WO2019241141A1 - Procédé de traitement d'une lésion de reperfusion myocardique à l'aide d'un inhibiteur de la phosphodiestérase de nucléotide cyclique pde1 - Google Patents

Procédé de traitement d'une lésion de reperfusion myocardique à l'aide d'un inhibiteur de la phosphodiestérase de nucléotide cyclique pde1 Download PDF

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WO2019241141A1
WO2019241141A1 PCT/US2019/036360 US2019036360W WO2019241141A1 WO 2019241141 A1 WO2019241141 A1 WO 2019241141A1 US 2019036360 W US2019036360 W US 2019036360W WO 2019241141 A1 WO2019241141 A1 WO 2019241141A1
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pyrazin
imidazo
methyl
pyran
fluorobenzyl
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PCT/US2019/036360
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English (en)
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Matthew Movsesian
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The United States Government As Represented By The Department Of Veterans Affairs
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    • 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
    • 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
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/74—Quinazolines; Hydrogenated quinazolines with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached to ring carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the invention provides methods of inhibiting myocardial injury in a subject which comprise administering a PDE1 or PDE1C inhibitor (such as a selective inhibitor) to the subject in an effective amount so as to inhibit a myocardial injury in the subject.
  • a PDE1 or PDE1C inhibitor such as a selective inhibitor
  • the PDE1 or PDE1C inhibitor may be administered before, at the time of or after myocardial injury including compositions containing PDE1 or PDE1C inhibitors and kits comprising the compositions of the invention.
  • a cyclic nucleotide phosphodiesterase PDE1 or PDE1C inhibitor comprising administering a cyclic nucleotide phosphodiesterase PDE1 or PDE1C inhibitor to the subject in an effective amount so as to inhibit cardiac muscle injury in the subject.
  • Also disclosed are methods of treating or preventing myocardial ischemia/reperfusion injury in a subject comprising administering a cyclic nucleotide phosphodiesterase PDE1 or PDE1C inhibitor to the subject in an effective amount so as to inhibit cardiac muscle injury in the subject.
  • Also disclosed are methods of reducing myocardial ischemia/reperfusion injury in a subject with an acute coronary syndrome comprising administering an effective amount of a PDE1 or PDE1C inhibitor so as to reduce myocardial ischemia/reperfusion injury in the subject, thereby reducing myocardial ischemia/reperfusion injury in the subject with the acute coronary syndrome.
  • FIG. 1 Isoforms of PDE1 in human heart. [0014] Figure 2. Synthesis of Inhibitor (ri)-3.
  • Figure 4 A protocol for treatment of myocardial reperfusion injury with QTP.
  • Figure 5 Effects of QTP/FWB101 on infarct size in ischemia/reperfusion in mice.
  • Figure 7 Examples of some Quinazoline PDE1 inhibitors.
  • Figure 9 X-ray crystal structure of compound (S)- 3 bound to the catalytic domain of PDE1B (PDB 5W6E). Color code: carbon, green; nitrogen, blue; oxygen, red.
  • Figure 10 Inhibition of cAMP and cGMP hydrolytic activity of recombinant enzymes by compound 3.(17) All measurements were made at cAMP or cGMP concentrations of 0.1 mM.
  • FIG. 11 Inhibition of cAMP and of cGMP hydrolytic activity in human myocardium by compound 3 (1 mM). Assays were carried out in soluble protein extracts prepared from human myocardium (i) in the presence of CaCl2 and exogenous calmodulin (CM) (“total” activity) or (ii) in the presence of the Ca2+ chelating agent EGTA, as described previously. All assays were carried out at substrate concentrations of 0.1 pM. Reported Ca2+/CM-dependent activity is the difference between total activity and activity in the presence of EGTA. (16)
  • Figure 12 Inhibition of dox-induced cardiomyopathy in a mouse model by compound PDE1 (1 mg/kg IP).
  • “treating” means using a therapy to ameliorate a disease or disorder relating to myocardial injury; to directly or indirectly interfere with (a) one or more points in the biological cascade that leads to, or is responsible for, the disease or disorder or (b) one or more of the biological manifestations of the disease or disorder; to alleviate one or more of the symptoms, effects or side effects associated with the disease or disorder or one or more of the symptoms or disorder or treatment thereof; or to slow the progression of the disease or disorder or one or more of the biological manifestations of the disease or disorder.
  • Treatment includes eliciting a clinically significant response. Treatment may also include improving quality of life for a subject afflicted with the disease or disorder.
  • the term“treat” when used in the context of the invention means partial or full treatment. It can also mean improvement.
  • the term“isolated” or“purified” in reference to a PDE1 inhibitor of the invention does not require absolute purity and is substantially free of impurities, e.g., interfering materials that inhibit the function of a PDE1 inhibitor of the invention .
  • the invention provides methods of inhibiting myocardial injury in a subject.
  • methods of treating or preventing myocardial ischemia/reperfusion injury in a subject comprising administering a cyclic nucleotide phosphodiesterase PDE1 or PDE1C inhibitor to the subject in an effective amount so as to inhibit cardiac muscle injury in the subject.
  • the method comprises administering a cyclic nucleotide
  • the cyclic nucleotide phosphodiesterase PDE1 or PDE1C inhibitor may be administered before, at the time of, or after myocardial injury.
  • a subject may be a mammal such as a human, equine, porcine, bovine, murine, canine, feline, or primate subject. Other mammals are also included in this invention.
