WO2005044801A1 - Pyridine carboxylic acid derivatives as glucokinase modulators - Google Patents
Pyridine carboxylic acid derivatives as glucokinase modulators Download PDFInfo
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- WO2005044801A1 WO2005044801A1 PCT/GB2004/004579 GB2004004579W WO2005044801A1 WO 2005044801 A1 WO2005044801 A1 WO 2005044801A1 GB 2004004579 W GB2004004579 W GB 2004004579W WO 2005044801 A1 WO2005044801 A1 WO 2005044801A1
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- methyl
- compound
- methoxy
- methylethoxy
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- 239000007901 soft capsule Substances 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 239000002594 sorbent Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 239000002294 steroidal antiinflammatory agent Substances 0.000 description 1
- 150000001629 stilbenes Chemical class 0.000 description 1
- 235000021286 stilbenes Nutrition 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 239000001117 sulphuric acid Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 239000012622 synthetic inhibitor Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 238000004885 tandem mass spectrometry Methods 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- QKSQWQOAUQFORH-UHFFFAOYSA-N tert-butyl n-[(2-methylpropan-2-yl)oxycarbonylimino]carbamate Chemical compound CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C QKSQWQOAUQFORH-UHFFFAOYSA-N 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 150000007979 thiazole derivatives Chemical class 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 229960004072 thrombin Drugs 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 125000005490 tosylate group Chemical group 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 230000032258 transport Effects 0.000 description 1
- 239000005483 tyrosine kinase inhibitor Substances 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 229960005080 warfarin Drugs 0.000 description 1
- PJVWKTKQMONHTI-UHFFFAOYSA-N warfarin Chemical compound OC=1C2=CC=CC=C2OC(=O)C=1C(CC(=O)C)C1=CC=CC=C1 PJVWKTKQMONHTI-UHFFFAOYSA-N 0.000 description 1
- 230000004584 weight gain Effects 0.000 description 1
- 235000019786 weight gain Nutrition 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
- 229910052726 zirconium Inorganic materials 0.000 description 1
- DGVVWUTYPXICAM-UHFFFAOYSA-N β‐Mercaptoethanol Chemical compound OCCS DGVVWUTYPXICAM-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/81—Amides; Imides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/79—Acids; Esters
- C07D213/80—Acids; Esters in position 3
-
- 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
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
- A61P5/50—Drugs for disorders of the endocrine system of the pancreatic hormones for increasing or potentiating the activity of insulin
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
Definitions
- the present invention relates to a group of benzoyl amino pyridyl carboxylic acids which are useful in the treatment or prevention of a disease or medical condition mediated through glucokinase (GLK), leading to a decreased glucose threshold for insulin secretion.
- GLK glucokinase
- the compounds are predicted to lower blood glucose by increasing hepatic glucose uptake. Such compounds may have utility in the treatment of Type 2 diabetes and obesity.
- the invention also relates to pharmaceutical compositions comprising said compounds and to methods of treatment of diseases mediated by GLK using said compounds.
- the main plasma membrane glucose transporter is GLUT2.
- GLK glucose-6-phosphate
- GLK glucokinase
- GLK activity is rate limiting for glucose utilisation and therefore regulates the extent of glucose induced insulin secretion and hepatic glycogen synthesis. These processes are critical in the maintenance of whole body glucose homeostasis and both are dysfunctional in diabetes [2].
- Type 2 maturity-onset diabetes of the young the diabetes is caused by GLK loss of function mutations [3, 4].
- Hyperglycaemia in MODY-2 patients results from defective glucose utilisation in both the pancreas and liver [5].
- Defective glucose utilisation in the pancreas of MODY-2 patients results in a raised threshold for glucose stimulated insulin secretion. Conversely, rare activating mutations of GLK reduce this threshold resulting in familial hyperinsulinism [6, 6a, 7].
- hepatic glucokinase activity is also decreased in type 2 diabetics [8].
- GLK GLK regulatory protein
- the GLK/GLKRP complex is stabilised by fructose-6-phosphate (F6P) binding to the GLKRP and destabilised by displacement of this sugar phosphate by fructose- 1 -phosphate (F1P).
- F1P is generated by fructokinase mediated phosphorylation of dietary fructose. Consequently, GLK/GLKRP complex integrity and hepatic GLK activity is regulated in a nutritionally dependent manner as F6P is elevated in the post-absorptive state whereas F1P predominates in the post-prandial state.
- the pancreatic ⁇ -cell expresses GLK in the absence of GLKRP.
- ⁇ -cell GLK activity is regulated exclusively by the availability of its substrate, glucose.
- Small molecules may activate GLK either directly or through destabilising the GLK/GLKRP complex.
- the former class of compounds are predicted to stimulate glucose utilisation in both the liver and the pancreas whereas the latter are predicted to act exclusively in the liver.
- compounds with either profile are predicted to be of therapeutic benefit in treating Type 2 diabetes as this disease is characterised by defective glucose utilisation in both tissues.
- GLK and GLKRP and the KA TP channel are expressed in neurones of the hypothalamus, a region of the brain that is important in the regulation of energy balance and the control of food intake [14-18].
- GLK activators may be of therapeutic use in treating eating disorders, including obesity, in addition to diabetes.
- the hypothalamic effects will be additive or synergistic to the effects of the same compounds acting in the liver and/or pancreas in normalising glucose homeostasis, for the treatment of Type 2 diabetes.
