
  • BEC bronchial epithelial cells
  • SAEC Primary human small airway epithelial cells
  • BEC bronchial epithelial cells
  • Cells were maintained and propagated at ⁇ 75 confluency in Airway Epithelial Cell Growth Medium or Small Airway Epithelial Cell Growth Medium (Promocell®; Heidelberg, Germany) at 20% 0 2 , 5% C0 2 , and -95% humidity.
  • To make primary cells senescent x-ray irradiation was employed.
  • SAEC/BEC cells were covered with TrypLE trypsin-containing reagent (Thermofisher Scientific, Waltham,
  • an exemplary test compound of the invention Compound 1 was combined with the cells as follows.
  • a DMSO dilution series of the test compound was prepared at 1000 times the final desired concentration in a 384-well plate.
  • the DMSO stocks were diluted 1 : 1000 into prewarmed complete medium.
  • Medium was aspirated from the cells in each well, and 25 ⁇ of the compound containing medium was added.
  • Compound 1 was cultured with the cells for 3 days.
  • the assay system used the properties of a thermostable luciferase to enable reaction conditions that generated a stable luminescent signal while simultaneously inhibiting endogenous ATPase released during cell lysis.
  • the luminescence readings were normalized to determine % cell survival/growth and plotted against test compound concentrations, and potencies (EC50 values) for Compound 1 were determined by non-linear curve fitting in Graphpad Prism®.
  • FIG. 6 shows the results.
  • the concentration-response curve demonstrated sensitivity of senescent lung epithelial cell (SnC) survival to incubation with different amounts of Compound 1 , whereas non-senescent cells (NsC) have very limited potency.
  • SnC senescent lung epithelial cell
  • NsC non-senescent cells
  • PCLS Precision-cut lung slices
  • Human PCLS will be prepared as follows. Lungs from normal, healthy individuals or IPF patients will be gently inflated with warm 1.5% agarose -D MEM mix. Afterwards, lung explants will be macroscopically assessed by an experienced pulmopathologist to identify regions of interest and exclude previously unknown medical conditions (e.g. neoplasias or infections). Next, sections (0 4-8 mm) will be sliced in cold EBSS using a Krumdieck Tissue Sheer (Alabama Research and Development 31 , Munford, AL, USA) into approx.
  • PCLS will be washed thoroughly before cultivation in DMEM (2 slice per 500 ⁇ ) under normal immersion culture conditions (37 °C, 5% C02, and >95% air humidity) for up to 15 days. PCLS will be treated for 1 h with 1% Triton X-100 to serve as a dead, negative control reference.
  • senescence marker pi 6 expression is upregulated in idiopathic pulmonary fibrosis (IPF), therefore any significant reduction of pi 6 expression as measured by qPCR or abundance of pi 6 as measured by IHC in IPF PCLS following administration of compounds of the invention will indicate effective senolysis.
  • Determination of the beneficial effects of compounds of the invention on reducing the senescence burden in PCLS obtained from IPF patients will be performed as follows. In each experiment three dose levels (10 ⁇ , 1 ⁇ and 0.1 ⁇ ) of a DMSO formulation of compounds of the invention will be tested, in addition to a vehicle control sample.
  • PCLSs will be exposed to such compounds for three days, followed by a media wash-out and a three-day recovery period. Upon harvest, PCLSs will be collected for staining and analysis of pl6/senescence and fibrosis, or flash frozen for RNA-seq/qPCR detection of relevant markers of senescence, fibrosis and epithelial regeneration. Supernatants will be harvested for studying changes in SASP factors through a Luminex® or MSD® analysis.
  • markers of fibrosis Upon observing senolysis through pl6 reduction, markers of fibrosis will be evaluated using established methodologies, including collagen level determination (picrosirius red staining) and gene expression changes of fibrosis markers, such as FN1, SERPINE1, COL1A1, CTGF, MMP7, and ACTA2, via qPCR.
  • Example 4 Effect of senolytic agents in an in vivo pharmacodynamic model
