WO2018014016A1 - Substance p et méthode pour le traitement de la grippe - Google Patents

Substance p et méthode pour le traitement de la grippe Download PDF

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Publication number
WO2018014016A1
WO2018014016A1 PCT/US2017/042331 US2017042331W WO2018014016A1 WO 2018014016 A1 WO2018014016 A1 WO 2018014016A1 US 2017042331 W US2017042331 W US 2017042331W WO 2018014016 A1 WO2018014016 A1 WO 2018014016A1
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WO
WIPO (PCT)
Prior art keywords
substance
met
sar
administering
radiation
Prior art date
Application number
PCT/US2017/042331
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English (en)
Inventor
Michael K. Wilhelm
Hal N. SIEGEL
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New Amsterdam Sciences
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Publication date
Application filed by New Amsterdam Sciences filed Critical New Amsterdam Sciences
Publication of WO2018014016A1 publication Critical patent/WO2018014016A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/046—Tachykinins, e.g. eledoisins, substance P; Related peptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/193—Colony stimulating factors [CSF]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents

Definitions

  • the present disclosure pertains to compounds and treatment methods that have utility for treating and/or preventing and/or mitigating the effects of radiation exposure, particularly exposure to high energy radiation and/or prolonged exposure to ionizing radiation from various sources.
  • Exposure to ionizing radiation, whether in therapeutic, accidental or hostile situation is known to cause a variety of health-related effects. These health-related effects can manifest in the short-term onset effects in hours or days or in long term or late effects presenting in months or years after the exposure. Non-limiting examples of such health-related effects can be classified as acute radiation syndrome, chronic radiation syndrome, as well as various radiation induced abnormalities such as thyroiditis.
  • Acute radiation syndrome is generally defined as a collection of health effects that are present within 24 hours of exposure to high amounts of ionizing radiation. The symptoms can vary depending on factors such as the type and/or intensity of the radiation and/or the nature of the exposure.
  • Relatively smaller doses result in gastrointestinal effects, such as nausea and vomiting, and symptoms related to falling blood counts, and predisposition to infection and bleeding. Relatively larger doses can result in neurological effects and rapid death.
  • Treatment of acute radiation syndrome is generally supportive with blood transfusions and antibiotics, with some more aggressive treatments, such as bone marrow transfusions. Similar symptoms may appear months to years after exposure as chronic radiation syndrome when the dose rate is too low to cause the acute form of radiation sickness.
  • Chronic radiation syndrome develops with a speed and severity proportional to the radiation dose received, i.e., it is a deterministic effect of radiation exposure, unlike radiation- induced cancer. It is distinct from acute radiation syndrome in that it occurs at dose rates low enough to permit natural repair mechanisms to compete with the radiation damage during the exposure period.
  • Dose rates high enough to cause the acute form are generally fatal long before onset of the chronic form.
  • the lower threshold for chronic radiation syndrome is between 0.7 and 1.5 Gy, at dose rates above 0.1 Gy/yr, being required in extreme cases.
  • Manifestations include various hematopoietic, gastrointestinal and neurovascular symptoms.
  • the exposure event can result in a prodromal stage that can manifest in symptoms such as nausea, vomiting, headaches, fatigue and fever.
  • Specific effects can include, but are not limited to burns, disorders of the blood, fibrosis. Such effects can occur in any type of exposure, be it therapeutic, occupations accidental or hostile indeed, therapeutic exposure to radiation in the cancer therapy setting can cause fibrotic organ compromise in organs such as the lungs.
  • a compound and method for treating an individual such as a mammalian life form that has been exposed to ionizing radiation.
  • the agent above can be administered in tandem with at least one additional therapeutic agent.
  • Non-limiting examples of such therapeutic agents include substance P, Granulocyte-colony
  • the method involves administration of an effective amount of an agent selected from the group consisting of [Met-OH u ]-substance P, [Met-OMe u ]-substance P, [Nle u ]-substance P, [Pro 9 ] -substance P, [Sar 9 ]-substance P, [Tyr 8 ]- substance P, Sar 9 ,Met (0 2 ) 11-Substance P, and [p-Cl-Phe 7 ' 8 ]-substance P is administered to the affected individual.
  • the agent above can be administered in tandem with at least one additional therapeutic agent.
  • Non-limiting examples of such therapeutic agents include substance P, Granulocyte-colony stimulating factor (GCSF) or mixtures thereof.
  • Fig. 1 is a space filling model of Substance P: Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-
  • Fig. 2 is a structural depiction of an analog of Substance P as disclosed herein;
  • Fig. 3 is a table depicting the amino acid sequence for Sar 9 , Met (0 2 ) n - SP and endogenous tachykinins.
