WO2004037159A2 - Composes, compositions et methodes permettant de moduler le metabolisme des graisses - Google Patents

Composes, compositions et methodes permettant de moduler le metabolisme des graisses Download PDF

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WO2004037159A2
WO2004037159A2 PCT/IL2003/000860 IL0300860W WO2004037159A2 WO 2004037159 A2 WO2004037159 A2 WO 2004037159A2 IL 0300860 W IL0300860 W IL 0300860W WO 2004037159 A2 WO2004037159 A2 WO 2004037159A2
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absent
pharmaceutical composition
cra
apobec
computer readable
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PCT/IL2003/000860
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WO2004037159A3 (fr
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Georges Gaudriault
Ahmet Kilinc
Olivier Bousquet
Anne Goupil-Lamy
Itzik Harosh
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Obetherapy Biotechnology
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Publication of WO2004037159A3 publication Critical patent/WO2004037159A3/fr

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    • 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
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
    • C12N9/14—Hydrolases (3)
    • C12N9/78—Hydrolases (3) acting on carbon to nitrogen bonds other than peptide bonds (3.5)

Definitions

  • the present invention relates to compounds, pharmaceutical compositions and methods which are useful for regulating an individual's fat metabolism and thus can be used in the treatment of diseases and disorders associated with fat metabolism and, more particularly, to compounds, pharmaceutical compositions and methods for treating disorders such as, but not limited to, overweight, obesity, atherosclerosis, hypertension, Type II or non-insulin dependent diabetes mellitus, pancreatitis, hypercholestrosaemia, hypertriglyceridaema and hyperlipidemia.
  • Obesity defined as an excess of body fat relative to lean body mass, is becoming a major public health problem, particularly in industrialized countries.
  • obesity and overweight affect more than one-half of the U.S. adult population.
  • Increased numbers of obese individuals have also been recently reported all over Europe.
  • obesity represents a chronic disease, which is associated with a wide range of psychological and medical co- morbidities, such as, for example, atherosclerosis, hypertension, Type II or non- insulin dependent diabetes mellitus, pancreatitis, hypercholestrosaemia, hypertriglyceridaema and hyperlipidemia.
  • Obesity related genes have been described in the art as targets for the treatment of obesity many years ago. These genes include, for example, the obese gene (ob), which encodes for the circulating hormone leptin, and its receptor, the diabetes gene (db) (Tartaglia et al. Cell 83(7): 1263-71; Zhang et al. Nature 372(6505): 425-32.).
  • ob the obese gene
  • db diabetes gene
  • obesity related genes include agouti (ag), tubby (tub), fat (fat), mahogany and neuropeptide Y (NPY) (Flier and Maratos-Flier, Cell 92(4): 437-40; Spiegelman and Flier, Cell 87(3): 377-89; Nagle et al., Nature 398: 148-152; Gunn et al., Nature, 398: 152-156), all of which are associated with the central nervous system (CNS) and therefore have divergent physiological targets in addition to energy balance and obesity.
  • CNS central nervous system
  • pancreatic lipase is responsible for the degradation of triglycerides to monoglycerides.
  • PL pancreatic lipase
  • MTP microsomal triglyceride-transfer protein
  • MTP inhibitors which are aimed at treating various conditions associated with excessive fat absorption.
  • treatments with MTP inhibitors suffer major disadvantages, which are attributed to the MTP expression in both the intestine and the liver. It was found that inhibition of the MTP activity in the liver resulted in severe side effects, an example of which is a development of a fatty liver [Kane and
  • appetite blockers which include for example the NPY neuropeptide
  • satiety stimulators which include, for example, the ob, db and agouti genes
  • energy or fatty acid burning agents which include the UCPs
  • fat absorption inhibitors such as the PL and MTP, described above.
  • Anderson disease related genes which modulate or partially inhibit the formation and secretion of chylomicrons only in the intestine, may serve as selective and efficient targets for treating obesity, as is detailed in FR 97 16655 and FR 97 04388, which are incorporated by reference as if fully set forth herein.
  • the Anderson disease is a rare monogenic disease characterized by fat malabsorption and, more specifically, by the absence of chylomicrons.
  • the chylomicrons are vesicles which transport dietary fat, which contain apolipoprotein B48 (apoB48) and are normally exclusively produced by the intestine.
  • apoB48 apolipoprotein B48
  • the apoB48 protein is produced as a result of a post-transcriptional editing by the apoB mRNA editing protein named Apobec-1.
  • the Apobec-1 editing protein deaminates cytidine to uridine, at position 6666 (GenBank Accession No. NP_001635) of the apoB mRNA, and produces a UAA in-frame stop codon (Chan, Biochimie, 77:75-78; Chan and Seeburg Scientific American Science and Medicine 2:68-77). It was thus postulated that by selectively inhibiting Apobec-1 activity, the formation of fat- transporting chylomicrons and, as a consequence, the abso ⁇ tion of fatty acids, would be reduced.
  • Apobec-1 activity is limited to the intestine, inhibition of this protein would result in substantially less harmful, if any, side effects. It was therefore postulated that effective inhibition of Apobec-1 would result in (i) selective inhibition of the formation of chylomicrons in the intestine, thereby minimizing side effects; (ii) enabling patients to continue eating ad libitum; and (iii) enabling oral administration of the inhibitor.
  • U.S. Pat. No. 6,210,888 which is incorporated herein by reference, teaches molecular-based methods for identifying molecules which are capable of inhibiting deaminating ezymes, such as Apobec-1. Briefly, the method is based on the ability to detect the presence or absence of a deaminated cytosine in a defined nucleic acid sequence using labeled primers which hybridize 3' of the deaminated site. The primer hybridizes with the nucleic acid template in the presence of an appropriate polymerase and modified adenine. If the site to be assayed is deaminated, one to three nucleotides are added to each primer hybridized to the nucleic acid template.
  • modified guanine is used. Following extension, the primers are denatured and placed in the presence of an exposure system, to quantify the incorporation of the modified nucleotides. Using this methodology it is possible to identify molecules which affect an enzyme deaminase activity.
  • U.S. Pat. No. 6,210,888 therefore teaches methods of screening for deaminase inhibiting molecules, which require the performance of a biological assay for each of the screened molecules, and as such are time consuming, expensive and require high technical skills. There is thus a widely recognized need for, and it would be highly advantageous to have a more efficient method for identifying compounds for treating obesity and related diseases and disorders devoid of the above limitations.