  • the invention further provides methods of treating or preventing myocardial ischemial reperfusion injury in a subject.
  • methods of inhibiting cardiac muscle injury in a subject comprising administering a cyclic nucleotide phosphodiesterase PDE1 or PDE1C inhibitor to the subject in an effective amount so as to inhibit cardiac muscle injury in the subject.
  • the method comprises administering a selective cyclic nucleotide phosphodiesterase PDE1 or PDE1C inhibitor to the subject in an amount so as to treat or prevent myocardial ischemia/reperfusion injury in the subject.
  • the cyclic nucleotide PDE1 or PDE1C inhibitor may be administered before, during, or after myocardial ischemia/reperfusion injury.
  • the invention further provides methods of reducing myocardial ischemia/reperfusion in a subject.
  • methods of reducing myocardial ischemia/reperfusion injury in a subject with an acute coronary syndrome comprising administering an effective amount of a PDE1 or PDE1C inhibitor so as to reduce myocardial ischemia/reperfusion injury in the subject, thereby reducing myocardial ischemia/reperfusion injury in the subject with the acute coronary syndrome.
  • the inhibitor is administered before, at the time of or after a period of myocardial ischemia or myocardial reperfusion.
  • preferential accumulation in the plasma over brain or central nervous may comprise an efflux of the inhibitor mediated by efflux transporter at the blood-brain barrier.
  • efflux transporters include, but are not limited to, a P-glycoprotein (P-gp) and/or breast cancer resistance protein (BCRP) or a combination thereof.
  • Examples of a PDE1 include any of PDE1 A, PDE1B, and PDE1C or a combination thereof.
  • Examples of PDE family members include any of PDE1, PDE2, PDE3, PDE4, PDE5, PDE6, PDE7, PDE8, PDE9, PDE10, and PDE11.
  • examples of other cyclic nucleotide phosphodiesterase PDE family members include any of PDE2A, PDE3A, PDE3B, PDE4A, PDE4B, PDE4C, PDE4D, PDE5A, PDE6A, PDE6B, PDE6C, PDE7A, PDE7B, PDE8A,
  • PDE8B, PDE9A, PDE10A, or PDE11 A or a combination thereof are PDE8B, PDE9A, PDE10A, or PDE11 A or a combination thereof.
  • myocardial ischemia/reperfusion may comprise restoration (e.g., spontaneous restoration) of blood flow through an occluded coronary artery.
  • restoration of blood flow may involve any of administration of medication, coronary artery angioplasty and/or coronary bypass surgery.
  • spontaneous restoration of blood flow involves merely as an example, a patient who has a clot that lyses on its own.
  • Suitable medication to restore blood flow includes, but are not limited to, an anticoagulant agent (e.g., heparin, rivaroxaban), antiplatelet agent (e.g., aspirin, clopidogrel), thrombolytic agent (e.g., recombinant tissue plasminogen activators), and/or coronary arterial vasodilator (e.g., nitroglycerine).
  • an anticoagulant agent e.g., heparin, rivaroxaban
  • antiplatelet agent e.g., aspirin, clopidogrel
  • thrombolytic agent e.g., recombinant tissue plasminogen activators
  • coronary arterial vasodilator e.g., nitroglycerine
  • An example of a myocardial ischemia/reperfusion injury include, but is not limited to, damage to a heart muscle of the subject in need with or without reduced contractility of the heart. In another embodiment, the damage to a heart muscle is associated with tissue infarction and cellular damage.
  • An example of a selective PDE1 or PDE1C inhibitor includes a small molecule that inhibits catalytic activity of PDE1 or PDE1C, e.g., one that inhibits PDE1 or PDE1C
  • a PDE1 or PDE1C inhibitor may be a small molecule that inhibits the catalytic activity of PDE1 or PDE1C.
  • the small molecule is or comprises a low- molecular-weight organic compound.
  • the low-molecular-weight organic compound may be 900 daltons or less.
  • the catalytic activity may include or involve hydrolysis of a phosphodiester bond in cAMP and/or cGMP.
  • the selective PDE1 inhibitor may inhibit the catalytic activity of a PDE1 over any of PDE2A, PDE3A, PDE3B, PDE4A, PDE4B, PDE4C, PDE4D, PDE5A, PDE6A, PDE6B, PDE6C, PDE7A, PDE7B, PDE8A, PDE8B, PDE9A, PDE10A, and PDE11 A or a combination thereof.
  • the selective PDE1 inhibitor may inhibit the catalytic activity of a PDE1 at an IC50 or Ki value at least 5-fold lower than its IC50 or Ki value for PDE1, PDE2, PDE3, PDE4, PDE5, PDE6, PDE7, PDE8, PDE9, PDE10, and/or PDE11.
  • the IC50 value is the inhibitor concentration that decreases or inhibits hydrolysis of cAMP or cGMP by cyclic nucleotide phosphodiesterase PDE by 50%. Comparison of IC50 values so as to obtain relative IC50 values may be based on using the same substrate (i.e., cAMP or cGMP) unless stated otherwise.