- the GLK/GLKRP system can be described as a potential "Diabesity" target (of benefit in both Diabetes and Obesity).
- WOO 1/44216 a series of benzylcarbamoyl compounds are described as glucokinase activators.
- WO9749708 disclose a number of intermediates used in the preparation of compounds useful as vasopressin agents which are structurally similar to those disclosed in the present invention. Structurally similar compounds are also disclosed in WO9641795 and JP8143565 (vasopressin antagonism), in JP8301760 (skin damage prevention) and in EP619116 (osetopathy).
- WO01/12621 describes the preparation of as isoxazolylpyrimidines and related compounds as inhibitors of c-JUN N-terminal kinases, and pharmaceutical compositions containing such compounds.
- US 5466715 and US 5258407 describe the preparation of 3,4-disubstituted phenol immunostimulants.
- JP 58069812 describes hypoglycemic pharmaceuticals containing benzamide derivatives.
- US 3950351 describes 2-benzamido-5- nitrothiazoles and Cavier et al [Eur J Med Chem - Chim Ther (1978) 13(6), 539-43] discuss the biological interest of these compounds.
- International application number WO03/015774 describes a group of benzoylamino heterocycle compounds as glucokinase activators and International application number WO03/000262 describes a group or vinyl phenyl derivatives as glucokinase activators.
- A is phenyl or a 5- or 6-membered heteroaryl ring, where A is unsubstituted or substituted by one or 2 groups independently selected from R ;
- R 1 is selected from hydrogen and methyl;
- R is selected from hydrogen and methyl
- R 3 is selected from methyl, methoxy, fluoro, chloro and cyano; with the proviso that at least one of R and R is methyl; or a salt, pro-drug or solvate thereof.
- Compounds of Formula (I) may form salts which are within the ambit of the invention.
- heteroaryl means an aromatic monocyclic 5-6-membered carbon ring incorporating at least one atom chosen from nitrogen, sulphur and oxygen.
- a 'heteroaryl' ring may, unless otherwise specified, be carbon or nitrogen linked, unless linking via nitrogen leads to a charged quaternary nitrogen.
- a “heteroaryl” ring is a 5-membered aromatic ring incorporating one heteroatom selected from nitrogen, sulphur and oxygen.
- aromatic monocyclic 5-6 membered ring incorporating at least one heteroatom examples include: thienyl, furanyl, thiazolyl, thiadiazolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, pyridyl, pyridonyl, pyrazinyl, pyridazinyl and pyrimidinyl, preferably furanyl or thienyl.
- the invention includes in its definition any such optically active or racemic form which possesses the property of stimulating GLK directly or inhibiting the GLK/GLKRP interaction.
- the synthesis of optically active forms may be carried out by standard techniques of organic chemistry well known in the art, for example by synthesis from optically active starting materials or by resolution of a racemic form.
- certain compounds may exist in tautomeric forms and that the invention also relates to any and all tautomeric forms of the compounds of the invention which activate GLK.
- Preferred compounds of Formula (I) are those wherein any one or more of the following apply:
- R 1 is methyl; preferably
- R 2 is hydrogen
- A is selected from phenyl, furanyl and thienyl, preferably phenyl and thienyl.
- A is unsubstituted or substituted by methyl or fluoro.
- A is selected from phenyl, thienyl and furanyl; A is optionally substituted with methyl, methoxy, chloro or fluoro; R 1 is selected from hydrogen and methyl; R 2 is selected from hydrogen and methyl; with the proviso that at least one of R and R is methyl; or a salt, solvate or pro-drug thereof.
- R 1 is selected from hydrogen and methyl
- R 2 is selected from hydrogen and methyl
- the proviso that at least one of R and R is methyl
- any two or more of the Examples, or a salt, solvate or pro-drug thereof there is provided any two or more of the Examples, or a salt, solvate or pro-drug thereof.
- Preferred compounds of the invention include any one, two or more of: - ⁇ 3-[(lS)-l-methyl-2-phenylethoxy]-5-[(lS)-2-methoxy- l-methylethoxy]-benzoylamino ⁇ -3- ⁇ yridine carboxylic acid;- ⁇ 3-[(lS)-l-methyl-2-furan-2-ylethoxy]-5-[(lS)-2-methoxy- l-methylethoxy]-benzoylamino ⁇ -3-pyridine carboxylic acid;- ⁇ 3-[(lS)-l-methyl-2-(2-methoxy ⁇ henyl)ethoxy]-5-[(lS)-2-methoxy- l-methylethoxy]-benzoylamino ⁇ -3-pyridine carboxylic acid;- ⁇ 3-[(lS)-l-methyl-2-thien-2-ylethoxy]-5-[(lS)-2-methoxy- l-methylethoxy]-benzo
- a pro-drug is a bioprecursor or pharmaceutically acceptable compound being degradable in the body to produce a compound of the invention (such as an ester or amide of a compound of the invention, particularly an in vivo hydrolysable ester).
- a compound of the invention such as an ester or amide of a compound of the invention, particularly an in vivo hydrolysable ester.
- prodrug derivatives see: a) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) and Methods in Enzymology, Vol. 42, p. 309-396, edited by K. Widder, et al. (Academic Press, 1985); b) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen; c) H.