  • a method of modulating fat metabolism in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound having a general Formulae I, II, III, IN or N:
  • a and B are each independently ⁇ or CRa;
  • W is -CR 20 R 21 -CR 22 R 23 -, -
  • X, Y and Z are each independently O, NRb, S, -CR 63 R 64 - or -R 65 R 66 C- CR 67 R 68 ;
  • U is an alkyl having 1-20 carbon atoms, an alkyl having 1-20 carbon atoms interrupted by at least one heteroatom selected from the group consisting of O, N and S, or absent;
  • Ra, Rb, Re and R ⁇ R 173 is independently is independently selected from the group consisting of hydrogen, lone pair electrons, alkyl, hydroxyalkyl, trihaloalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroalicyclic, halo, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, sulfinyl, sulfonyl, cyano, nitro, azo, sulfonyl, sulfinyl, sulfonamide, phosphonyl, phosphinyl, phosphonium, ketoester, carbonyl, thiocarbonyl, ester, ether, carboxy, thiocarboxy, thioether, thiocarbamate, urea, thiourea, O-carbamyl, N-carbamyl, O-thio
  • a method of modulating fat metabolism in a subject in need thereof comprising administering to the subject a therapeutically effective amount of any of the compounds listed in Tables 1-5.
  • a method of modulating fat metabolism in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound capable of inhibiting Apobec-1 activity.
  • the modulating of the fat metabolism is for a treatment of a condition or disorder selected from the group consisting of overweight, obesity, type II diabetes, hypercholesterolemia, atherosclerosis, hypertension, pancreatitis, hypertriglyceridaema and hyperlipidemia.
  • a method of inhibiting Apobec-1 activity comprising exposing an Apobec-1 to an inhibitory amount of a compound having a general Formulae I, II, III, IN or N:
  • a and B are each independently ⁇ or CRa;
  • X, Y and Z are each independently O, NRb, S, -CR 63 R 64 - or -R 65 R 66 C-
  • V is O, S, Pd, -NR 69 , -CR 70 R 71 -, -R 72 R 73 C-CR 74 R 75 -, -R 76 R 77 C-CR 78 R 79 -
  • CR 80 R 81 -, -R 82 R 83 C-CR 84 R 85 -CR 86 R 87 -CR 88 R 89 -, -R 90 C CR 91 -, -R 92 R 93 C-NR 94 - CR 95 R 96 -, -R 97 R 98 C-NR 99 R 100 , -R 101 R 102 C-NR 103 R 104 -CR 105 R 106 -NR 107 R 108 - or -O-
  • U is an alkyl having 1-20 carbon atoms, an alkyl having 1-20 carbon atoms interrupted by at least one heteroatom selected from the group consisting of O, N and S, or absent;
  • D, E and F are each independently -CR m R 112 -, -NR 113 -, O, S, -CR 114 R 115 -
  • Li and 1 ⁇ are each independently C, CRc or N;
  • T is ⁇ CR 157 R 158 R 159 ,-CR 160 R 161 -CR 162 R 163 R 164 or-R 165 ;
  • Ra, Rb, Re and R ⁇ R 173 is independently is independently selected from the group consisting of hydrogen, lone pair electrons, alkyl, hydroxyalkyl, trihaloalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroalicyclic, halo, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, sulfinyl, sulfonyl, cyano, nitro, azo, sulfonyl, sulfinyl, sulfonamide, phosphonyl, phosphinyl, phosphonium, ketoester, carbonyl, thiocarbonyl, ester, ether, carboxy, thiocarboxy, thioether, thiocarbamate, urea, thiourea, O-carbamyl, N-carbamyl, O-thio
  • a method of inhibiting Apobec-1 activity comprising exposing an Apobec- 1 to an inhibitory amount of any of the compounds listed in Tales 1-5.
  • a pharmaceutical composition for the treatment or prevention of a condition or disorder in which modulating fat metabolism is beneficial comprising, as an active ingredient, a compound capable of inhibiting an Apobec-1 activity, and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition for the treatment or prevention of a condition or disorder in which modulating fat metabolism is beneficial comprising, as an active ingredient, any of the compound listed in Tabled 1-5, and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition for the treatment or prevention of a condition or disorder in which modulating fat metabolism is beneficial comprising, a pharmaceutically acceptable carrier, and, as an active ingredient, a compound having a general Formulae I, II, III, IV or V:
  • a and B are each independently N or CRa;
  • X, Y and Z are each independently O, NRb, S, -CR 63 R 64 - or -R 65 R 66 C- CR 67 R 68 ;
  • U is an alkyl having 1-20 carbon atoms, an alkyl having 1-20 carbon atoms interrupted by at least one heteroatom selected from the group consisting of O, N and S, or absent;
  • Li and 1 ⁇ are each independently C, CRc or N;
  • T is-CR 157 R 158 R 159 ,-CR 160 R 161 -CR 162 R 163 R 164 or- 165 ;
  • R 171 , N N-R 172 or C-C-R 173 or absent;
  • Each of Ra, Rb, Re and R ! -R 173 is independently is independently selected from the group consisting of hydrogen, lone pair electrons, alkyl, hydroxyalkyl, trihaloalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroalicyclic, halo, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, sulfinyl, sulfonyl, cyano, nitro, azo, sulfonyl, sulfinyl, sulfonamide, phosphonyl, phosphinyl, phosphonium, ketoester, carbonyl, thiocarbonyl, ester, ether, carboxy, thiocarboxy, thioether, thiocarbamate, urea, thiourea, O-carbamyl, N-carbamyl,
  • a method of identifying a candidate compound for modulating fat metabolism by inhibiting Apobec-1 activity comprising: obtaining a set of structural coordinates defining the three-dimensional structure of at least the active site cavity of Apobec-1; and computationally identifying a compound which is capable of specifically binding to the three-dimensional structure of the active site cavity, thereby identifying the candidate compound for modulating fat metabolism by inhibiting Apobec-1 activity.
  • a method of identifying a candidate compound for modulating fat metabolism by inhibiting Apobec-1 activity comprising: obtaining a set of structural coordinates defining the three-dimensional structure of at least the active site cavity of Apobec-1; and computationally identifying a compound which is capable of specifically binding to the three-dimensional structure of the active site cavity, thereby identifying the candidate compound for modulating fat metabolism by inhibiting Apobec-1 activity.
  • identifying is effected by: determining a position and orientation of at least one pharmacophore interacting moiety in the active site cavity; and identifying a compound that both spatially and chemically fits to the three-dimensional structure of the active site cavity.
  • the at least one pharmacophore interacting moiety comprises a plurality of pharmacophore interacting moieties, whereby the identifying the compound that chemically binds to the three-dimensional structure of the active site cavity is based on at least one of a plurality of combinations of the plurality of pharmacophore interacting moieties.
  • the determining a position and orientation of the at least one pharmacophore interacting moiety is by computational means.