  • the selective PDE1 inhibitor may inhibit the catalytic activity of a PDE1 at an IC50 or Ki value at least 350-fold lower than IC50 or Ki value for PDE1, PDE2, PDE3, PDE4, PDE5, PDE6, PDE7, PDE8, PDE9, and/or PDE11. Additionally, in another embodiment, the selective PDE1 inhibitor may inhibit the catalytic activity of a PDE1 at an IC50 or Ki value at least 9-fold lower than IC50 or Ki value PDE10. In a further embodiment, the selective PDE1 inhibitor may have an IC50 or Ki value of 50 nM or less for a PDE1.
  • An example of a selective PDE1 or PDE1C inhibitor is or may comprise a quinazoline.
  • the quinazoline inhibitor additionally comprises a pyrazole methyl substituent.
  • the selective PDE1 or PDE1C inhibitor is or may comprise a
  • quinazoline-tethered pyrazole is designated QTP.
  • An example of a QTP is shown in Figure 3.
  • the quinazoline- tethered pyrazole may be an (S) enantiomer.
  • PDE1 inhibitors include, but are not limited to, IC86340, 8-methoxymethyl-
  • the selective PDE1C inhibitor inhibits the catalytic activity of PDE1C preferentially over PDE1 A and/or PDE1B. In yet another embodiment, the selective PDE1C inhibitor inhibits the catalytic activity of PDE1C preferentially over any of PDE2A, PDE3A, PDE3B, PDE4A, PDE4B, PDE4C, PDE4D, PDE5A, PDE6A, PDE6B, PDE6C,
  • the selective PDE1C inhibitor may inhibit the catalytic activity of PDE1C at an IC50 or Ki value at least ten-fold lower than IC50 value for PDE1, PDE2, PDE3, PDE4, PDE5, PDE6, PDE7, PDE8, PDE9 and PDE11 .
  • the selective PDE1C inhibitor inhibits the catalytic activity of PDE1C at an IC50 value at least 9-fold lower than IC50 value PDE10.
  • the selective PDE1C inhibitor may inhibit the catalytic activity of PDE1C preferentially over PDE1 A and/or PDE1B.
  • the selective PDE1C inhibitor may have an IC50 value of 50 nM or less for PDE1C.
  • the PDE1 inhibitor inhibits the catalytic activity of a PDE1.
  • the PDE1C inhibitor may inhibit catalytic activity of PDE1C.
  • the PDE1 inhibitor does not cross the blood-brain barrier.
  • the inhibitor is not or is only poorly CNS-penetrant.
  • the selective PDE1 or PDE1C inhibitor preferentially accumulates in the plasma over cerebrospinal fluid.
  • the PDE1 or PDE1C inhibitor accumulates in the plasma over cerebrospinal fluid.
  • the preferential accumulation in the plasma over cerebrospinal fluid comprises an efflux of the inhibitor mediated by efflux transporter at the blood-brain barrier.
  • efflux transporters include, but are not limited to, a P-glycoprotein (P-gp) or breast cancer resistance protein (BCRP) or a combination thereof.
  • the invention further provides methods of reducing myocardial ischemia/reperfusion injury in a subject with an acute coronary syndrome.
  • the subject may have acute coronary syndrome or be suspected of having an acute coronary syndrome. Further, in another embodiment, the subject is in need of myocardial
  • the method comprises administering an effective amount of a PDE1 or PDE1C inhibitor so as to reduce myocardial ischemia/reperfusion injury in the subject, thereby reducing myocardial ischemia/reperfusion injury in the subject with the acute coronary syndrome.
  • the method further comprises administering medication prior to, at the time of or following the administration of a PDE1 or PDE1C inhibitor.
  • the PDE1 or PDE1C inhibitor may be a selective PDE1 or PDE1C inhibitor.
  • ischemia/reperfusion injury involves injury that occurs in any setting, including e.g., surgery— i.e., when injury occurs during cardiac surgery.
  • Suitable medications include, but are not limited to, an anticoagulant agent, antiplatelet agent, thrombolytic agent and/or coronary arterial vasodilator and a combination thereof.
  • the administration of medication may comprise administration of the medication prior to, at the time of or following the administration of PDE1 selective or PDE1C selective inhibitor.
  • acute coronary syndrome may include a myocardial infarction and/or an unstable angina.
  • the myocardial infarction is ST elevation or non-ST elevation.
  • ST refers to a part of the electrocardiogram.
  • the ST segments are elevated during the period of injury, and in others they are not.
  • the methods of the invention cover both categories.
  • the method further comprises cardiac catheterization and/or coronary artery angioplasty prior to, at the time of or following the administration of PDE1 or PDE1C inhibitor such as a selective PDE1 or PDE1C inhibitor.
  • the method further comprising coronary artery bypass surgery prior to, at the time of or following the administration of PDE1 or PDE1C inhibitor such as a selective PDE1 or PDE1C inhibitor.
  • administration of the inhibitor reduces myocardial infarct size following myocardial ischemia/reperfusion or associated with myocardial ischemia/reperfusion injury.
  • administration of the inhibitor attenuates a decrease in contractile function of the heart.
  • administration of the inhibitor restores contractile function of the heart.
  • reduction in myocardial infarct size, attenuation of a decrease in contractile function of heart, and/or restoration of contractile function of heart in the subject following administration of the inhibitor and myocardial ischemia/reperfusion is irrespective of reduction in angiotensin-II or TGF- b-induced activation of cardiac fibroblasts.
  • reduction in myocardial infarct size, attenuation of a decrease in contractile function of heart, and/or restoration of contractile function of heart in the subject following administration of the inhibitor and myocardial ischemia/reperfusion is irrespective of attenuation of isoproterenol-induced interstitial fibrosis.