- Bundgaard Chapter 5 "Design and Application of Prodrugs", by H. Bundgaard p. 113-191 (1991); d) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992); e) H. Bundgaard, et al, Journal of Pharmaceutical Sciences, 77, 285 (1988); and f) N. Kakeya, et al, Chem Pharm Bull, 32, 692 (1984).
- pro-drugs are as follows.
- An in- vivo hydrolysable ester of a compound of the invention containing a carboxy or a hydroxy group is, for example, a pharmaceutically- acceptable ester which is hydrolysed in the human or animal body to produce the parent acid or alcohol.
- Suitable pharmaceutically-acceptable esters for carboxy include
- Ci to C 6 alkoxymethyl esters for example methoxymethyl
- Ci to C 6 aIkanoyloxymethyl esters for example pivaloyloxymethyl
- phthalidyl esters C 3 to C 8 cycloalkoxycarbonyloxyC ⁇ to C 6 alkyl esters for example 1-cyclohexylcarbonyloxyethyl
- l,3-dioxolen-2-onylmethyl esters for example 5-methyl- l,3-dioxolen-2-onylmethyl
- C ⁇ -6 alkoxycarbonyloxyethyl esters for example methoxymethyl
- Ci to C 6 aIkanoyloxymethyl esters for example pivaloyloxymethyl
- phthalidyl esters C 3 to C 8 cycloalkoxycarbonyloxyC ⁇ to C 6 alkyl esters for example 1-cyclohexylcarbonyloxyethyl
- An in-vivo hydrolysable ester of a compound of the invention containing a hydroxy group includes inorganic esters such as phosphate esters (including phosphoramidic cyclic esters) and ⁇ -acyloxyalkyl ethers and related compounds which as a result of the in-vivo hydrolysis of the ester breakdown to give the parent hydroxy group/s.
- inorganic esters such as phosphate esters (including phosphoramidic cyclic esters) and ⁇ -acyloxyalkyl ethers and related compounds which as a result of the in-vivo hydrolysis of the ester breakdown to give the parent hydroxy group/s.
- -acyloxyalkyl ethers include acetoxymethoxy and 2,2-dimethylpropionyloxy-methoxy.
- a selection of in-vivo hydrolysable ester forming groups for hydroxy include alkanoyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl, alkoxycarbonyl (to give alkyl carbonate esters), dialkylcarbamoyl and N-(dialkylaminoethyl)-N-alkylcarbamoyl (to give carbamates), dialkylaminoacetyl and carboxyacetyl.
- a suitable pharmaceutically-acceptable salt of a compound of the invention is, for example, an acid-addition salt of a compound of the invention which is sufficiently basic, for example, an acid-addition salt with, for example, an inorganic or organic acid, for example hydrochloric, hydrobromic, sulphuric, phosphoric, trifluoroacetic, citric or maleic acid.
- a suitable pharmaceutically-acceptable salt of a benzoxazinone derivative of the invention which is sufficiently acidic is an alkali metal salt, for example a sodium or potassium salt, an alkaline earth metal salt, for example a calcium or magnesium salt, an ammonium salt or a salt with an organic base which affords a physiologically-acceptable cation, for example a salt with methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine.
- a further feature of the invention is a pharmaceutical composition
- a pharmaceutical composition comprising a compound of Formula (I), (la), (lb), (Ic), (Id) or (Ie) as defined above, or a salt, solvate or prodrug thereof, together with a pharmaceutically-acceptable diluent or carrier.
- a compound of Formula (I), (la), (Tb), (Ic), (Id) or (Ie) for use in the preparation of a medicament for treatment of a disease mediated through GLK, in particular type 2 diabetes.
- the compound is suitably formulated as a pharmaceutical composition for use in this way.
- a method of treating GLK mediated diseases, especially diabetes by administering an effective amount of a compound of Formula (I), (la), (lb), (Ic), (Id) or (Ie), or salt, solvate or pro-drug thereof, to a mammal in need of such treatment.
- Specific diseases which may be treated by a compound or composition of the invention include: blood glucose lowering in Diabetes Mellitus type 2 without a serious risk of hypoglycaemia (and potential to treat type 1), dyslipidemia, obesity, insulin resistance, metabolic syndrome X, impaired glucose tolerance.
- the GLK/GLKRP system can be described as a potential "Diabesity" target (of benefit in both Diabetes and Obesity).
- a compound of Formula (I), (la), (lb), (Ic), (Id) or (Ie), or salt, solvate or pro-drug thereof in the preparation of a medicament for use in the combined treatment or prevention of diabetes and obesity.
- a compound of Formula (I), (la), (lb), (Ic), (Id) or (Ie), or salt, solvate or pro-drug thereof in the preparation of a medicament for use in the treatment or prevention of obesity.
- a method for the combined treatment of obesity and diabetes by administering an effective amount of a compound of Formula (I), (la), (lb), (Ic), (Id) or (Ie), or salt, solvate or pro-drug thereof, to a mammal in need of such treatment.
- a method for the treatment of obesity by administering an effective amount of a compound of Formula (I), (la), (lb), (Ic), (Id) or (Ie), or salt, solvate or pro-drug thereof, to a mammal in need of such treatment.
- compositions of the invention may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for example as a finely divided powder or a liquid aerosol), for administration by insufflation (for example as a finely divided powder) or for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular or intramuscular dosing or as a suppository for rectal dosing).
- oral use for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixir
- compositions of the invention may be obtained by conventional procedures using conventional pharmaceutical excipients, well known in the art.