  • the identifying is by computational means.
  • the obtaining the set of structural coordinates is by computational means.
  • a computer readable medium comprising a data storing device storing therein in a retrievable or executable format a computational representation of a set of structural coordinates defining a three-dimensional structure of at least an active site cavity of Apobec-1 and of at least one pharmacophore interacting moiety in the active site cavity of Apobec-1.
  • a computer readable medium comprising a data storing device storing, in a retrievable or executable format, data including a set of structure coordinates defining at least a portion of a three-dimensional structure of Apobec-1.
  • the data including the set of structure coordinates defining at least the portion of the three- dimensional structure of Apobec-1 is derived from the set of coordinates presented in the Table of Figures 1-96.
  • a computer readable medium comprising a data storing device storing in a retrievable or executable format, data including a set of structural coordinates defining at least a portion of a three-dimensional structure of Apobec-1 complexed with an Apobec-1 inhibitor.
  • a method of identifying a candidate compound for inhibiting Apobec-1 activity comprising: obtaining a set of structural coordinates defining a three- dimensional atomic structure of at least the active site cavity of Apobec-1; and computationally screening a plurality of compounds for a compound capable of specifically binding the active site cavity, thereby identifying the candidate compound for inhibiting Apobec-1 activity.
  • a computing platform for generating a three-dimensional model of at least the active site cavity of Apobec-1, the computing platform comprising: a data-storage device storing data comprising a set of structural coordinates defining at least the active site cavity of Apobec-1; and a processing unit being for generating the three-dimensional model from the data stored in the data-storage device.
  • a computing platform for generating a three-dimensional model of at least a portion of Apobec-1 complexed with an Apobec-1 inhibitor
  • the computing platform comprising: a data-storage device storing data comprising a set of structural coordinates defining at least a portion of a three-dimensional structure of at least the active site of Apobec-1 complexed with the Apobec-1 inhibitor; and a processing unit being for generating the three-dimensional model from the data stored in the datastorage device.
  • a method of identifying a candidate compound for modulating fat metabolism by inhibiting Apobec-1 activity comprising: identifying a compound that spatially and chemically binds to a three-dimensional structure of the active site cavity of Apobec-1; and biologically assaying the compound for its activity in inhibiting Apobec-1 and/or in modulating fat metabolism.
  • the biologically assaying the compound in effected by an assay selected from the group consisting of: determining fat levels in a biological sample; determining apoB expression; determining apoB secretion; and determining cytidine deaminase activity.
  • the compound has a general Formulae I, II, III, IN or V:
  • a and B are each independently ⁇ or CRa;
  • X, Y and Z are each independently O, NRb, S, -CR 63 R 64 - or -R 65 R 66 C- CR 67 R 68 ;
  • V is O, S, Pd, -NR 69 , -CR 70 R 71 -, -R 72 R 73 C-CR 74 R 75 -, -R 76 R 77 C-CR 78 R 79 - CR 80 R 81 -, -R 82 R 83 C-CR 84 R 85 -CR 86 R 87 -CR 88 R 89 -, -R 90 OCR 91 -, -R 92 R 93 C-NR 94 - CR 95 R 96 -, -R 97 R 98 C-NR 99 R 100 , -R 101 R 102 C-NR 103 R 104 -CR 105 R 106 -NR 107 R 108 - or -O-
  • U is an alkyl having 1-20 carbon atoms, an alkyl having 1-20 carbon atoms interrupted by at least one heteroatom selected from the group consisting of O, N and S, or absent;
  • Li and L 2 are each independently C, CRc or N;
  • T is-OR 157 R 158 R 159 ,-CR 160 R 161 -CR 162 R 163 R 164 or ⁇ . 165 ;
  • Each of Ra, Rb, Re and R ! -R 173 is independently is independently selected from the group consisting of hydrogen, lone pair electrons, alkyl, hydroxyalkyl, trihaloalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroalicyclic, halo, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, sulfinyl, sulfonyl, cyano, nitro, azo, sulfonyl, sulfinyl, sulfonamide, phosphonyl, phosphinyl, phosphonium, ketoester, carbonyl, thiocarbonyl, ester, ether, carboxy, thiocarboxy, thioether, thiocarbamate, urea, thiourea, O-carbamyl, N-carbamyl,
  • the compound has a general Formula I.
  • A is CRa; B is N;
  • W is-R 32 ON-; and Q is-R 55 N.
  • a and B are each CRa; W is-R 32 N-; and Q is-R 49 R 50 C-NR 51 -.
  • a and B are each CRa;
  • W is-R 26 R 27 C-NR 28 -;
  • Q is-R 49 R 50 C-NR 51 -.
  • a and B are each CRa;
  • a and B are each CRa;
  • Q is NR 42 .
  • a and B are each CRa; W is-R 32 ON-; and
  • Q is NR 42 .
  • a and B are each CRa
  • W is-R 26 R 27 C-NR 28 -; and Q is NR 42 .
  • A is N;
  • B is CRa
  • W is ⁇ CR 20 R 21 -CR 22 R 23 -; and Q is NR 42 .
  • a and B are each N;
  • W is-CR 20 R 21 -CR 22 R 23 -;
  • A is N;
  • B is CRa
  • W is R 29 N-CR 30 R 31 ;
  • a and B are each N;
  • W is -R 29 N-CR 30 R 31 ;
  • a and B are each CRa
  • W is -R 26 R 27 C-NR 28 -;
  • A is N;
  • B is CRa
  • W is-CR 20 R 21 -CR 22 R 23 -;
  • a and B are each N;
  • W is -R 29 N-CR 30 R 31 ;
  • Q is ⁇ CR 43 R 44 -CR 45 R 46 .
  • the compound has the general Formula II.
  • V is-R 72 R 73 C-CR 74 R 75 -; and U is absent.
  • X and Z are each -CR 63 R 64 -;
  • Y is O.
  • each of R , R , R , R , R and R is independently selected from the group consisting of hydroxy, alkoxy, aryloxy, hydrogen and hydroxyalkyl. According to still further features in the described preferred embodiments,
  • X and Z are each oxygen
  • Y is -CR 63 R 64 -.
  • each of R , R , R , R , R and R is independently selected from the group consisting of hydroxy, alkoxy, aryloxy, hydrogen and hydroxyalkyl.
  • V is-R 82 R 83 C-CR 84 R 85 -CR 86 R 87 -CR 88 R 89 -; and U is absent. According to still further features in the described preferred embodiments,
  • X and Z are each -CR 63 R 64 -;
  • Y is O.