  • reduction in myocardial infarct size, attenuation of a decrease in contractile function of heart, and/or restoration of contractile function of heart in the subject following administration of the inhibitor and myocardial ischemia/reperfusion is irrespective of restoration of vasodilatory responses to sodium nitroprusside.
  • reduction in myocardial infarct size, attenuation of a decrease in contractile function of heart, and/or restoration of contractile function of heart in the subject following administration of the inhibitor and myocardial ischemia/reperfusion is irrespective of attenuation of proliferation and migration of vascular smooth muscle cells.
  • reduction in myocardial infarct size, attenuation of a decrease in contractile function of heart, and/or restoration of contractile function of heart in the subject following administration of the inhibitor and myocardial ischemia/reperfusion is irrespective of reduction in injury-induced neointimal formation in coronary artery.
  • reduction in myocardial infarct size, attenuation of a decrease in contractile function of heart, and/or restoration of contractile function of heart in the subject following administration of the inhibitor and myocardial ischemia/reperfusion is irrespective of carotid artery disease or chronic coronary artery disease.
  • the inhibitor preferentially accumulates in the plasma over brain or central nervous system.
  • myocardial ischemia/reperfusion comprises restoration of blood flow through an occluded coronary artery.
  • the restoration of blood flow is spontaneous.
  • the spontaneous restoration of blood flow comprises a clot or other obstruction of blood flow in a coronary artery lysing or resolving on its own.
  • the clot or other obstruction of blood flow in a coronary artery lysing or resolving on its own is free of additional treatment or procedure directed against the clot or other obstruction of blood flow in the coronary artery.
  • the restoration of blood flow is assisted.
  • the assisted restoration of blood flow comprises administration of medication, coronary artery angioplasty, stenting and/or coronary bypass surgery.
  • the medication is selected from the group consisting of anticoagulant agent, antiplatelet agent, thrombolytic agent and/or coronary arterial vasodilator.
  • myocardial ischemia/reperfusion injury comprises damage to heart muscle with or without reduced contractility of heart.
  • damage to heart muscle is associated with tissue infarction and cellular damage.
  • the PDE1 or PDE1C inhibitor is or comprises a small molecule that inhibits catalytic activity of PDE1 or PDE1C.
  • the PDE1 or PDE1C inhibitor is a selective inhibitor.
  • the selective PDE1 or PDE1C inhibitor is or comprises a small molecule that inhibits catalytic activity of PDE1 or PDE1C preferentially over other cyclic nucleotide phosphodiesterases.
  • the PDE1 or PDE1C inhibitor is or comprises a small molecule that inhibits catalytic activity of PDE1 or PDE1C preferentially over one or more other cyclic nucleotide phosphodiesterase(s).
  • the small molecule is or comprises a low-molecular-weight organic compound.
  • the low-molecular-weight organic compound is 900 daltons or less.
  • the catalytic activity is or comprises hydrolysis of a phosphodiester bond in cAMP and/or cGMP.
  • PDE1 is any of PDE1 A, PDE1B and PDE1C or a combination thereof.
  • the other cyclic nucleotide is any of PDE1 A, PDE1B and PDE1C or a combination thereof.
  • phosphodiesterase is selected from the group consisting of PDE2, PDE3, PDE4, PDE5, PDE6, PDE7, PDE8, PDE9, PDE10 and PDE11 and a combination thereof.
  • the selective PDE1 inhibitor inhibits the catalytic activity of PDE1 over any of PDE2A, PDE3A, PDE3B, PDE4A, PDE4B, PDE4C, PDE4D, PDE5A, PDE6A, PDE6B, PDE6C, PDE7A, PDE7B, PDE8A, PDE8B, PDE9A, PDE10A and PDE11 A or a combination thereof.
  • the selective PDE1 inhibitor inhibits the catalytic activity of PDE1 at a Ki value at least 5-fold lower than Ki value for PDE1, PDE2, PDE3, PDE4, PDE5, PDE6, PDE7, PDE8, PDE9, PDE10 and PDE11 or a combination thereof.
  • selective PDE1 inhibitor inhibits the catalytic activity of PDE1 at an Ki value at least lO-fold lower than Ki value for PDE1, PDE2, PDE3, PDE4, PDE5, PDE6, PDE7, PDE8, PDE9 and PDE11 or a combination thereof.
  • the selective PDE1 inhibitor inhibits the catalytic activity of PDE1 at a Ki value at least 9-fold lower than Ki value PDE10.
  • the selective PDE1 inhibitor has a Ki value of less than mM for PDE1 or PDE1C, less than 0.1 pM for PDE1 or PDE1C, or less than 100 nM for PDE1 or PDE1C.
  • the selective PDE1 or PDE1C inhibitor is or comprises a quinazoline.
  • the quinazoline inhibitor additionally comprises a pyrazole methyl substituent.
  • the selective PDE1 or PDE1C inhibitor is or comprises a quinazoline- tethered pyrazole.
  • the quinazoline-tethered pyrazole is designated QTP or alternatively designated the compound shown in Figure 3.
  • the compound of Figure 3 is a racemic mixture.
  • the compound of Figure 3 is an (S) enantiomer.
  • the compound of Figure 3 is an (R) enantiomer.
  • cardiac muscle injury results from myocardial ischemia.
  • myocardial ischemia is or comprises partial or complete blockage of a coronary artery.