  • Bioactive analogs of substance P administered during asymptomatic and/or prodromal intervals subsequent to exposure to ionizing radiation to address and reduce symptoms and injuries associated with such exposure.
  • Bioactive analogs of Substance P such as Sar 9 , Met (0 2 ) n -Substance P, [Met-OH u ]-substance P, [Met-OMe u ]-substance P, [Nle 11 ]- substance P, [Pro 9 ] -sub stance P, [Sar 9 ]-substance P, [Tyr 8 ] -substance P, [p-Cl-Phe 7 ' 8 ]-substance P can be administered to treat deleterious physical injury brought about by exposure to ionizing radiation.
  • the bioactive analog can be selected from the group that includes [Met-OH u ]-substance P, [Met-OMe u ]-substance P, [Nle 11 ] -sub stance P, [Pro 9 ]- substance P, [Sar 9 ]-substance P, [Tyr 8 ] -sub stance P, Sar 9 , Met (0 2 ) 1 ⁇ Substance P, and [p-Cl- Phe 7 ' 8 ]-substance P.
  • the bioactive compounds compete for binding to the NK1 receptor or for their ability to agonize the NK-1 receptor. Routine assays for such activities are known in the art and can be used.
  • the active agent such as the bioactive analogs of substance P can be administered by any method known in the art, including via aerosol inhalation. Intravenous, intratracheal, intrabronchial, intramuscular, sublingual, and oral administrations can also be used.
  • Contemplated intravenous dosages include 0.05 to 5 nanomolar substance P or analog for intravenous administration. In certain intravenous applications a dose concentration of 0.1 to 2 nanomolar may be employed; while in other applications 0.5 to 1.5 nanomolar concentrations can be used.
  • contemplated dosages include 0.05 to 5.0 micromolar substance P or analog with dosages from 0.1 to 2 micromolar employed in certain applications and dosages from 0.5 to 1.5 micromolar employed in others.
  • Typical concentration ranges of substance P or its bioactive analog in the aerosol administered is between 0.001 and 10 ⁇ . It can be advantageously administered as a liquid at a concentration between about 0.1 and 10 ⁇ .
  • Bioactive analogs are those which act as competitive inhibitors of SP by binding to the SP receptor (NK-1 receptor).
  • the analogs may be agonists of the NK-1 receptor.
  • Other derivatives as are known in the art and commercially available (e.g., from Sigma) can be used.
  • the composition can be administered with Substance P, substance P fragments and derivatized substance P fragments. Substitution, deletion, or insertion of one to eight amino acid residues, and preferably from one to three amino acid residues, will lead to analogs which can be routinely tested for biological activity.
  • functional groups may be modified on SP while retaining the same amino acid backbone. Again, routine testing will determine which of such modifications do not adversely affect biological activity.
  • Substance P the parent compound for the various analogs disclosed herein, is a relatively small (1,348 Daltons), endogenous peptide first discovered in 1931 and characterized chemically about 40 years later.
  • Neuropeptides, such as SP were originally discovered as being distributed throughout the peripheral and central nervous systems.
  • SP has since been shown to be produced in non-neuronal cells such as human endothelial cells, Leydig cells, enterochromaffin cells, epithelial cells, fibroblasts, keratinocytes, intestinal and airway smooth muscle cells,
  • Substance P has been recognized as a mediator of nonadrenergic, noncholinergic (NANC) excitatory neurotransmission, and as playing a role in the transmission of pain. More recent studies have called into question Substance P's role in pain and pain perception, however, and Substance P antagonists do not affect pain or pain perception.
  • NANC nonadrenergic, noncholinergic
  • Substance P Modern research has brought forth additional functions for Substance P including the following: vasodilation, smooth muscle contraction, submucosal gland secretion; increased vascular permeability; stimulation of mast cells, B- and T-lymphocytes and
  • the Substance P analogs disclosed herein bind to one or more of the three neurokinin receptors (NK-1, NK-2 and NK-3), though Substance P analogs as disclosed preferentially interact at the NK-IR to mediate its biological effects.
  • the neurokinin receptors belong to "family 1" (rhodopsin-like) of the G protein-coupled receptors.
  • the NK-IR consists of seven putative a-helical transmembrane segments, an intracellular carboxyl tail, and an extracellular amino-terminus.
  • the Neurokinin-1 receptor has been identified in stem cell lines as well as cells derived from human placental cord blood, rich in hematopoietic stem and progenitor cells.
  • the K-1R has been identified in a various tissues and cell type and is expressed in immune cells such as T and B lymphocytes, monocytes/macrophages, neutrophils, and mast cells.
  • Nonimmune cells like vascular endothelial cells, bone marrow stromal cells, muscle cells, astrocytes, adipocytes, keratinocytes, and fibroblasts also express the NK-1R.
  • the NK-1R receptor is appears to be involved in a number of physiological systems that may be of significance to the immune system, and the cells that support the immune system.
  • Substance P are distinct from the tachykinins Neurokinin A (NKA) and Neurokinin B (NKB) at the N-terminus (referenced by the start of the amino acid sequence as seen in FIG 3. These differences result in NKA and NKB binding with significantly less affinity to the Neurokinin- 1 receptor (NK-IR) than do Sar 9 , Met (O2) 1 ⁇ Substance P, which share an identical N-terminal sequence.