  • each of R 63 , R 64 , R 82 , R 83 , R 84 , R 85 , R 86 , R 87 , R 88 and R 89 is independently selected from the group consisting of hydroxy, alkoxy, aryloxy, hydrogen and hydroxyalkyl.
  • X and Z are each oxygen
  • Y is -CR 63 R 64 -.
  • each of R 63 , R 64 , R 82 , R 83 , R 84 , R 85 , R 86 , R 87 , R 88 and R 89 is independently selected from the group consisting of hydroxy, alkoxy, aryloxy, hydrogen and hydroxyalkyl.
  • the compound has the general Formula III. According to still further features in the described preferred embodiments,
  • Li and L 2 are each C
  • E is-CR m R 112 -;
  • Li and L 2 are each C
  • F is-NR 113 -;
  • Li and L 2 are each C
  • D is-NR 113 -;
  • D is-NR 113 -; E is absent;
  • F is-NR 113 -;
  • L and L ⁇ are each C
  • G is-NR 136 -;
  • I is-CR 134 R 135 .
  • Li and 1 ⁇ are each C; D is-NR 113 -;
  • F is R 126 ON-
  • G is-NR 136 -; and I is-CR 134 R 135 .
  • Li and L 2 are each C
  • F is-NR 113 -;
  • G is-NR 136 -; and I is-CR 134 R 135 .
  • Li and L 2 are each C
  • D is-NR 113 -;
  • E is absent;
  • G is-NR 136 -;
  • I is-CR 134 R 135 .
  • Li and L 2 are each C
  • D is-NR 113 -;
  • J is-CR 134 R 135 -;
  • G is-R 146 N-CR 147 R 148 -;
  • I is-NR 136 .
  • F is-NR 113 -;
  • J is-CR 134 R 135 -;
  • G is-R 146 N-CR 147 R 148 -;
  • I is-NR 136 . According to still further features in the described preferred embodiments,
  • Li and L 2 are each C
  • D is-CR m CR 112 -;
  • E is absent;
  • J is-CR 134 R 135 -;
  • G is-R 146 N-CR 147 R 148 -;
  • I is-NR 136 . According to still further features in the described preferred embodiments,
  • G is-R 146 N-CR 147 R 148 -;
  • I is-NR 136 .
  • D is-NR 113 -;
  • F is-NR 113 -; J and G are each CR 1 ⁇ CR 119 -; and
  • D is-CR m CR 112 -; E is absent;
  • Li and L 2 are each C
  • E is absent;
  • F is-CR m CR 112 -;
  • each of R 3 -R 13 and of R 157 -R 164 is independently selected from the group consisting of hydrogen, alkyl, hydrxyalkyl, carboxy, hydroxy, alkoxy, aryloxy, amido, thiohydroxy, thioalkoxy and carbohydrate.
  • the compound has the general Formula N.
  • Mi, Li, R 18 and R 19 are absent.
  • M and L are each OO. According to still further features in the described preferred embodiments the compound is any of the compounds listed in Tables 1-5.
  • the modulating of the fat metabolism is effected by inhibiting Apobec-1 activity. According to still further features in the described preferred embodiments the modulating of the fat metabolism is by inhibiting apoB48 formation and/or secretion.
  • At least the active site cavity of Apobec-1 is defined by amino acid coordinates 31-116 of A ⁇ obec-1. According to still further features in the described preferred embodiments at least the active site cavity of Apobec-1 is defined by amino acid coordinates 1-142 of A ⁇ obec-1. According to still further features in the described preferred embodiments the at least the active site cavity of Apobec-1 is defined by amino acid coordinates 59-98 of Apobec-1.
  • the at least the active site cavity of Apobec-1 is defined by at least five amino acid residues present in the sequence defined by amino acid coordinates 59-98 of Apobec-
  • the at least five amino acid residues are as set forth in histidine 61, cysteine 93, cysteine 96, valine 62 and glutamate 63.
  • the present invention successfully addresses the shortcomings of the presently known configurations by providing compounds, compositions and methods for modulating fat metabolism.
  • FIG. 1 is a schematic illustration showing amino acid sequence alignment between bacterial ECCDA (GenBank Accession No. PI 3652) and human Apobec-1 as generated using a two-step analysis involving primary sequence alignment and structural alignment, Green residues designate non homologous residues, red residues designate similar or homologous residues;
  • FIG. 2 is an image illustrating the three-dimensional model of a conformation of a human Apobec-1, interacted with 3-deazacytidine (one monomer is presented in green, the other monomer is presented in blue and two molecules of 3-deazacytidine are presented in both active sites as Van der Waals spheres);
  • FIG. 3 is an image presenting the LUDI interactions of human Apobec-1, as generated by SBF (the atoms of the active site are represented by cylinders; the hydrogen bond donors are represented by blue and white, the hydrogen bonds acceptors are represented by red and gray; and the hydrophobic residues are represented by gray sphere). Also designated are some of the DAC coordinating moieties in the Apobec-1 protein;
  • FIG. 4 presents the three-dimensional structures of representative examples of potential Apobec-1 inhibitors, selected by screening the Maybridge database
  • FIGs. 5a-c present the three-dimensional structures of representative examples of potential Apobec-1 inhibitors, selected by screening the NCI database; and FIG. 6 is a box diagram showing a computing platform 10 which can be used for practicing the present invention and which comprises computer readable medium, e.g., a data storage device 12, storing therein data 14 which is retrievable and processable by data processing unit 16 and the data or processed data can be displayed via a display such as a display screen 18 and/or a printer 20.
  • FIGs. 7-132 present the coordinates of the three-dimensional model of a homodimer of human Apobec-1.
  • the present invention is of compounds, pharmaceutical compositions and methods which are useful in the treatment of diseases and disorders associated with fat metabolism.
  • the present invention is further of methods of identifying compounds which are useful in the treatment of diseases and disorders associated with fat metabolism.
  • the present invention relates to compounds, pharmaceutical compositions and methods for treating disorders such as overweight, obesity, atherosclerosis, hypertension, Type II or non-insulin dependent diabetes mellitus, pancreatitis, hypercholestrosaemia, hypertriglyceridaema and hyperlipidemia.
  • disorders such as overweight, obesity, atherosclerosis, hypertension, Type II or non-insulin dependent diabetes mellitus, pancreatitis, hypercholestrosaemia, hypertriglyceridaema and hyperlipidemia.
  • Overweight and obesity are recognized health problems with approximately 97 million people considered clinically overweight or obese in the United States. Obesity and overweight are associated with a number of psychological and medical conditions including atherosclerosis, hypertension, Type II or non-insulin dependent diabetes mellitus, pancreatitis, hypercholestrosaemia, hypertriglyceridaema and hyperlipidemia.