  • blockage of a coronary artery comprises buildup of plaque(s) in the artery due to atherosclerosis, a blood clot and/or a coronary artery spasm.
  • myocardial ischemia results in myocardial infarction, arrhythmia and/or heart failure.
  • the selective PDE1C inhibitor inhibits the catalytic activity of PDE1C preferentially over PDE1 A and/or PDE1B.
  • the selective PDE1C inhibitor inhibits the catalytic activity of PDE1C preferentially over any of PDE2A, PDE3A, PDE3B, PDE4A, PDE4B, PDE4C, PDE4D, PDE5A, PDE6A, PDE6B, PDE6C, PDE7A, PDE7B, PDE8A, PDE8B, PDE9A, PDE10A and PDE11 A or a combination thereof.
  • the selective PDE1C inhibitor inhibits the catalytic activity of PDE1C at a Ki value at least lO-fold lower than a Ki value for PDE1, PDE2, PDE3, PDE4, PDE5, PDE6, PDE7, PDE8, PDE9 and/or PDE11 or a combination thereof.
  • the selective PDE1C inhibitor inhibits the catalytic activity of PDE1C at a Ki value at least 9-fold lower than Ki value PDE10.
  • the selective PDE1C inhibitor inhibits the catalytic activity of PDE1C preferentially over PDE1 A and/or PDE1B.
  • the selective PDE1C inhibitor has a Ki value of 50 nM or less for PDE1C.
  • the PDE1 inhibitor inhibits catalytic activity of PDE1.
  • the PDE1C inhibitor inhibits catalytic activity of PDE1C.
  • the inhibitor fails to cross the blood-brain barrier
  • the inhibitor is not or is only poorly CNS-penetrant.
  • preferential accumulation of the inhibitor in the plasma over brain or central nervous comprises an efflux of the inhibitor mediated by efflux transporter at the blood- brain barrier.
  • the efflux transporter is selected from the group consisting of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) and a combination thereof.
  • the inhibitor preferentially accumulates in the plasma over cerebrospinal fluid.
  • preferential accumulation of the inhibitor in the plasma over cerebrospinal fluid comprises an efflux of the inhibitor mediated by efflux transporter at the blood-brain barrier.
  • the efflux transporter is selected from the group consisting of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) or a combination thereof.
  • the subject has acute coronary syndrome or is an acute coronary syndrome suspect.
  • administration is intravenous, intraarterial, intraperitoneal, intramuscular, intradermal, or oral administration.
  • the PDE1 or PDE1C inhibitor is a selective PDE1 or PDE1C inhibitor.
  • the PDE I inhibitor is any of IC86340, 8-methoxymethyl-3 -isobutyl- l-methylxanthine, vinpocetine, dioclein, IC295, 7-(3-Fluorobenzyl)-3-propylimidazo[l,5-a]pyrazin-8(7H)-one, 6-Benzyl-7-(3- fluorobenzyl)-3-(tetrabydro-2H-pyran-4-yl)imidazo[l,5-a]pyrazin-8(7H)- one, 6-Benzyl-7- (cyclohexylmethyl)-3-(tetrahydro-2H-pyran-4-yl)imidazo [l,5-a]pyrazin-8(7H)- one, 7- (Cyclohexylmethyl)-6-methyl-3-(tetrahydro-2H-pyran-4- yl)imidazo [l,5-a]pyra
  • the inhibitor is a QTP as shown in Figure 3.
  • the method further comprises administration of medication prior to, at the time of, or following the administration of the PDE1 or PDE1C inhibitor.
  • the method further comprises administration of medication prior to, at the time of or following the administration of selective PDE1 or PDE1C inhibitor.
  • the medication is selected from the group consisting of anticoagulant agent, antiplatelet agent, thrombolytic agent and/or coronary arterial vasodilator and a combination thereof.
  • the administration of medication comprises
  • acute coronary syndrome comprises myocardial infarction and/or unstable angina.
  • the myocardial infarction is ST elevation or non-ST elevation.
  • the method further comprises cardiac catheterization and/or coronary artery angioplasty prior to, at the time of or following the administration of PDE1 or PDE1C inhibitor. In a further embodiment, the method further comprises cardiac catheterization and/or coronary artery angioplasty prior to, at the time of, or following the administration of selective PDE1 or PDElC inhibitor.
  • the method further comprises coronary artery bypass surgery prior to, at the time of, or following the administration of PDE1 or PDE1C inhibitor. In a further embodiment, the method further comprises coronary artery bypass surgery prior to, at the time of, or following the administration of selective PDE1 or PDE1C inhibitor.
  • administration of the inhibitor reduces myocardial infarct size following myocardial ischemia/reperfusion or associated with myocardial ischemia/reperfusion injury.
  • administration of the inhibitor attenuates a decrease in contractile function of the heart.
  • administration of the inhibitor restores contractile function of the heart.
  • reduction in myocardial infarct size, attenuation of a decrease in contractile function of heart, and/or restoration of contractile function of heart in the subject following administration of the inhibitor and myocardial ischemia/reperfusion is irrespective of reduction in angiotensin- 11 or TGF- b induced activation of cardiac fibroblasts.
  • reduction in myocardial infarct size, attenuation of a decrease in contractile function of heart, and/or restoration of contractile function of heart in the subject following administration of the inhibitor and myocardial ischemia/reperfusion is irrespective of attenuation of isoproterenol-induced interstitial fibrosis.