  • mice Male C57BL/6 mice (The Jackson Laboratory) were administered 2.2 U/kg of bleomycin or its vehicle (PBS) by oral aspiration (50 mL). On day 11, each mouse received either vehicle (2.5% glycerin in PBS) or increasing concentrations of Compound 1 via oral aspiration (50 mL). On day 14, mice were euthanized, exsanguinated, and perfused PBS, 1 mL of dispase, and 0.2 mL of a 1% low melt agarose. Individual lobes of the lungs were collected for either single cell isolation, cell enrichment, and qPCR or for fixing, staining, and IHC analysis.
  • Left lung lobes were collected for epithelial cell enrichment as follows. Lung lobes were placed in 2 mL of dispase on a rocker for 45 minutes. To obtain isolated cells, a serological pipet was then used to dissociate the lung tissue prior to adding 10 mL of sort buffer containing 50U/ml of DNase. Next, samples were incubated on a rocker for 10 minutes at 37°C and then passed through both 100 mm and 70 mm cell strainers. The collected suspension was then spun at 550 g for 5 minutes at 4°C to pellet the cells. The supernatant was then removed, and 1 mL cold RBC lysis buffer was added at room temperature for 20 seconds.
  • the supernatant was removed, cells were resuspended in 500 uL MACS buffer and added to a MACS separator cell column. The column was washed 4 times with 500 uL MACS buffer and the effluent (CD45-) collected. Cells were then counted with a cell counter. The sample was then spun at 350 g for 5 minutes at 4°C. The supernatant was removed, and the cells resuspended in MACS buffer containing 10% CD326+ microbeads at a volume of 100 uL per 1 x 10 7 cells. Cells were mixed and incubated for 15 minutes at 4°C. Next, 2 mL of MACS buffer was added and then the cells spun at 350 g for 5 minutes at 4°C.
  • Quantification of pl6 mRNA by qPCR was performed as follows. Desired frozen cells (CD45-, EpCAM+) were thawed, 20% chloroform added, and sample vortexed until milky in appearance. Cells were then spun at 15,000 g for 15 minutes. The supernatant was removed, collected into a new tube, diluted with equal volume 100% ethanol, and added to the Zymo column (Zymo Research Direct- zol RNA MicroPrep kit; Cat# R2063). Column was spun at 15,000 g for 1 minute. Next, 400 uL wash buffer was added to each sample and respun at 15,000 g for 1 minute.
  • Taqman® gene-specific primers for pl6TM K !l All signals were normalized to ⁇ -actin. Relative gene expression was calculated by the AACt method where the ACt was calculated using the ⁇ -actin reference gene. AACt was calculated relative to the PBS/Vehicle control group.
  • FIG. 7 shows the results.
  • the concentration-response curve for Compound 1 demonstrates sensitivity of mouse lung epithelial cell pi 6 mRNA induced by bleomycin to a senolytic molecule following local (OA) administration. These data show that senolytic agents are capable of selectively eliminating senescent lung airway epithelial cells in vivo.
  • Slides were then incubated with SEA BLOCK® blocking buffer (Thermo Fisher Scientific Cat #37527) for 30 minutes at room temperature and washed with TBST 3 times. Slides were then incubated in mouse IgG block for 20 minutes and then incubated in primary pl6 antibody (BD Biosciences Cat # 550834) at a 1:50 dilution in TBST for 1 hour. Next, slides were washed with TBST 3 times and incubated with goat anti-mouse poly-HRP secondary antibody (Thermo Fisher Scientific Cat # B40961) for 30 minutes at room temperature. Next, slides were washed with TBST 3 times and a DAB substrate solution was added and incubated for 10 min at room temperature.
  • SEA BLOCK® blocking buffer Thermo Fisher Scientific Cat #37527
  • slides were washed with dH 2 0 3 times and then placed in hematoxylin for 1 minute. Slides were then washed thoroughly in dH 2 0 for several exchanges, placed in a bluing reagent for 30 seconds, and then rinsed in tap water for 5 minutes. Finally, slides were mounted using water-based mounting medium and left to dry overnight. Quantification was performed with the number of pi 6+ foci determined in reference to the total number of cells.
  • FIG. 8 demonstrates sensitivity of mouse lung epithelial cell pl6+ cells, induced to senesce by bleomycin, to Compound 1 following local (OA) administration.

