Classifications

• • 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
  • A61K38/1767—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from invertebrates
• • 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
• • 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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/04—Anorexiants; Antiobesity agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
  • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
  • C07K14/43504—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from invertebrates
  • C07K14/43595—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from invertebrates from coelenteratae, e.g. medusae
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides

Definitions

• the present invention provides methods for treatment of obesity and obesity- related disorders in a human or animal subject or patient by administration of a potassium channel inhibitor.
• the present invention also provides uses of potassium channel inhibiting agents in the treatment of obesity and obesity-related disorders.
• Examples of chemical entities having an anionic charge that may be attached to ShK include but are not necessarily limited to AEEAc-L-Tyr(P0 3 H 2 ), AEEAc-L-Pmp(OH 2 ), AEEAc-D-Pmp(OH 2) , AEEAc-D-Pmp(OH, Et), AEEAc-L- Pmp(Et 2 ), AEEAc-D-Pmp(Et 2 ), AEEAc-L-Tyr, AEEAc-L-Phe(p-NH 2 ), AEEAc-L-Phe(p- C0 2 H), AEEAc-L-Aspartate, AEEAc-D-Aspartate, AEEAc-L-Glutamate, or AEEAc-D- Glutamate.
• the term "pharmacologically effective amount” means an amount of a peptide according to the invention that is sufficient to induce a desired therapeutic or biological effect.
• the term "therapeutically effective amount” means the amount of a peptide of the invention that will elicit a biological or medical response in the mammal that is being treated by a medical doctor or other clinician.
• Peptides of the invention are particularly believed to be useful for treatment of obesity and type 2 diabetes, more specifically obesity. It will be understood that there are medically accepted definitions of obesity and overweight.
• Figure 2A shows triglyceride and non-esterified fatty acid levels in plasma.
• Figures 6A and 6B show PET scans with 18Fluoro-deoxyglucose ( 18 FDG) uptake in brown adipose tissue highlighted by arrows.
• Figure 6A shows that ShK-186 (at 100 and 500 pg/kg) induces 18 FDG-uptake by brown adipose tissue.
• Figure 6B shows that 18 FDG uptake by brown adipose tissue is inhibited by propranolol (5m/kg).
• FIG. 7 shows PET imaging with 18 FDG uptake by skeletal muscle highlighted by arrows.
• ShK-186 at 20, 100 and 500 pg/kg
• propranolol 5mg/kg
• PET scanning was performed in the same manner as in relation to Figure 6.
• One or more peptides of the invention may be combined with one or more other pharmacologically active agent (s) that is (are) useful in the treatment of various weight and feeding-related disorders, such as obesity and/or overweight, in particular other anti-obesity drugs that affect energy expenditure, glycolysis, gluconeogenesis, glucogenolysis, lipolysis, lipogenesis, fat absorption, fat storage, fat excretion, hunger and/or satiety and/or craving mechanisms, appetite/ motivation, food intake, or gastrointestinal motility.
• Drugs that reduce energy intake include, in part, various pharmacological agents, referred to as anorectic drugs, which are used as adjuncts to behavioral therapy in weight reduction programs.
• miglitol and acarbose and (7) agents which antagonise the actions of or reduce secretion of glucagon, such as amylin analogues (e.g. pramlintide); (7) agents that prevent the reabsorption of glucose by the kidney, such as sodium-dependent glucose transporter 2 (SGLT-2) inhibitors (e.g. dapagliflozin); (8) agents designed to treat the complications of prolonged hyperglycaemia, such as aldose reductase inhibitors (e.g.
• anti-obesity agents such as appetite suppressant (e.g. ephedrine), including noradrenergic agents (e.g. phentermine) and serotonergic agents (e.g. sibutramine), pancreatic lipase inhibitors (e.g. orlistat), microsomal transfer protein (MTP) modulators, diacyl glycerolacyltransferase (DGAT) inhibitors, and cannabinoid (CB1 ) receptor antagonists (e.g.
• appetite suppressant e.g. ephedrine
• noradrenergic agents e.g. phentermine
• serotonergic agents e.g. sibutramine
• pancreatic lipase inhibitors e.g. orlistat
• MTP microsomal transfer protein
• DGAT diacyl glycerolacyltransferase
• CB1 cannabinoid receptor antagonists
• Alpha amino groups may be protected by a suitable protecting group, including a urethane-type protecting group, such as benzyloxycarbonyl (Z) and substituted benzyloxycarbonyl, such as p-chlorobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, p- bromobenzyloxycarbonyl, p-biphenyl-isopropoxycarbonyl, 9- fluorenylmethoxycarbonyl (Fmoc) and p-methoxybenzyloxycarbonyl (Moz) and aliphatic urethanetype protecting groups, such as t-butyloxycarbonyl (Boc), diisopropylmethoxycarbonyl, isopropoxycarbonyl, and allyloxycarbonyl (Alloc).
• a urethane-type protecting group such as benzyloxycarbonyl (Z) and substituted benzyloxycarbonyl, such as p-ch
• alpha amino Fmoc protecting groups are removed under basic conditions. Piperidine, piperazine, diethylamine, or morpholine (20-40% v/v) in N.Ndimethylformamide (DMF) may be used for this purpose. Following removal of the alpha amino protecting group, the subsequent protected amino acids are coupled stepwise in the desired order to obtain an intermediate, protected peptide-resin.
• DMF N.Ndimethylformamide
• the activating reagents used for coupling of the amino acids in the solid phase synthesis of the peptides are well known in the art. After the peptide is synthesized, if desired, the orthogonally protected side chain protecting groups may be removed using methods well known in the art for further derivatization of the peptide.
• Reactive groups in a peptide can be selectively modified, either during solid phase synthesis or after removal from the resin.
• peptides can be modified at their N-terminus to obtain several of the preferred embodiments of the application including by addition of AEEAc-L- Tyr(P0 3 H 2 ), AEEAc-L-Pmp(OH 2 ), AEEAc-D-Pmp(OH 2) , AEEAc-D-Pmp(OH, Et), AEEAc-L-Pmp(Et 2 ), AEEAc-D-Pmp(Et 2 ), AEEAc-L-Tyr, AEEAc-L-Phe(p-NH 2 ), AEEAc-L-Phe(p-C0 2 H), AEEAc-L-Aspartate, AEEAc-D-Aspartate, AEEAc-L- Glutamate, or AEEAc-D-Glutamate.
• Peptides of the present invention may be in the form of any pharmaceutically acceptable salt.
• pharmaceutically acceptable salts refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic or organic bases and inorganic or organic acids (see “Handbook of Pharmaceutical Salts: Properties, Selection and Use", P. H. Stahl, P. G. Wermuth, lUPAC, Wiley-VCH, 2002).
• Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc, and the like. Particularly preferred are the ammonium, calcium, lithium, magnesium, potassium, and sodium salts.
• the invention provides a pharmaceutical composition that includes one or more peptides of the present invention and a pharmaceutically acceptable carrier.
• a pharmaceutically acceptable carrier When formulated with a pharmaceutically acceptable carrier, the compound of the invention may be present in the pharmaceutical composition in a concentration from 0.0001 to 99.5%, such as from 0.001 to 95%, by weight of the total composition.
• carrier is within the knowledge of a person skilled in the art and depends on, for instance, the mode of administration, the dosage form, and the physical properties of the active compound, such as solubility and stability.
• carrier as used herein relates to a therapeutically inactive ingredient.
• the dosage form may be a solid, semi-solid, liquid or self-gelling system.
• a preferred embodiment includes a liquid formulation containing 1 , 10, or 25 mg/mL peptide in a solution composed of 10 mM sodium phosphate, 0.8% (w/v) NaCI, 0.05% (w/v) polysorbate 20, in water for injection (pH 6).
• the tablets, pills, capsules, and the like may also contain a binder such as povidone, gum tragacanth, acacia, corn starch or gelatin; diluents; fillers such as microcrystalline cellulose; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch or alginic acid; preservatives; colorants; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, lactose or saccharin.
• a dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as fatty oil.
• tablets may be coated with shellac, sugar or both.
• a syrup or elixir may contain, in addition to the active ingredient, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and a flavoring such as cherry or orange flavor.
• Materials that may be used includes cellulose acetate phthalate, hydroxypropylmethylethylcellulose succinate, hydroxypropylmethylcellulose phthalate, polyvinyl acetate phthalate, and methacrylic acidmethyl methacrylate copolymer.
• the enteric coating employed promotes dissolution of the dosage form primarily at a site outside the stomach, and may be selected such that the enteric coating dissolves at a pH of approximately at least 5.5, more preferable at a pH of from about 6.0 to about 8.0.
• any elements, steps, members, components, compositions, reactants, parts or portions of one embodiment or example may be incorporated into or used with another embodiment or example, unless otherwise specified or unless doing so would render that embodiment or example unsuitable for its intended use.
• steps of a method or process have been described or listed in a particular order, the order of such steps may be changed unless otherwise specified or unless doing so would render the method or process unsuitable for its intended purpose.
• the elements, steps, members, components, compositions, reactants, parts or portions of any invention or example described herein may optionally exist or be utilized in the substantial absence of other elements, steps, members, components, compositions, reactants, parts or portions unless otherwise noted. All reasonable additions, deletions, modifications and alterations are to be considered equivalents of the described examples and embodiments and are to be included within the scope of the following claims.