  • the C-terminal penta-peptide, Phe-Phe/Val-Gly-Leu-Met-NH2 is conserved between all natural tachykinins and is required for receptor activation.
  • one particular analog that has been found to be particularly efficacious in treatment is created by modifying two of the eleven amino acids in the Substance P sequence. These modifications included replacing glycine (Gly) with sarcosine (Sar or N-methyl glycine) at the ninth position and introducing an oxidized form of methionine
  • Substance P and the other such analogues disclosed herein mediate predominately through interactions with the Neurokinin-1 receptor located on the plasma membrane of many cell types.
  • Substance P analogs bind to all three neurokinin receptors (NK-1, NK-2 and NK-3), though such materials preferentially interact at the NK-IR to mediate its biological effects.
  • SP analogues such as Sar 9 Met (0 2 ) u -SP are capable of utilizing both
  • PI phosphatidylinositol
  • the Substance P analog, Sar 9 Met (0 2 ) u -SP is a 1393 Da, 11-amino acid, synthetically-manufactured analog of Substance P (SP).
  • Sar 9 Met (0 2 ) u -SP is modified at the 9th [N-Methyl glycine (or Sarcosine) instead of glycine] and 11th (addition of a Sulphone) positions. These modifications render Sar 9 Met (O2) 11 - Sub stance P receptor-specific for the Neurokinin-1 receptor, and also make Sar 9 Met (0 2 ) u -SP more resistant to proteolytic degradation relative to the endogenous peptide, Substance P.
  • ECE-1 endothelin-converting enzyme-1
  • ECE-1 hydrolyzes SP at Gln 6 -Phe 7 and Gly 9 -Leu 10 linkages and degradation of endocytosed neuropeptides regulates trafficking and signaling of internalized receptors.
  • This enzyme facilitates the release of the receptor from the ligand-receptor complex and allows for the receptor to be recycled back to the cell surface, which mediates resensitization.
  • Substance P analogues have applicability as a primary or adjunct therapeutic material for treatment of radiation exposure.
  • Suitable analogues include but are not limited to [Met-OH u ]-substance P, [Met-OMe u ]-substance P, [Nle u ]-substance P, [Pro 9 ]- substance P, [Sar 9 ]-substance P, [Tyr 8 ] -sub stance P, Sar 9 , Met (O2) 1 ⁇ Substance P, and [p-Cl- Phe 7 ' 8 ]-substance P.
  • the material can be administered in a concentration sufficient to active bioactive effect in the patient.
  • Bioactive effect as the term is employed herein, is taken to mean a dose response exhibited in an average of 50% of the symptomatic or pre-symptomatic patients treated.
  • Dose response as defined herein can include but are not limited to the following: reduction in fever; improved lung histopathology expressed as interstitial pathology and/or alveolitis; reduced lung viral titers, increased positive hematopoietic activity and the like.
  • the material disclosed herein can be formulated as an ingestible liquid with active component present in an amount between 0.1 and 10 ⁇ . It is also contemplated that the active component can be formulated as a solid dose form as a pill or tablet or as a powder or granular material. In certain applications in which the dose form employed is a pill or powder, it is contemplated that the bioactive analog of Substance P active disclosed herein can be present in the dose form at a concentration between 0.05 to 7 nanomolar. In certain applications, it is contemplated that the active compound disclosed herein can be present at suitable therapeutic concentrations, for example 0.05 to 5 nanomolar.
  • Suitable devices for administering the aerosol of the present invention include nebulizers as well as hand-held aerosol ''puffer” devices.
  • Suitable treatment regimens for treatment according to the present invention include daily or multiple daily treatment by aerosol.
  • Other modes of treatment include continual transdermal infusion, intravenous injection, intramuscular, sublingual, subcutaneous injection, and oral administration.
  • Suitable formulations of substance P for administration are any which are pharmaceutically acceptable and in which substance P retains its biological activity. Generally, such formulations include substance P dissolved in normal sterile saline.
  • Other formulations for changing absorption and half-life characteristics can be used, including liposomal formulations and slow-release formulations.
  • Exposed animals are either dosed immediately and for 14 consecutive days, or, following a single acute radiation exposure, are allowed to develop symptoms for 12 weeks prior to the 14 days of drug treatment
  • Acute protection provided by bioactive analogs of Substance P as disclosed herein [0041] Lethally irradiated animals are treated with Sar 9 , Met (O2) 1 ⁇ Substance P acutely, at 24hrs, and continuing daily for 14 days. In these studies, animals are exposed to LD50 gamma radiation doses (7.75Gy, whole body), where half the animals should have died. In these acute survival studies, all Sar 9 , Met (O2) 1 ⁇ Substance P— treated animals survive. This is similar to efficacy in an acute treatment paradigm as seen with GCSF (granulocyte colony stimulating factor, or Neupogen®), and demonstrates that bioactive analogues of substance P as disclosed herein are an acute radiation protectant of the hematopoietic stem cell population