- compositions intended for oral use may contain, for example, one or more colouring, sweetening, flavouring and/or preservative agents.
- Suitable pharmaceutically acceptable excipients for a tablet formulation include, for example, inert diluents such as lactose, sodium carbonate, calcium phosphate or calcium carbonate, granulating and disintegrating agents such as corn starch or algenic acid; binding agents such as starch; lubricating agents such as magnesium stearate, stearic acid or talc; preservative agents such as ethyl or propyl p-hydroxybenzoate, and anti-oxidants, such as ascorbic acid.
- Tablet formulations may be uncoated or coated either to modify their disintegration and the subsequent absorption of the active ingredient within the gastrointestinal tract, or to improve their stability and/or appearance, in either case, using conventional coating agents and procedures well known in the art.
- Compositions for oral use may be in the form of hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with water or an oil such as peanut oil, liquid paraffin, or olive oil.
- Aqueous suspensions generally contain the active ingredient in finely powdered form together with one or more suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents such as lecithin or condensation products of an alkylene oxide with fatty acids (for example polyoxethylene stearate), or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol
- the aqueous suspensions may also contain one or more preservatives (such as ethyl or propyl p-hydroxybenzoate, anti- oxidants (such as ascorbic acid), colouring agents, flavouring agents, and/or sweetening agents (such as sucrose, saccharine or aspartame).
- Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil (such as arachis oil, olive oil, sesame oil or coconut oil) or in a mineral oil (such as liquid paraffin).
- the oily suspensions may also contain a thickening agent such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set out above, and flavouring agents may be added to provide a palatable oral preparation.
- compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
- Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water generally contain the active ingredient together with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients such as sweetening, flavouring and colouring agents, may also be present.
- the pharmaceutical compositions of the invention may also be in the form of oil-in- water emulsions.
- the oily phase may be a vegetable oil, such as olive oil or arachis oil, or a mineral oil, such as for example liquid paraffin or a mixture of any of these.
- Suitable emulsifying agents may be, for example, naturally-occurring gums such as gum acacia or gum tragacanth, naturally-occurring phosphatides such as soya bean, lecithin, an esters or partial esters derived from fatty acids and hexitol anhydrides (for example sorbitan monooleate) and condensation products of the said partial esters with ethylene oxide such as polyoxyethylene sorbitan monooleate.
- the emulsions may also contain sweetening, flavouring and preservative agents.
- Syrups and elixirs may be formulated with sweetening agents such as glycerol, propylene glycol, sorbitol, aspartame or sucrose, and may also contain a demulcent, preservative, flavouring and/or colouring agent.
- the pharmaceutical compositions may also be in the form of a sterile injectable aqueous or oily suspension, which may be formulated according to known procedures using one or more of the appropriate dispersing or wetting agents and suspending agents, which have been mentioned above.
- a sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example a solution in 1,3-butanediol.
- Compositions for administration by inhalation may be in the form of a conventional pressurised aerosol arranged to dispense the active ingredient either as an aerosol containing finely divided solid or liquid droplets.
- Conventional aerosol propellants such as volatile fluorinated hydrocarbons or hydrocarbons may be used and the aerosol device is conveniently arranged to dispense a metered quantity of active ingredient.
- Chapter 25.2 in Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of Editorial Board), Pergamon Press 1990 The amount of active ingredient that is combined with one or more excipients to produce a single dosage form will necessarily vary depending upon the host treated and the particular route of administration.
- a formulation intended for oral administration to humans will generally contain, for example, from 0.5 mg to 2 g of active agent compounded with an appropriate and convenient amount of excipients which may vary from about 5 to about 98 percent by weight of the total composition.
- Dosage unit forms will generally contain about 1 mg to about 500 mg of an active ingredient.
- the size of the dose for therapeutic or prophylactic purposes of a compound of the Formula (I), (la), (lb), (Ic), (Id) or (Ie) will naturally vary according to the nature and severity of the conditions, the age and sex of the animal or patient and the route of administration, according to well known principles of medicine.
- a compound of the Formula (I), (la), (lb), (Ic), (Id) or (Ie) for therapeutic or prophylactic purposes it will generally be administered so that a daily dose in the range, for example, 0.5 mg to 75 mg per kg body weight is received, given if required in divided doses. In general lower doses will be administered when a parenteral route is employed.
- a dose in the range for example, 0.5 mg to 30 mg per kg body weight will generally be used.
- a dose in the range for example, 0.5 mg to 25 mg per kg body weight will be used.
- Oral administration is however preferred.
- the elevation of GLK activity described herein may be applied as a sole therapy or in combination with one or more other substances and/or treatments for the indicated being treated. Such conjoint treatment may be achieved by way of the simultaneous, sequential or separate administration of the individual components of the treatment. Simultaneous treatment may be in a single tablet or in separate tablets.