  • appetite blockers which include for example the NPY neuropeptide
  • satiety stimulators which include, for example, the ob, db and agouti genes
  • energy or fatty acid burning agents which include the UCPs
  • fat absorption inhibitors such as the LP and MTP, described above.
  • Chylomicrons are fat globules, which transport fat, and contain apiloprotein
  • the apoB48 protein is produced as a result of a post-transcriptional editing by the apoB mRNA editing protein termed, Apobec-1 (GenBank Accession No. NP_001635).
  • the Apobec-1 editing protein deaminates cytidine to uridine, at position 6666 of the apoB mRNA, and produces a UAA in-frame stop codon [Chen, L. (1995). Biochemie 77:75-78;
  • the present inventors While reducing the present invention to practice and while searching for novel therapeutic agents which can be used to treat clinical conditions associated with abnormal fat metabolism, the present inventors identified a set of coordinates which define the active site cavity of Apobec-1 as well as the location and number of pharmacophore interacting moieties therein, thus allowing, for the first time, identification of specific and efficacious Apobec-1 inhibitors, which can be used to modulate fat metabolism in an individual.
  • the present inventors were able to elucidate, through laborious computational experimentation, the three dimensional structure of the active site cavity of Apobec-1. Using this structural information the three dimensional structure of potential Apobec-1 inhibitors (pharmacophores) was constructed using a Structure Based Focusing (SBF) procedure, to obtain a general formula of potential Apobec-1 inhibitors. Information derived form this general formula was used to identify candidate compounds capable of modulating fat metabolism.
  • SBF Structure Based Focusing
  • candidate compound' refers to a compound which is capable of inhibiting Apobec-1 activity uncovered using the methodology described herein.
  • a candidate compound of the present invention is a compound which is capable of modulating fat metabolism to a degree which is beneficial for treatment.
  • Candidate compounds according to this aspect of the present invention can bind to one or more active sites (i.e. functional domains) of Apobec-1.
  • candidate compounds according to this aspect of the present invention can be molecules which act as competitive inhibitors, non- competitive inhibitors, molecules which interfere with Apobec-1 binding of apobec-1 associated proteins (e.g., microsomal triglyceride transfer protein (MTTP) or apobec- 1 -interacting protein (ABBP-1)] or interfere with Apobec-1 dimerization by binding at the interface between the two Apobec-1 monomers.
  • apobec-1 associated proteins e.g., microsomal triglyceride transfer protein (MTTP) or apobec- 1 -interacting protein (ABBP-1)
  • an active site as defined herein includes any site which participates in any of the above described Apobec-1 activities or interactions.
  • fat metabolism refers to increasing or decreasing transport of fat across the intestine.
  • fat' refers to glycerol esters of saturated fatty acids such as triglycerides and fat-like substances such as steroid alcohol such as cholesterol.
  • the term 'M biting Apobec-1 activity refers to inhibiting or partially inhibiting the cytidine deaminase activity of Apobec-1, preferably human Apobec-1, such as set forth in GenBank Accession No. NP_001635. It will be appreciated that due to sequence homology shared between Apobec-1 and other members of this protein family, compounds of the present invention may serve as inhibitors of Apobec-1 related proteins, which are implicated in hyperproliferative diseases such as cancer and psoriasis.
  • the method of this aspect of the present invention is effected by obtaining a set of coordinates which define the three dimensional structure of at least the active site cavity of Apobec-1 and computationally identifying a compound which specifically binds the active site cavity of Apobec-1, to thereby identify candidate compounds which modulate fat metabolism by inhibiting Apobec-1 activity.
  • the "active site cavity of Apobec-1" refers to at least one functional domain of Apobec-1 (i.e., when in monomeric or dimeric form).
  • the active site cavity of apobec-1 is the zinc-dependent deaminase domain and/or the RNA binding domain, which are positioned within the sequence defined by amino acid coordinates 1-42 of Apobec-1, preferably within the sequence defined by amino acid coordinates 31-116 of Apobec-1, even more preferably within the sequence defined by amino acid coordinates 59-98 of Apobec-1.
  • the active site of the Apobec-1 dimer is shown in Figure 2.
  • Other functional domains of Apobec-1 include a leucine rich region, an RG region and an Apobec-1 complementation region, which depends on ACF binding to both Apobec-1 and connected RNA sequence. Further description of these domains and approaches suitable for inhibition thereof is provided by GeneCard GC12M007970 (available in GeneCards www.rzpd.de/cards/index.html).
  • the active site can be represented by the three-dimentional structure and/or the pharmacophore-interacting moieties
  • obtaining the set of atomic coordinates which define the three dimensional structure of the active site cavity of an enzyme can be effected using various approaches which are well known in the art. Examples include, but are not limited to, neutron diffraction, or by nuclear magnetic resonance (NMR) [See, e.g., Moore, W. J., Physical Chemistry, 4.sup.th Edition, Prentice-Hall, N . (1972)], and X-ray crystallography which is preferred for obtaining the secondary and tertiary structure information, which requires detailed information about the arrangement of atoms within a protein.
  • NMR nuclear magnetic resonance
  • X-ray crystallography is effected by exposing crystals to an X-ray beam and collecting the resultant X-ray diffraction data. This process usually involves the measurements of many tens of thousands of data points over a period of one to several days depending on the crystal form and the resolution of the data required. The crystals diffract the rays, creating a geometrically precise pattern of spots recorded on photographic film or electronic detectors. The distribution of atoms within the crystal influences the pattern of spots. The quality of protein crystals is determined by the ability of the crystal to scatter X-rays of wavelengths (preferably 1.0-2.8. A) suitable to determine the atomic coordinates of the macromolecule.
  • ⁇ the angle of incidence of the reflected X-ray beam
  • d the distance between atomic layers in a crystal
  • ⁇ the wavelength of the incident X-ray beam
  • n is an integer
  • space groups These are called the 230 "space groups.”
  • the designation of the space group in addition to the unit cell constants (which define the explicit size and shape of the cell which repeats periodically within the crystal) is routinely used to uniquely identify a crystalline substance.
  • Certain conventions have been established to ensure the proper identification of crystalline materials and these conventions have been set forth and documented in the International Tables for Crystallography, incorporated herein by reference.
  • U.S. Pat. No. 6,093,573 describes in details X-ray crystallography.
  • a three dimensional structure of a polypeptide of interest can be constructed using computer-based protein modeling techniques (such as described in the Examples section which follows).
  • the three dimensional structure of a protein is solved by finding target sequences that are most compatible with profiles representing the structural environments of the residues in known three- dimensional protein structures (See, e.g., U.S. Pat. No. 5,436,850).