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• Health & Medical Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Medicinal Chemistry (AREA)
• General Health & Medical Sciences (AREA)
• Engineering & Computer Science (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Pharmacology & Pharmacy (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Animal Behavior & Ethology (AREA)
• Proteomics, Peptides & Aminoacids (AREA)
• Gastroenterology & Hepatology (AREA)
• Epidemiology (AREA)
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• Organic Chemistry (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• General Chemical & Material Sciences (AREA)
• Chemical Kinetics & Catalysis (AREA)
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• Obesity (AREA)
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• Child & Adolescent Psychology (AREA)
• Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
• Medicines Containing Material From Animals Or Micro-Organisms (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

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• 2012
  • 2012-10-02 US US14/347,602 patent/US20150072940A1/en not_active Abandoned
  • 2012-10-02 WO PCT/US2012/058495 patent/WO2013052507A1/en not_active Ceased
  • 2012-10-02 SG SG11201401193XA patent/SG11201401193XA/en unknown
  • 2012-10-02 CN CN201280049696.6A patent/CN103987408A/zh active Pending
  • 2012-10-02 HK HK15101586.1A patent/HK1201048A1/xx unknown
  • 2012-10-02 EP EP12838795.8A patent/EP2763702A4/en not_active Withdrawn
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  • 2012-10-02 RU RU2014117558/15A patent/RU2014117558A/ru not_active Application Discontinuation
  • 2012-10-02 JP JP2014534641A patent/JP2014531469A/ja active Pending
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  • 2012-10-02 AU AU2012318736A patent/AU2012318736A1/en not_active Abandoned
  • 2012-10-02 CA CA2850357A patent/CA2850357A1/en not_active Abandoned
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• 2016
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