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Abstract

La présente invention est basée sur la découverte selon laquelle de nombreuses maladies pulmonaires associées au vieillissement sont à médiation au moins en partie par des cellules portant un phénotype sénescent. Des cellules sénescentes s'accumulent avec l'âge et expriment des facteurs qui contribuent à la pathophysiologie d'affections liées à l'âge. La gravité des affections liées à l'âge est typiquement en corrélation avec l'abondance de cellules sénescentes : ainsi, l'élimination de cellules sénescentes peut aider à éliminer l'affection, soulager des symptômes, et potentiellement inhiber la progression de la maladie. Selon la présente invention, une famille d'inhibiteurs des protéines Bcl a été développée pour le traitement de maladies pulmonaires. Ces agents senolytiques ont un profil de dose et de spécificité approprié pour être efficaces dans la gestion clinique de maladies pulmonaires antérieurement réfractaires.
PCT/US2018/046567 2017-08-11 2018-08-13 Traitement de maladies pulmonaires à l'aide d'agents pharmaceutiques qui éliminent des cellules sénescentes WO2019033122A1 (fr)

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WO2019241567A1 (fr) * 2018-06-13 2019-12-19 Unity Biotechnology Acylsulfonamides à titre d'antagonistes de la famille bcl destinés à être utilisés dans la gestion clinique d'états pathologiques provoqués ou induits par des cellules sénescentes ainsi que dans le traitement du cancer
US10703745B2 (en) 2018-04-30 2020-07-07 Unity Biotechnology, Inc. Acyl phosphonamidates and acyl benzylamines that are Bcl family antagonists for use in clinical management of conditions caused or mediated by senescent cells and for treating cancer
US10717722B2 (en) * 2018-06-13 2020-07-21 Unity Biotechnology, Inc. Acyl sulfonamides that are Bcl family antagonists for use in clinical management of conditions caused or mediated by senescent cells and for treating cancer
US10738042B2 (en) 2018-04-30 2020-08-11 Unity Biotechnology, Inc. Phosphonamidates that are Bcl family antagonists for use in clinical management of conditions caused or mediated by senescent cells and for treating cancer
US10745429B2 (en) 2018-04-30 2020-08-18 Unity Biotechnology, Inc. Phospholidines that are Bcl family antagonists for use in clinical management of conditions caused or mediated by senescent cells and for treating cancer
CN114053288A (zh) * 2020-07-31 2022-02-18 苏州亚盛药业有限公司 肺部疾病治疗的组合物和方法
WO2022099431A1 (fr) * 2020-11-10 2022-05-19 Unity Biotechnology, Inc. Inhibiteur de sel de méglumine solide cristallin de bcl et leurs procédés de production et d'utilisation
WO2024051741A1 (fr) * 2022-09-06 2024-03-14 西藏海思科制药有限公司 Composé pour inhiber bcl-2 ou bcl-xl et son utilisation en médecine

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Cited By (9)

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Publication number Priority date Publication date Assignee Title
US10703745B2 (en) 2018-04-30 2020-07-07 Unity Biotechnology, Inc. Acyl phosphonamidates and acyl benzylamines that are Bcl family antagonists for use in clinical management of conditions caused or mediated by senescent cells and for treating cancer
US10738042B2 (en) 2018-04-30 2020-08-11 Unity Biotechnology, Inc. Phosphonamidates that are Bcl family antagonists for use in clinical management of conditions caused or mediated by senescent cells and for treating cancer
US10745429B2 (en) 2018-04-30 2020-08-18 Unity Biotechnology, Inc. Phospholidines that are Bcl family antagonists for use in clinical management of conditions caused or mediated by senescent cells and for treating cancer
WO2019241567A1 (fr) * 2018-06-13 2019-12-19 Unity Biotechnology Acylsulfonamides à titre d'antagonistes de la famille bcl destinés à être utilisés dans la gestion clinique d'états pathologiques provoqués ou induits par des cellules sénescentes ainsi que dans le traitement du cancer
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US10981892B2 (en) 2018-06-13 2021-04-20 Unity Biotechnology, Inc. Acyl sulfonamides that are Bcl family antagonists for use in clinical management of conditions caused or mediated by senescent cells and for treating cancer
CN114053288A (zh) * 2020-07-31 2022-02-18 苏州亚盛药业有限公司 肺部疾病治疗的组合物和方法
WO2022099431A1 (fr) * 2020-11-10 2022-05-19 Unity Biotechnology, Inc. Inhibiteur de sel de méglumine solide cristallin de bcl et leurs procédés de production et d'utilisation
WO2024051741A1 (fr) * 2022-09-06 2024-03-14 西藏海思科制药有限公司 Composé pour inhiber bcl-2 ou bcl-xl et son utilisation en médecine

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