- chemotherapy may include the following main categories of treatment: 1) Insulin and insulin analogues;
- Insulin secretagogues including sulphonylureas (for example glibenclamide, glipizide), prandial glucose regulators (for example repaglinide, nateglinide);
- Agents that improve incretin action for example dipeptidyl peptidase TV inhibitors, and GLP-1 agonists;
- Insulin sensitising agents including PPARgamma agonists (for example pioglitazone and rosiglitazone), and agents with combined PPARalpha and gamma activity;
- Agents that modulate hepatic glucose balance for example metfor in, fructose 1, 6 bisphosphatase inhibitors, glycogen phopsphorylase inhibitors, glycogen synthase kinase inhibitors);
- Anti-obesity agents for example sibutramine and orlistat
- Anti- dyslipidaemia agents such as, HMG-CoA reductase inhibitors (eg statins); PPAR ⁇ agonists (fibrates, eg gemfibrozil); bile acid sequestrants (cholestyramine); cholesterol absorption inhibitors (plant stanols, synthetic inhibitors); bile acid absorption inhibitors (IB ATi) and nicotinic acid and analogues (niacin and slow release formulations);
- Antihypertensive agents such as, ⁇ blockers (eg atenolol, inderal); ACE inhibitors (eg lisinopril); Calcium antagonists (eg. nifedipine); Angiotensin receptor antagonists (eg candesartan), a antagonists and diuretic agents (eg. furosemide, benzthiazide);
- ⁇ blockers eg atenolol, inderal
- ACE inhibitors eg lisinopril
- Calcium antagonists eg. nifedipine
- Angiotensin receptor antagonists eg candesartan
- diuretic agents eg. furosemide, benzthiazide
- Haemostasis modulators such as, antithrombotics, activators of fibrinolysis and antiplatelet agents; thrombin antagonists; factor Xa inhibitors; factor Vila inhibitors); antiplatelet agents (eg. aspirin, clopidogrel); anticoagulants (heparin and Low molecular weight analogues, hirudin) and warfarin;
- Anti-inflammatory agents such as non-steroidal anti-inflammatory drugs (eg. aspirin) and steroidal anti-inflammatory agents (eg. cortisone).
- non-steroidal anti-inflammatory drugs eg. aspirin
- steroidal anti-inflammatory agents eg. cortisone
- a compound of the invention, or a salt thereof may be prepared by any process known 5 to be applicable to the preparation of such compounds or structurally related compounds.
- Functional groups may be protected and deprotected using conventional methods. For examples of protecting groups such as amino and carboxylic acid protecting groups (as well as means of formation and eventual deprotection), see T.W. Greene and P.G.M.
- Formula (Dlf) Formula (Dig) wherein X 3 is a leaving group and X 4 is a hydroxyl group or X 3 is a hydroxyl group and X 4 is a leaving group; or
- Suitable leaving groups for processes a) to e) are well known to the skilled person and include for example activated hydroxy leaving groups (such as mesylate and tosylate groups) and halo leaving groups such as fluoro, chloro or bromo.
- an appropriate coupling reaction such as a carbodiimide coupling reaction performed with ED AC in the presence of DMAP in a suitable solvent such as DCM, chloroform or DMF at room temperature; or
- a suitable solvent such as methylene chloride.
- the acid chloride can then be reacted with a compound of Formula DIb in the presence of a base, such as triethylamine or pyridine, in a suitable solvent such as chloroform or DCM at a temperature between 0°C and room temperature.
- Process b) - de-protection reactions are well know in the art.
- P 1 include C 1-6 alkyl and benzyl. Wherein P 1 is an C 1-6 alkyl, the reaction can be performed in the presence of sodium hydroxide in the suitable solvent such as THF/water.
- Process c) - compounds of Formula (Did) and (Die) can be reacted together in a suitable solvent, such as DMF or THF, with a base such as sodium hydride or potassium tert-butoxide, at a temperature in the range 0 to 100°C, optionally using metal catalysis such as palladium on carbon or cuprous iodide;
- a suitable solvent such as DMF or THF
- a base such as sodium hydride or potassium tert-butoxide
- compounds of Formula (Did) and (Die) can be reacted together in a suitable solvent, such as THF or DCM, with a suitable phosphine such as triphenylphosphine, and azodicarboxylate such as diethylazodicarboxylate
- Process d) - the reaction of compounds of Formula (Dli) and Formula (Dig) can be performed using reactions conditions as described for process c) above.
- Process e) - reaction of a compound of Formula (Dlh) with a compound of Formula (Dli) can be performed in a polar solvent, such as DMF or a non-polar solvent such as THF with a strong base, such as sodium hydride or potassium tert-butoxide at a temperature between 0 and 100°C, optionally using metal catalysis, such as palladium on carbon or cuprous iodide.
- a polar solvent such as DMF or a non-polar solvent such as THF
- a strong base such as sodium hydride or potassium tert-butoxide
- metal catalysis such as palladium on carbon or cuprous iodide.
- Protecting groups may be removed by any convenient method as described in the literature or known to the skilled chemist as appropriate for the removal of the protecting group in question, such methods being chosen so as to effect removal of the protecting group with minimum disturbance of groups elsewhere in the molecule.
- Specific examples of protecting groups are given below for the sake of convenience, in which "lower” signifies that the group to which it is applied preferably has 1-4 carbon atoms. It will be understood that these examples are not exhaustive. Where specific examples of methods for the removal of protecting groups are given below these are similarly not exhaustive. The use of protecting groups and methods of deprotection not specifically mentioned is of course within the scope of the invention.
- a carboxy protecting group may be the residue of an ester-forming aliphatic or araliphatic alcohol or of an ester-forming silanol (the said alcohol or silanol preferably containing 1-20 carbon atoms).