  • the known three-dimensional structures of proteins in a given family are superimposed in-order to define the structurally conserved regions of that protein family.
  • This protein modeling technique also uses a known three- dimensional structure of a homologous protein to approximate the structure of a polypeptide of interest (See e.g., U.S. Pat. Nos. 5,557,535; 5,884,230; and 5,873,052).
  • Conventional homology modeling techniques have been used routinely to build models of proteases and antibodies [Sowdhamini et al., Protein Engineering 10:207, 215 (1997)].
  • Comparative approaches can also be used to develop three- dimensional protein models when the protein of interest has poor sequence identity to template proteins.
  • proteins fold into similar three-dimensional structures despite having very weak sequence identities.
  • the three- dimensional structures of a number of helical cytokines fold in similar three- dimensional topology in spite of low sequence homology.
  • elucidating the three dimensional structure of proteins can be effected using Multiple Sequence Threading (MST) in which structural equivalences are deduced from the threading output using the distance geometry program DRAGON that constructs a low resolution model.
  • MST Multiple Sequence Threading
  • a full-atom representation is then constructed using a molecular modeling package such as QUANTA.
  • structural data obtained is preferably recorded on a computer readable medium so as to enable data manipulation and construction of computational models.
  • computer readable medium refers to any medium which can be read and accessed directly by a computer.
  • Such media include, but are not limited to: magnetic storage media, such as floppy discs, hard disc storage medium, and magnetic tape; optical storage media such as optical discs or CD-ROM; electrical storage media such as RAM and ROM; and hybrids of these categories such as magnetic/optical storage media. Selection and use of appropriate storage media is well within the capabilities of one of ordinary skill in the art. As used herein, “recorded” refers to a process of storing information on computer readable medium.
  • a number of data storage devices can be used for creating a computer readable medium having recorded thereon the structural data of the present invention.
  • the choice of the data storage structure is typically based on the means chosen to access the stored information.
  • a variety of data processor programs and formats can be used to store the data information of the present invention on computer readable medium.
  • the sequence information can be represented in a word processing text file, formatted in commercially-available software such as WordPerfect and MICROSOFT Word, or represented in the form of an ASCII file, stored in a database application, such as DB2, Sybase, Oracle, or the like.
  • the coordinate data used to define the structure of the active site cavity of Apobec-1 or a portion thereof is derived from the set of coordinate data set forth in Figures 7-132 which represent Apobec-1 complexed with the DAC inhibitor.
  • structure models of the present invention are preferably generated by a computing platform, which generates a graphic output of the models via a display generating device such as screen or printer.
  • the computing platform generates graphic representations of atomic structure models via a processing unit which processes structure coordinate data stored in a retrievable format in the data storage device (such as described above, see Figure 6).
  • Suitable software applications which may be used by the processing unit to process structure coordinate data so as to provide a graphic output of three-dimensional structure models generated therewith via display include RIBBONS (Carson, M., 1997. Methods in Enzymology 277, 25),
  • RDD is a potent means of identifying enzyme inhibitors which, for example, has notably been used to identify HIV protease (Lam et al, 1994. Science 263, 380; Wlodawer et al, 1993. Ann Rev Biochem. 62, 543; Appeli, 1993. Perspectives in Drug Discovery and Design 1, 23; Erickson, 1993. Perspectives in Drug Discovery and Design 1, 109), and bcr-abl tyrosine kinase inhibitors (Mauro MJ. et al, 2002. J Clin Oncol.
  • AIDS human acquired immunodeficiency syndrome
  • HJN human immunodeficiency virus
  • chronic myeloid leukemia chronic myeloid leukemia
  • Suitable chemical structure databases for identifying the candidate molecules of the present invention include ISIS (MDL Information Systems, San Leandro, http://www.molinfo.com), MACCS-3D (Martin, Y. C, 1992. J. Med. Chem. 35, 2145-2154), The Cambridge Structural Database (CSD; ht1n://www.ccdc.cam.ac.uk/prods/csd/csd.html), Fine Chemical Database (reviewed in
  • Modeling DataBase MMDB; http://www.ncbi.nlm.nih.gov/Strucrure/MMDB/mmdb.shtml.
  • Other libraries of chemicals are commercially available from, for example,
  • identifying the candidate compounds can be effected using de novo rational drug design, or via modification of a known chemical structure.
  • software comprising "builder" type algorithms utilizes a set of atomic coordinates defining a three-dimensional structure of the binding pocket and the three- dimensional structures of basic chemical building blocks to computationally assemble a putative inhibitor.
  • Such an approach may be employed to structurally refine a putative inhibitor identified, for example, via chemical database screening as described above.
  • Criteria employed by software programs used in rational drug design to qualify the binding of screened chemical structures with binding pockets include gap space, hydrogen bonding, electrostatic interactions, van der Waals forces, hydrophilicity/hydrophobicity, etc.
  • Gap space refers to unoccupied space between the van der Waals surface of a screened molecule positioned within a binding pocket and the surface of the binding pocket defined by amino acid residues in the binding pocket. Gap space may be identified, for example, using an algorithm based on a series of cubic grids surrounding the docked molecule. Gap space represents volume that could advantageously be occupied by modifying a molecule positioned within the apoB48 binding region of the Apobec-1.
  • Contact area between compounds may be directly calculated from the coordinates of the compounds in docked conformation using the MS program (Connolly ML., 1983. Science 221, 709-713).
  • Suitable software employing "scanner” type algorithms include, for example, docking software such as GRAM, DOCK, or AUTODOCK (reviewed in Dunbrack et al, 1997. Folding and Design 2, 27), AFFINITY software of the INSIGHTII package (Molecular Simulations Inc., 1996, San Diego, Calif.), GRID (Goodford PJ., 1985. "A Computational Procedure for Determining Energetically Favorable Binding Sites on Biologically Important Macromolecules", J. Med. Chem. 28, 849-857; GRID is available from Oxford University, Oxford, UK), and MCSS (Miranker A. and Karplus M., 1991. "Functionality Maps of Binding Sites: A Multiple Copy Simultaneous Search Method", Proteins: Structure Function and Genetics 11, 29-34; MCSS is available from Molecular Simulations, Burlington, Mass.).
  • docking software such as GRAM, DOCK, or AUTODOCK (reviewed in Dunbrack et al
  • the AUTODOCK program (Goodsell DS. and Olson AJ., 1990. Proteins: Struct Funct Genet. 8, 195-202; available from -Scripps Research Institute, La Jolla, Ca.) helps in docking screened molecules to binding pockets in a flexible manner using a Monte Carlo simulated annealing approach. The procedure enables a search without bias introduced by the researcher which can influence orientation and conformation of a screened molecule in the targeted binding pocket.