  • reduction in myocardial infarct size, attenuation of a decrease in contractile function of heart, and/or restoration of contractile function of heart in the subject following administration of the inhibitor and myocardial ischemia/reperfusion is irrespective of restoration of vasodilatory responses to sodium nitroprusside.
  • reduction in myocardial infarct size, attenuation of a decrease in contractile function of heart, and/or restoration of contractile function of heart in the subject following administration of the inhibitor and myocardial ischemia/reperfusion is irrespective of attenuation of proliferation and migration of vascular smooth muscle cells.
  • reduction in myocardial infarct size, attenuation of a decrease in contractile function of heart, and/or restoration of contractile function of heart in the subject following administration of the inhibitor and myocardial ischemia/reperfusion is irrespective of reduction in injury-induced neointimal formation in coronary artery.
  • reduction in myocardial infarct size, attenuation of a decrease in contractile function of heart, and/or restoration of contractile function of heart in the subject following administration of the inhibitor and myocardial ischemia/reperfusion is irrespective of carotid artery disease or chronic coronary artery disease.
  • the subject is in need of myocardial ischemia/reperfusion or myocardial ischemia/reperfusion therapy.
  • the subject has been diagnosed as having a need for treatment of a cardiomyopathy (e.g., dilated cardiomyopathy).
  • a cardiomyopathy e.g., dilated cardiomyopathy.
  • cardiomyopathy is induced by a chemotherapeutic.
  • the chemotherapeutic is an anthracycline (e.g., doxorubicin, daunorubicin, epirubicin, idarubicin).
  • the chemotherapeutic is doxorubicin. In an even further aspect, the chemotherapeutic is trastuzumab.
  • the PDE1 inhibitors is any of 1C86340, 8-methoxym ethyl-3 - isobutyl- l-methylxanthine, vinpocetine, dioclein, IC295, 7-(3-Fluorobenzyl)-3- propylimidazo[l,5-a]pyrazin-8(7H)-one, 6-Benzyl-7-(3-fluorobenzyl)-3-(tetrabydro-2H-pyran-4- yl)imidazo[l,5-a]pyrazin-8(7H)- one, 6-Benzyl-7-(cyclohexylmethyl)-3-(tetrahydro-2H-pyran-4- yl)imidazo [l,5-a]pyrazin-8(7H)- one, 6-Benzyl-7-(cycl
  • compositions comprising a PDE1 or PDE1C inhibitor (such as for example a selective PDE1 or PDE1C inhibitor) and a pharmaceutically acceptable carrier for use in the methods of the invention.
  • a PDE1 or PDE1C inhibitor such as for example a selective PDE1 or PDE1C inhibitor
  • a pharmaceutically acceptable carrier for use in the methods of the invention.
  • dosage forms or compositions containing active ingredient e.g., a PDE1 or PDE1C inhibitor
  • active ingredient e.g., a PDE1 or PDE1C inhibitor
  • the contemplated compositions may contain 0.005%-l00% (wt %) active ingredient, in one embodiment 0.1-95% (wt %), in another embodiment 75-85% (wt %).
  • the phrase“pharmaceutically acceptable carrier” refers to any carrier known to those skilled in the art to be suitable for the particular mode of administration.
  • the PDE1 inhibitors of the invention may be formulated as the sole pharmaceutically active ingredient in the composition or may be combined with other active ingredients.
  • compositions herein comprise one or more PDE1 or PDE1C inhibitor of the invention.
  • the PDE1 or PDE1C inhibitors are, in one embodiment, formulated into suitable pharmaceutical preparations such as solutions, suspensions, tablets, dispersible tablets, pills, capsules, powders, sustained release formulations or elixirs, for oral administration or in sterile solutions or suspensions for parenteral administration, as well as transdermal patch preparation and dry powder inhalers.
  • the PDE1 inhibitors of the invention described above are formulated into pharmaceutical compositions using techniques and procedures well known in the art (see, e.g., Ansel Introduction to Pharmaceutical Dosage Forms, Fourth Edition 1985, 126).
  • the compositions may be formulated for single dosage administration.
  • the PDE1 or PDE1C inhibitor is dissolved, suspended, dispersed or otherwise mixed in a selected carrier at an effective concentration in an amount such that the treated condition may be relieved, prevented, or one or more symptoms are ameliorated.
  • the active compound e.g., PDE1 or PDE1C inhibitor of the invention
  • the therapeutically effective concentration may be determined empirically by testing the compounds in in vitro and in vivo systems known in the art, and then extrapolated therefrom for dosages for subjects such as humans.
  • the active ingredient may be administered at once, e.g., a continuous IV administration for a period of time, or may be divided into a number of smaller doses to be administered at intervals of time. It is understood that the precise dosage and duration of treatment is a function of the disease being treated and may be determined empirically using known testing protocols or by extrapolation from in vivo or in vitro test data. It is to be noted that concentrations and dosage values may also vary with the severity of the condition to be alleviated.
  • the pharmaceutical compositions may be provided for administration to humans and animals in unit dosage forms, such as tablets, capsules, pills, powders, granules, sterile parenteral solutions or suspensions, and oral solutions or suspensions, and oil-water emulsions containing suitable quantities of the compounds or pharmaceutically acceptable derivatives thereof.
  • the pharmaceutically therapeutically active compounds and derivatives thereof are, in one embodiment, formulated and administered in unit-dosage forms or multiple-dosage forms.