- Examples of carboxy protecting groups include straight or branched chain (l-12C)alkyl groups (e.g. isopropyl, t-butyl); lower alkoxy lower alkyl groups (e.g. methoxymethyl, ethoxymethyl, isobutoxymethyl; lower aliphatic acyloxy lower alkyl groups, (e.g.
- lower alkoxycarbonyloxy lower alkyl groups e.g. 1-methoxycarbonyloxyethyl, 1-ethoxycarbonyloxyethyl
- aryl lower alkyl groups e.g. p-methoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, benzhydryl and phthalidyl
- tri(lower alkyl)silyl groups e.g. trimethylsilyl and t-butyldimethylsilyl
- tri(lower alkyl)silyl lower alkyl groups e.g.
- hydroxy protecting groups include lower alkenyl groups (e.g. allyl); lower alkanoyl groups (e.g. acetyl); lower alkoxycarbonyl groups (e.g. t-butoxycarbonyl); lower alkenyloxycarbonyl groups (e.g. allyloxycarbonyl); aryl lower alkoxycarbonyl groups (e.g.
- amino protecting groups include formyl, aralkyl groups (e.g. benzyl and substituted benzyl, e.g.
- lower alkoxycarbonyl e.g. t-butoxycarbonyl
- lower alkenyloxycarbonyl e.g. allyloxycarbonyl
- aryl lower alkoxycarbonyl groups e.g. benz
- protecting groups for amide groups include aralkoxymethyl (e.g. benzyloxymethyl and substituted benzyloxymethyl); alkoxymethyl (e.g. methoxymethyl and trimethylsilylethoxymethyl); tri alkyl/arylsilyl (e.g.
- alk-1-enyl e.g. allyl, but-1-enyl and substituted vinyl e.g. 2- phenyl vinyl.
- Aralkoxymethyl, groups may be introduced onto the amide group by reacting the latter group with the appropriate aralkoxymethyl chloride, and removed by catalytic hydrogenation.
- Alkoxymethyl, tri alkyl/arylsilyl and tri alkyl/silyloxymethyl groups may be introduced by reacting the amide with the appropriate chloride and removing with acid; or in the case of the silyl containing groups, fluoride ions.
- the alkoxyphenyl and alkoxybenzyl groups are conveniently introduced by arylation or alkylation with an appropriate halide and removed by oxidation with eerie ammonium nitrate.
- alk-1-enyl groups may be introduced by reacting the amide with the appropriate aldehyde and removed with acid.
- Example 2 was prepared from the corresponding ester, methyl 6- ⁇ 3-[(lS)-l-methyl-2- furan-2-ylethoxy]-5- [( 1 S)-2-methoxy- 1 -methylethoxy] -benzoylamino ⁇ -3-pyridinecarboxylate using an analogous method to the preparation of Example 1.
- Method B (lR)-l-Methyl-2-(5-methylthiophene)-2-ylethanol
- a solution of diisopropylamine (2.4 ml; 17.05mmol) in dry THF (25mL) at -78°C was treated dropwise with nbutyl lithium in hexanes (10.7ml of 1.6M) and the reaction mixture stirred at - 78°C for 30 minutes.
- the mixture was then introduced via cannula into a flask containing a solution of 2-methyl thiophene (1.5 ml, 15.5mmol) in THF (25 ml) and the reaction was allowed to stir at -78°C for one hour.
- the reaction mixture was neutralised with hydrochloric acid solution (6 ml of IM) and the THF removed in vacuo; more water was added, and the resulting solid was filtered off and washed with more distilled water.
- the final purification was achieved by preparative LC-MS eluting with 5-100% acetonitrile in water containing 0.1% formic acid on a Phenonemex LUNA lO ⁇ m C18 column at a flow rate 25 ml/min to give a white solid (176 mg).
- Enzymatic activity of GLK may be measured by incubating GLK, ATP and glucose.
- the rate of product formation may be determined by coupling the assay to a G-6-P dehydrogenase, NADP/NADPH system and measuring the linear increase with time of the optical density at 340nm (Matschinsky et al 1993). Activation of GLK by compounds can be assessed using this assay in the presence or absence of GLKRP as described in Brocklehurst et al (Diabetes 2004, 53, 535-541).
- a GLK/GLKRP binding assay for measuring the binding interactions between GLK and GLKRP. The method may be used to identify compounds which modulate GLK by modulating the interaction between GLK and GLKRP.
- GLKRP and GLK are incubated with an inhibitory concentration of F-6-P, optionally in the presence of test compound, and the extent of interaction between GLK and GLKRP is measured.
- Compounds which either displace F-6-P or in some other way reduce the GLK/GLKRP interaction will be detected by a decrease in the amount of GLK/GLKRP complex formed.
- Compounds which promote F-6-P binding or in some other way enhance the GLK/GLKRP interaction will be detected by an increase in the amount of GLK/GLKRP complex formed.
- a specific example of such a binding assay is described below
- GLK/GLKRP scintillation proximity assay Recombinant human GLK and GLKRP were used to develop a "mix and measure" 96 well SPA (scintillation proximity assay) as described in WO01/20327 (the contents of which are incorporated herein by reference).
- GLK Biotinylated
- GLKRP are incubated with streptavidin linked SPA beads (Amersham) in the presence of an inhibitory concentration of radiolabelled [3H]F-6-P (Amersham Custom Synthesis TRQ8689), giving a signal.