  • the DOCK program (Kuntz ID. et al, 1982. J Mol Biol. 161, 269-288; available from University of California, San Francisco), is based on a description of the negative image of a space-filling representation of the binding pocket, and includes a force field for energy evaluation, limited conformational flexibility and consideration of hydrophobicity in the energy evaluation.
  • Modeling or docking may be followed by energy minimization with standard molecular mechanics force fields or dynamics with programs such as CHARMM (Brooks BR. et al, 1983. J Comp Chem. 4, 187-217) or AMBER (Weiner SJ. et al,
  • minimization of energy means achieving an atomic geometry of a chemical structure via systematic alteration such that any further minor perturbation of the atomic geometry would cause the total energy of the system, as measured by a molecular mechanics force-field, to increase.
  • Minimization and molecular mechanics force fields are well understood in computational chemistry (for example, refer to Burkert U. and Allinger NL., "Molecular Mechanics", ACS
  • the CAVEAT program suggests possible binding molecules based on desired bond vectors.
  • the HOOK program proposes docking sites by using multiple copies of functional groups in simultaneous searches.
  • LUDI is a program based on fragments rather than on descriptors which proposes somewhat larger fragments as possible matches with a binding pocket and scores its hits based on geometric criteria taken from the Cambridge Structural Database (CSD), the Protein Data Bank (PDB) and on criteria based on binding data.
  • CSD Cambridge Structural Database
  • PDB Protein Data Bank
  • LUDI may be advantageously employed to calculate the inhibition constant of a docked chemical structure. Inhibition constants (Ki values) of compounds in the final docking positions can be evaluated using LUDI software.
  • the candidate molecule is identified by further determining the position and orientation of at least one pharmacophore interacting moiety in the active site cavity of Apobec-1 and identifying a compound which fits both structurally and chemically to the three dimensional structure of the active site cavity.
  • This is preferably effected by "fitting" a compound capable of inhibiting Apobec-1 [e.g., 3-deazacytidine (DAC)] into the three-dimensional structure of an active site cavity (as illustrated in the Examples section which follows), to thereby identify the position and orientation of one or more pharmacophore interacting moieties in the active site cavity.
  • Apobec-1 e.g., 3-deazacytidine (DAC)
  • pharmacophore interacting moieties include hydrogen bonds donor and acceptor moieties, hydrophobic moieties and the like.
  • the pharmacophore interacting moieties which participate in inhibitory binding to the catalytic site of Apobec-1 are Val62, Cys96, Cys93 and
  • Additional pharmacophore interacting moieties can be identified using the methodologies described in the examples section, combined with the PDB data of Figures 7-132 and the chemical structure presented in Figure 3. Thus, when screening compounds for capability of inhibiting Apobec-1, binding of a putative inhibitor to at least one of these moieties is preferably qualified.
  • docking of an intermediate chemical structure or of the putative inhibitor with the binding pocket may be visualized via structural models, such as three-dimensional models thereof displayed on a computer screen, so as to advantageously allow user intervention during the rational drug design to optimize a chemical structure.
  • candidate compounds having the general Formulae I, II, III, IV and V can be used to modulate fat metabolism by inhibiting Apobec-1 activity.
  • a and B are each independently ⁇ or CRa;
  • X, Y and Z are each independently O, NRb, S, -CR 63 R 64 - or -R 65 R 66 C- CR 67 R 68 ;
  • U is an alkyl having 1-20 carbon atoms, an alkyl having 1-20 carbon atoms interrupted by at least one heteroatom selected from the group consisting of O, N and S, or absent;
  • Li and L 2 are each independently C, CRc or N;
  • T is-CR 157 R 158 R 159 ,-CR 160 R 161 -CR 162 R 163 R 164 or-R 165 ;
  • R 171 , N N-R 172 or OC-R 173 or absent; and each of Ra, Rb, Re and R ! -R 173 of the above described general formula is independently selected from the group consisting of hydrogen, lone pair electrons, alkyl, hydroxyalkyl, trihaloalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroalicyclic, halo, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, sulfinyl, sulfonyl, cyano, nitro, azo, sulfonyl, sulfinyl, sulfonamide, phosphonyl, phosphinyl, phosphonium, ketoester, carbonyl, thiocarbonyl, ester, ether, carboxy, thiocarboxy, thioether, thiocarba
  • a and B are each N; W is -R 29 N-CR 30 R 31 ; and Q is-CR 43 R 44 -CR 45 R 46 .
  • Some of these compounds are pyrimidine, pyridine, benezene and imidazole derivatives. Such compounds preferably include at least one carbohydrate moiety, the nature of which is defined hereinbelow.
  • the compounds described above also include, without limitation, compounds wherein:
  • V is-R 72 R 73 C-CR 74 R 75 -; U is absent, X and Z are each -CR 63 R 64 -; and Y is O, or X and Z are each oxygen; and Y is -CR 63 R 64 -.
  • Such compounds are either tetrahydrofurane derivatives or dioxolane derivatives, being preferably substituted by hydroxy, alkoxy, aryloxy, hydrogen and hydroxyalkyl groups.
  • the class of compounds described by Formula II of the present invention include compounds wherein: V is -R 82 R 83 C-CR 84 R 85 -CR 86 R 87 -CR 88 R 89 -; U is absent, and X and Z are each -
  • CR 63 R 64 - is O, or X and Z are each oxygen; andY is -CR 63 R 64 -.
  • G is-R 146 N-CR 147 R 148 -; and I is-NR 136 .
  • Li and L 2 are each C; D is-R 126 ON -; E is absent; F is-CR m CR 112 -; J is-CR 134 R 135 -
  • the class of compounds described by Formula IN of the present invention include, without limitation, alkylenes which are substituted, inter alia, by alkyl, hydrxyalkyl, carboxy, hydroxy, alkoxy, aryloxy, amido, thiohydroxy, thioalkoxy and carbohydrate.
  • Preferred compounds that have the general Formula N according to the present invention include, without limitation, compounds wherein Mi, L l5 R 18 and R 19 are absent and M and L are each OO. Such compounds often form a configuration which mimic a nuclotide.
  • alkyl refers to a saturated aliphatic hydrocarbon including straight chain and branched chain groups.
  • the alkyl group has 1 to 20 carbon atoms.
  • the alkyl group may contain 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 20 carbon atoms. More preferably, the alkyl is a medium size alkyl having 1 to 10 carbon atoms. Most preferably, unless otherwise indicated, the alkyl is a lower alkyl having 1 to 4 carbon atoms.
  • the alkyl group may be substituted or unsubstituted.