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
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  • Pharmacology & Pharmacy (AREA)
  • General Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Epidemiology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Immunology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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Abstract

Les analogues de la substance P sont utiles pour le traitement et la protection contre l'exposition à un rayonnement ionisant, tel que le syndrome de rayonnement aigu, le syndrome de rayonnement chronique et autres syndromes similaires. Les agents actifs peuvent être administrés par inhalothérapie, par voie intraveineuse, intramusculaire, sublinguale ou par d'autres méthodes. Les indices de maladie sont réduits par traitement.
PCT/US2017/042331 2016-07-15 2017-07-17 Substance p et méthode pour le traitement de la grippe WO2018014016A1 (fr)

Applications Claiming Priority (2)

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US201662362900P 2016-07-15 2016-07-15
US62/362,900 2016-07-15

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006047625A2 (fr) * 2004-10-27 2006-05-04 Immuneregen Biosciences, Inc. Procede pour favoriser la guerison de plaies
US20070172447A1 (en) * 2003-05-16 2007-07-26 Kazuhiro Sakurada Agent for preventing and/or treating tissue disruption-accompanied diseases
US20090156504A1 (en) * 2007-07-30 2009-06-18 Immuneregen Biosciences, Inc. Methods of treating blood cell depletion
WO2015168682A1 (fr) * 2014-05-02 2015-11-05 Wilhelm Michael K Substance et méthode pour le traitement de la grippe

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070172447A1 (en) * 2003-05-16 2007-07-26 Kazuhiro Sakurada Agent for preventing and/or treating tissue disruption-accompanied diseases
WO2006047625A2 (fr) * 2004-10-27 2006-05-04 Immuneregen Biosciences, Inc. Procede pour favoriser la guerison de plaies
US20090156504A1 (en) * 2007-07-30 2009-06-18 Immuneregen Biosciences, Inc. Methods of treating blood cell depletion
WO2015168682A1 (fr) * 2014-05-02 2015-11-05 Wilhelm Michael K Substance et méthode pour le traitement de la grippe

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