- Compounds which either displace the F-6-P or in some other way disrupt the GLK / GLKRP binding interaction will cause this signal to be lost.
- Binding assays were performed at room temperature for 2 hours.
- the reaction mixtures contained 50mM Tris-HCl (pH 7.5), 2mM ATP, 5mM MgCl 2 , 0.5mM DTT, recombinant biotinylated GLK ( 0.1 mg), recombinant GLKRP (0.1 mg), 0.05mCi [3H] F-6-P (Amersham) to give a final volume of 100ml.
- the extent of GLK/GLKRP complex formation was determined by addition of O.lmg/well avidin linked SPA beads (Amersham) and scintillation counting on a Packard TopCount NXT.
- a F-6-P / GLKRP binding assay for measuring the binding interaction between GLKRP and F-6-P This method may be used to provide further information on the mechanism of action of the compounds.
- Compounds identified in the GLK/GLKRP binding assay may modulate the interaction of GLK and GLKRP either by displacing F-6-P or by modifying the GLK/GLKRP interaction in some other way.
- protein-protein interactions are generally known to occur by interactions through multiple binding sites. It is thus possible that a compound which modifies the interaction between GLK and GLKRP could act by binding to one or more of several different binding sites.
- the F-6-P / GLKRP binding assay identifies only those compounds which modulate the interaction of GLK and GLKRP by displacing F-6-P from its binding site on GLKRP.
- GLKRP is incubated with test compound and an inhibitory concentration of F-6-P, in the absence of GLK, and the extent of interaction between F-6-P and GLKRP is measured.
- Compounds which displace the binding of F-6-P to GLKRP may be detected by a change in the amount of GLKRP/F-6-P complex formed.
- a specific example of such a binding assay is described below
- F-6-P I GLKRP scintillation proximity assay Recombinant human GLKRP was used to develop a "mix and measure" 96 well scintillation proximity assay ) as described in WO01/20327 (the contents of which are incorporated herein by reference).
- FLAG-tagged GLKRP is incubated with protein A coated SPA beads (Amersham) and an anti-FLAG antibody in the presence of an inhibitory concentration of radiolabelled [3H]F-6-P. A signal is generated. Compounds which displace the F-6-P will cause this signal to be lost.
- a combination of this assay and the GLK/GLKRP binding assay will allow the observer to identify compounds which disrupt the GLK/GLKRP binding interaction by displacing F-6-P.
- Binding assays were performed at room temperature for 2 hours.
- the reaction mixtures contained 50mM Tris-HCl (pH 7.5), 2mM ATP, 5mM MgCl 2 , 0.5mM DTT, recombinant FLAG tagged GLKRP (0.1 mg), Anti-Flag M2 Antibody (0.2mg) ( D3I Kodak), 0.05mCi [3H] F-6-P (Amersham) to give a final volume of 100ml.
- the extent of F-6-P/GLKRP complex formation was determined by addition of O.lmg/well protein A linked SPA beads (Amersham) and scintillation counting on a Packard TopCount NXT.
- mRNA Human liver total mRNA was prepared by polytron homogenisation in 4M guanidine isothiocyanate, 2.5mM citrate, 0.5% Sarkosyl, lOOmM b-mercaptoethanol, followed by centrifugation through 5.7M CsCl, 25mM sodium acetate at 135,000g (max) as described in Sambrook J, Fritsch EF & Maniatis T, 1989.
- Poly A + mRNA was prepared directly using a FastTrackTM mRNA isolation kit (Invitrogen).
- GLK and GLKRP cDNA sequences Human GLK and GLKRP cDNA was obtained by PCR from human hepatic mRNA using established techniques described in Sambrook, Fritsch & Maniatis, 1989. PCR primers were designed according to the GLK and GLKRP cDNA sequences shown in Tanizawa et al 10 1991 and Bonthron, D.T. et al 1994 (later corrected in Warner, J.P. 1995).
- GLK and GLKRP cDNA was cloned in E. coli using pBluescript ⁇ , (Short et al 1998) a recombinant cloning vector system similar to that employed by Yanisch-Perron C et al 15 (1985), comprising a colEI-based replicon bearing a polylinker DNA fragment containing multiple unique restriction sites, flanked by bacteriophage T3 and T7 promoter sequences; a filamentous phage origin of replication and an ampicillin drug resistance marker gene.
- GLK was expressed from the vector pTB375NBSE in E.coli BL21 cells,, producing a recombinant protein containing a 6-His tag immediately adjacent to the N-terminal methionine.
- another suitable vector is pET21(+)DNA, Novagen, Cat number 697703.
- the 6-His tag was used to allow purification of the recombinant protein on a column packed with nickel-nitrilotriacetic acid agarose purchased from Qiagen (cat no 30250).
- GLKRP was expressed from the vector pFLAG CTC (D3I Kodak) in E.coli BL21 cells, producing a recombinant protein containing a C-terminal FLAG tag.
- the protein was purified initially by DEAE Sepharose ion exchange followed by utilisation of the FLAG tag for final purification on an M2 anti-FLAG immunoaffinity column purchased from Sigma- Aldrich (cat no. A1205).
- Biotinylation of GLK was biotinylated by reaction with biotinamidocaproate N-hydroxysuccinimide ester (biotin-NHS) purchased from Sigma-Aldrich (cat no. B2643). Briefly, free amino groups of the target protein (GLK) are reacted with biotin-NHS at a defined molar ratio forming stable amide bonds resulting in a product containing covalently bound biotin. Excess, non- conjugated biotin-NHS is removed from the product by dialysis.