  • the substituent group can be, for example, hydroxyalkyl, trihaloalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroalicyclic, halo, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, sulfinyl, sulfonyl, cyano, nitro, azo, sulfonyl, sulfinyl, sulfonamide, phosphonyl, phosphinyl, phosphonium, ketoester, carbonyl, thiocarbonyl, ester, ether, carboxy, thiocarboxy, thioether, thiocarbamate, urea, thiourea, O-carbamyl, N-carbamyl, O- thiocarbamyl, N-thiocarbamyl, C-amido, N-a
  • a "cycloalkyl” group refers to an all-carbon monocyclic or fused ring (i.e., rings which share an adjacent pair of carbon atoms) group wherein one of more of the rings does not have a completely conjugated pi electron system.
  • examples, without limitation, of cycloalkyl groups are cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane, cyclohexadiene, cycloheptane, cycloheptatriene, and adamantane.
  • a cycloalkyl group may be substituted or unsubstituted.
  • the substituent group can be, for example, alkyl, hydroxyalkyl, trihaloalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroalicyclic, halo, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, sulfinyl, sulfonyl, cyano, nitro, azo, sulfonyl, sulfinyl, sulfonamide, phosphonyl, phosphinyl, phosphonium, ketoester, carbonyl, thiocarbonyl, ester, ether, carboxy, thiocarboxy, thioether, thiocarbamate, urea, thiourea, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido,
  • aryl refers to an all-carbon monocyclic or fused-ring polycyclic
  • aryl groups i.e., rings which share adjacent pairs of carbon atoms
  • aryl groups phenyl, naphthalenyl and anthracenyl.
  • the aryl group may be substituted or unsubstituted.
  • the substituent group can be, for example, alkyl, hydroxyalkyl, trihaloalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroalicyclic, halo, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, sulfinyl, sulfonyl, cyano, nitro, azo, sulfonyl, sulfinyl, sulfonamide, phosphonyl, phosphinyl, phosphonium, ketoester, carbonyl, thiocarbonyl, ester, ether, carboxy, thiocarboxy, thioether, thiocarbamate, urea, thiourea, O-carbamyl, N-carbamyl, O- thiocarbamyl, N-thiocarbamyl, C-amido
  • heteroaryl group refers to a monocyclic or fused ring (i.e., rings which share an adjacent pair of atoms) group having in the ring(s) one or more atoms, such as, for example, nitrogen, oxygen and sulfur and, in addition, having a completely conjugated pi-electron system.
  • heteroaryl groups include pyrrole, furane, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrimidine, quinoline, isoqumoline and purine.
  • the heteroaryl group may be substituted or unsubstituted.
  • the substituent group can be, for example, alkyl, hydroxyalkyl, trihaloalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroalicyclic, halo, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, sulfinyl, sulfonyl, cyano, nitro, azo, sulfonyl, sulfinyl, sulfonamide, phosphonyl, phosphinyl, phosphonium, ketoester, carbonyl, thiocarbonyl, ester, ether, carboxy, thiocarboxy, thioether, thiocarbamate, urea, thiourea, O-carbamyl, N- carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido,
  • heteroalicyclic group refers to a monocyclic or fused ring group having in the ring(s) one or more atoms such as nitrogen, oxygen and sulfur.
  • the rings may also have one or more double bonds. However, the rings do not have a completely conjugated pi-electron system.
  • the heteroalicyclic may be substituted or unsubstituted.
  • the substituted group can be, for example, lone pair electrons, alkyl, hydroxyalkyl, trihaloalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroalicyclic, halo, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, sulfinyl, sulfonyl, cyano, nitro, azo, sulfonyl, sulfinyl, sulfonamide, phosphonyl, phosphinyl, phosphonium, ketoester, carbonyl, thiocarbonyl, ester, ether, carboxy, thiocarboxy, thioether, thiocarbamate, urea, thiourea, O-carbamyl, N- carbamyl, O-thiocarbamyl, N-thiocarbamyl, N-
  • a "hydroxy” group refers to an -OH group.
  • alkoxy refers to both an -O-alkyl and an -O-cycloalkyl group, as defined herein.
  • aryloxy refers to both an -O-aryl and an -O-heteroaryl group, as defined herein.
  • a "thiohydroxy” group refers to an -SH group.
  • a “thioalkoxy” group refers to both an -S-alkyl group, and an -S-cycloalkyl group, as defined herein.
  • thioaryloxy refers to both an -S-aryl and an -S-heteroaryl group, as defined herein.
  • aldehyde refers to a carbonyl group, where R' is hydrogen.
  • a “carboxylic acid” group refers to a C-carboxyl group in which R" is hydrogen.
  • halo refers to fluorine, chlorine, bromine or iodine.
  • trihalomethyl refers to a -CX group wherein X is a halo group as defined herein.
  • trihalomethanesulfonyl refers to an group wherein X is a halo group as defined herein.
  • a “sulfonyl” group refers to an group, where R" is as defined herein.
  • S-sulfonamido refers to a group, with R' and R"as defined herein.
  • a "trihalomethanesulfonamido” group refers to an X CS ⁇ O ⁇ N - group, where R' and X are as defined herein.
  • An “Amino” group refers to an-NR'R” group where R' and R" are as defined herein.
  • a “nitro” group refers to an -NO2 group.
  • a "cyano" group refers to a -ON group.
  • 'phosphinyl describes a -PR'- group, with R' as defined hereinabove.
  • phosphonium is a -P + R'R", where R' and R" are as defined hereinabove.
  • 'hydrazine?' described a NR'-NR" group, with R and R" as defined hereinabove.
  • carbohydrate describes a molecule that includes a combination of carbons, hydrogens and oxygens.
  • the carbohydrate can be cyclic or linear, saturated or unsaturated and sunstituted and unsubstituted.
  • the substituent can be, for example, lone pair electrons, alkyl, hydroxyalkyl, trihaloalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroalicyclic, halo, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, sulfinyl, sulfonyl, cyano, nitro, azo, sulfonyl, sulfinyl, sulfonamide, phosphonyl, phosphinyl, phosphonium, ketoester, carbonyl, thiocarbonyl, ester, ether, carboxy, thiocarbonyl
  • Candidate compounds matching the above-described general formulae can be retrieved from chemical databases and/or synthesized using methodologies of combinatorial chemistry, well known in the art.

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Abstract

L'invention concerne des méthodes, des compositions ainsi que des méthodes d'identification de composés candidats, permettant de moduler le métabolisme des graisses et/ou d'inhiber l'activité de Apobec-1.
PCT/IL2003/000860 2002-10-23 2003-10-23 Composes, compositions et methodes permettant de moduler le metabolisme des graisses WO2004037159A2 (fr)

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