  • Unit-dose forms as used herein refers to physically discrete units suitable for human and animal subjects and packaged individually as is known in the art. Each unit-dose contains a
  • unit-dose forms include ampoules and syringes and individually packaged tablets or capsules. Unit-dose forms may be administered in fractions or multiples thereof.
  • a multiple-dose form is a plurality of identical unit-dosage forms packaged in a single container to be
  • multiple dose forms include vials, bottles of tablets or capsules or bottles of pints or gallons.
  • multiple dose form is a multiple of unit-doses which are not segregated in packaging.
  • Kits according to the invention include package(s) comprising compositions of the invention.
  • the phrase“package” means any vessel containing compounds or compositions presented herein.
  • the package can be a box or wrapping.
  • Packaging materials for use in packaging pharmaceutical products are well known to those of skill in the art. Examples of pharmaceutical packaging materials include, but are not limited to, blister packs, bottles, tubes, inhalers, pumps, bags, vials, containers, syringes, bottles, and any packaging material suitable for a selected formulation and intended mode of administration and treatment.
  • the kit can also contain items that are not contained within the package but are attached to the outside of the package, for example, pipettes.
  • Kits may optionally contain instructions for administering compositions of the present invention to a subject having a condition in need of treatment.
  • Kits may also comprise instructions for approved uses of compounds herein by regulatory agencies, such as the United States Food and Drug Administration.
  • Kits may optionally contain labeling or product inserts for the present compounds.
  • the package(s) and/or any product insert(s) may themselves be approved by regulatory agencies.
  • the kits can include compositions in the solid phase or in a liquid phase (such as buffers provided) in a package.
  • the kits also can include buffers for preparing solutions for conducting the methods, and pipettes for transferring liquids from one container to another.
  • the kit may optionally also contain one or more other compositions for use in combination therapies as described herein.
  • the package(s) is a container for intravenous administration.
  • compositions are provided in a polymeric matrix or in the form of a liposome.
  • PDE1C is the predominant isoform (figure l) 2 .
  • PDE1B predominates in human brain 3 .
  • QTP was administered intraperitoneally (IP, 1 mg/kg) 60 minutes prior to a 30-minute ligation of the left anterior descending (LAD) coronary artery (‘pretreatment’); in another, QTP was administered as an IV bolus (1 mg/kg) five minutes before the ligation was released (‘dosing at reperfusion’) (figure 4). 24 hours later, fractional shortening was assessed by echocardiography, and infarct size was quantified by staining with triphenyltetrazolium chloride (TTC).
  • IP intraperitoneally
  • LAD left anterior descending coronary artery
  • Cyclic nucleotide phosphodiesterases are a superfamily of enzymes that shape the spatial and temporal aspects of second messenger signaling throughout the body. Enzymes in the PDE1 family hydrolyze both cGMP and cAMP in a mutually competitive manner. PDE1 catalytic activity is uniquely stimulated by binding to Ca 2+ /calmodulin, (1) giving this class a defining role in the integration of Ca 2+ - and cyclic nucleotide-mediated signaling.
  • the PDE1 family includes three isoforms, PDE1 A, PDE1B, and PDE1C, which differ with respect to their relative affinities for cGMP and cAMP. These isoforms are differentially expressed throughout the body, including the central nervous (CNS) and cardiovascular systems. (2,3) While PDE1 is among the most studied of the PDE families, full elucidation of the scope of PDE1 -regulated signaling has been hampered, until recently, by a lack of potent and selective inhibitors.
  • PDE1 inhibitors could offer therapeutic utility to treat cardiovascular disease (vide infra) with the caveat that CNS exposure may pose a liability.
  • quinazoline 3 PF-04677490, Figure 7
  • quinazoline 3 efficaciously inhibits cAMP- and cGMP -hydrolytic activity in preparations from human myocardium at concentrations selective for PDE1.
  • inhibitor 3 was accomplished via S N AT reaction of 4-chloro-7,8- dimethoxy quinazoline 6 (4) and the amine 7 (Scheme 1, Figure 2), the latter of which was prepared through a modification of a published procedure as described in the Experimental Section. (11,12) After resolution by chiral HPLC (see Experimental Section), the absolute stereochemistry of (S)-3 was determined by X-ray crystallography of the PDElB-bound structure.
  • Enzymes are human in origin except for PDE6A (bovine). Assays utilized cAMP or cGMP substrates, as appropriate for each enzyme, at concentrations ⁇ 1/3 of the Km.
  • n-PK neuropharmacokinetics
  • PDE1 inhibitor The SAR for this inhibitory activity is consistent with that described previously by our group with regard to quinazoline PDE1 inhibitors.
  • the (S)-3 is distinguished by limited brain exposure, a feature that stems primarily from the compound being a substrate for blood— brain barrier efflux transporter activities.
  • PDE1 isoforms are highly expressed throughout the brain, restricted brain exposure may be advantageous to the use of this compound as a probe for in vivo studies of the role of PDE1 in peripheral organ systems.
  • systemic administration of compound (S)-3 readily delivers free plasma concentrations well in excess of the IC50 values for inhibition of PDE1 isoforms, supporting the utility of the compound as a probe for in vivo studies.