- biotinamidocaproate N-hydroxysuccinimide ester purchased from Sigma-Aldrich (cat no. B2643). Briefly, free amino groups of the target protein (GLK) are reacted with biotin-NHS at a defined molar ratio forming stable amide bonds resulting in a product containing covalently bound biotin. Excess, non- conjugated biotin-NHS is removed from the product by dialysis.
- Samples of plasma were obtained either by conscious blood sampling or terminal blood sampling as follows: Conscious blood sampling (for compound level or blood chemistry) - Intravenous blood samples were taken from tail vein using 600 ⁇ l Starstedt Multivette (EDTA) and 22G needle at the required time point. Samples were kept on ice and centrifuged at 3000rpm for 10 minutes within 15-30 minutes of withdrawal. The plasma was aspirated and stored at -20°C Terminal blood sampling for compound level or blood chemistry - At the end of experiment animals were euthanased by exposure to CO /O 2 . Blood sample were taken by cardiac puncture. Samples were kept on ice and centrifuged at 3000rpm for 10 minutes within 15-30 minutes of withdrawal. The plasma was aspirated and stored at -20°C
- HPLC-MS-MS high performance liquid chromatography with tandem mass spectrometry detection
- Mass spectroscopy was performed using an Applied Biosystems API3000 Mass spectrometer (Applied Biosystems, Foster City, California, USA ). Prior to the running of samples the mass spectrometer was optimised for the structure of the test compound.
- the concentration of test samples was determined from the ratio of the peak height of the test sample to the peak height of the internal standard. The concentration of the test sample was calculated with reference to a standard curve relating the ratio to the concentration prepared by using known concentrations of test sample added to samples of rat plasma using (3-isopropoxy-5-benzyoxy-benzoyl)amino pyridine 3-carboxylic acid as an internal standard, treated as described above.
- Plasma protein binding of compounds was measured using the equilibrium dialysis technique (W. Lindner et al, J.Chromatography, 1996, 677, 1-28 ). Compound was dialysed at a concentration of 20 ⁇ M for 18 hours at 37 °C with plasma and isotonic phosphate buffer pH 7.4 (1ml of each in the dialysis cell). A Spectrum® 20-cell equilibrium dialyser was used together with Teflon, semi-micro dialysis cells and Spectra Por®2 membrane discs with a molecular weight cut off 12-14000 Dalton, 47mm (supplied by PerBio Science UK Ltd, Tattenhall, Cheshire). Plasma and buffer samples are removed following dialysis and analysed using HPLCUV/MS (high performance liquid chromatography with UV and mass spec detection) to give the % free level in plasma.
- HPLCUV/MS high performance liquid chromatography with UV and mass spec detection
- Compounds of the invention activate glucokinase with an EC 50 of less than about 150nM, with a percentage free in plasma of between about 0.05% and about 1% and a peak blood levels (including both bound and free) of between about l ⁇ M and about lO ⁇ M for a normalised dose of lmg compound per kilogram of rat body weight.
- Example 2.1 has the following values:
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AU2004286899A AU2004286899A1 (en) | 2003-10-31 | 2004-10-28 | Pyridine carboxylic acid derivatives as glucokinase modulators |
EP04791616A EP1682509A1 (en) | 2003-10-31 | 2004-10-28 | Pyridine carboxylic acid derivatives as glucokinase modulators |
BRPI0416004-5A BRPI0416004A (en) | 2003-10-31 | 2004-10-28 | compound or a salt, prodrug or solvate thereof, pharmaceutical composition, method for treating glk-mediated diseases, use of a compound or salt, solvate or prodrug thereof, methods for the combined treatment of obesity and diabetes and for the treatment of obesity, and a process for preparing a compound or a salt, prodrug or solvate thereof |
US10/578,021 US20070078168A1 (en) | 2003-10-31 | 2004-10-28 | Pyridine carboxylic acid derivatives as glucokinase modulators |
JP2006537425A JP2007509917A (en) | 2003-10-31 | 2004-10-28 | Pyridinecarboxylic acid derivatives as glucokinase regulators |
CA002543643A CA2543643A1 (en) | 2003-10-31 | 2004-10-28 | Pyridine carboxylic acid derivatives as glucokinase modulators |
IL175199A IL175199A0 (en) | 2003-10-31 | 2006-04-25 | Pyridine carboxylic acid derivatives as glucokinase modulators |
NO20062269A NO20062269L (en) | 2003-10-31 | 2006-05-19 | Pyridine carboxylic acid derivatives as glucokinase modulators |
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Also Published As
Publication number | Publication date |
---|---|
IL175199A0 (en) | 2006-09-05 |
NO20062269L (en) | 2006-05-24 |
BRPI0416004A (en) | 2007-01-02 |
AU2004286899A1 (en) | 2005-05-19 |
EP1682509A1 (en) | 2006-07-26 |
JP2007509917A (en) | 2007-04-19 |
KR20060123228A (en) | 2006-12-01 |
ZA200603412B (en) | 2007-07-25 |
CN1898209A (en) | 2007-01-17 |
GB0325402D0 (en) | 2003-12-03 |
CA2543643A1 (en) | 2005-05-19 |
US20070078168A1 (en) | 2007-04-05 |
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