  • PDE1 prevents phenylephrine-induced myocyte hypertrophy in neonatal and adult rat ventricular myocytes.18 Inhibition of PDE1A reduces angiotensin-II or TGF- -induced activation of rat cardiac fibroblasts, and attenuates isoproterenol-induced interstitial fibrosis in mice.19 Cellular senescence in vascular smooth muscle myocytes leads to elevated PDE1 expression, and PDE1 inhibition restores vasodilatory responses to sodium nitroprusside in aging mice.20 PDE1C expression in vascular smooth muscle cells in vitro increases with the transition from the contractile to the synthetic phenotype, and PDE1 inhibition attenuates proliferation and migration of vascular smooth muscle cells in culture.21 PDE1C expression is increased in mouse vascular injury models in vivo and in neointimal smooth muscle cells of human coronary arteries
  • Reagents and starting materials were obtained from commercial sources and used without purification unless otherwise indicated.
  • the chloroquinazoline 6 was obtained from commercial sources or prepared as described previously. (4) Depending on storage conditions, 6 may undergo partial hydrolysis to the pyridone over time. In this event, either silica gel chromatography or a partition between DCM and 1 M sodium hydroxide may be used to purge the pyridone impurity. Silica gel chromatography was performed with glass columns hand- packed with JT Baker 40 mM flash silica gel.
  • NMR spectra are presented as chemical shifts in ppm relative to the solvent with multiplicities reported as s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br s (broad singlet), and br m (broad multiplet).
  • the mixture was diluted with 10 mL of water and cooled to rt with continued stirring. The mixture was stirred at rt for 1 h and then was cooled in an ice bath and stirred for an additional 40 min. The resultant precipitate was isolated via filtration, rinsed with water, and dried under a stream of air to afford a white solid in the amount of 1.21 g (83%); mp 230-232 °C.
  • the oil was dissolved in DCM and filtered through a generous wad of cotton to complete the drying process.
  • the resultant pale-yellow solution was concentrated once again to afford a constant mass of 3.79 g (89%) of the free base amine as a viscous syrup.
  • the material was dissolved in 20 mL of methanol and cooled in an ice bath. Concentrated HC1 (5 mL, ⁇ 60 mmol) was added, and the solvent was removed under vacuum.
  • the resultant oil was dissolved in 100 mL of methanol and again concentrated to an oil. This was then dissolved in 25 mL of methanol and with stirring was diluted with 100 mL of ethyl acetate. Continued stirring afforded a white precipitate.
  • AUC area under the curve; BLQ, below limit of quantitation; cAMP, 3’, 5’ -cyclic adenosine monophosphate; cGMP, 3’,5’-cyclic guanosine monophosphate; CM, calmodulin; CSF, cerebrospinal fluid; DCM, dichloromethane; DMF, N,N-dimethylformamide; DMSO, dimethyl sulfoxide; EGTA, ethylene glycol -bis( ?-aminoethyl ether)-N,N,N’,N’-tetraacetic acid; ESI electrospray ionization; HRMS, high resolution mass spectrometry; Kpuu, free partition coefficient; m/z, mass/charge number; MPO, multiparameter optimization; mp, melting point; MS, mass spectrometry; PDB, Protein Data Bank; PDE, phosphodiesterase; SAR, structure— activity relationship; SNAr, nu
  • Bender A Calmodulin-stimulated cyclic nucleotide phosphodiesterases.
  • Compound (S)-3 (PF-04837736) has been made commercially available via Sigma Aldrich (catalogue no. PZ0379).
  • Cyclic nucleotide phosphodiesterase 1A a key regulator of cardiac fibroblast activation and extracellular matrix remodeling in the heart.

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Abstract

L'invention concerne des procédés d'inhibition d'une lésion myocardique chez un sujet, qui comprend l'administration d'un inhibiteur PDE1 ou PDE1C au sujet en une quantité efficace de manière à inhiber une lésion myocardique chez le sujet. Selon la pratique de l'invention, l'inhibiteur PDE1 ou PDE1C peut être administré avant ou après une lésion myocardique ou au moment de celle-ci, comprenant des compositions contenant des inhibiteurs PDE1 ou PDE1C et des kits comprenant les compositions de l'invention.
PCT/US2019/036360 2018-06-11 2019-06-10 Procédé de traitement d'une lésion de reperfusion myocardique à l'aide d'un inhibiteur de la phosphodiestérase de nucléotide cyclique pde1 WO2019241141A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100160444A1 (en) * 2002-07-09 2010-06-24 Radical Therapeutix Method to inhibit ischemia and reperfusion injury
US20120070443A1 (en) * 2008-12-02 2012-03-22 University Of Utah Research Foundation Pde1 as a target therapeutic in heart disease
US20170128453A1 (en) * 2013-03-15 2017-05-11 Intra-Cellular Therapies, Inc. Novel uses
US20180000825A1 (en) * 2013-02-17 2018-01-04 Intra-Cellular Therapies, Inc. Novel uses

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100160444A1 (en) * 2002-07-09 2010-06-24 Radical Therapeutix Method to inhibit ischemia and reperfusion injury
US20120070443A1 (en) * 2008-12-02 2012-03-22 University Of Utah Research Foundation Pde1 as a target therapeutic in heart disease
US20180000825A1 (en) * 2013-02-17 2018-01-04 Intra-Cellular Therapies, Inc. Novel uses
US20170128453A1 (en) * 2013-03-15 2017-05-11 Intra-Cellular Therapies, Inc. Novel uses

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