- Discovery of Potent Non-Nucleoside Inhibitors of Dengue Viral RNA-Dependent RNA Polymerase from a Fragment Hit Using Structure-Based Drug Design
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The discovery and optimization of non-nucleoside dengue viral RNA-dependent-RNA polymerase (RdRp) inhibitors are described. An X-ray-based fragment screen of Novartis fragment collection resulted in the identification of a biphenyl acetic acid fragment 3, which bound in the palm subdomain of RdRp. Subsequent optimization of the fragment hit 3, relying on structure-based design, resulted in a >1000-fold improvement in potency in vitro and acquired antidengue activity against all four serotypes with low micromolar EC50 in cell-based assays. The lead candidate 27 interacts with a novel binding pocket in the palm subdomain of the RdRp and exerts a promising activity against all clinically relevant dengue serotypes.
- Yokokawa, Fumiaki,Nilar, Shahul,Noble, Christian G.,Lim, Siew Pheng,Rao, Ranga,Tania, Stefani,Wang, Gang,Lee, Gladys,Hunziker, Jürg,Karuna, Ratna,Manjunatha, Ujjini,Shi, Pei-Yong,Smith, Paul W.
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p. 3935 - 3952
(2016/05/19)
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- LONG CHAIN BASE SPHINGOSINE KINASE INHIBITORS
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The invention relates to inhibitors of sphingosine kinase enzymatic activity, compounds and pharmaceutical compositions that inhibit sphingosine kinase 1 and sphingosine kinase 2 (SphK1 and SphK2) enzymes and further relates to methods of treating diseases and disorders mediated by sphingosine 1 phosphate activity, comprising administering an effective amount of sphingosine kinase inhibitors.
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Paragraph 0311; 0204
(2013/08/28)
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- PHARMACEUTICAL COMPOUNDS
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The invention provides a compound for use in medicine, the compound being a compound of the formula (VI0) or a salt, solvate, tautomer or N-oxide thereof: wherein the bicyclic group: is selected from the structures C1, C5 and C6: wherein n is 0, 1, 2 or 3; R1 is hydrogen, hydroxy, or O—Rz; R2a is hydroxy, methoxy or O—Rz; provided that at least one of R1 and R2a is O—Rz; Rz is Lp-Rp1; SO3H; a glucuronide residue; a mono-, di- or tripeptide residue; or Lp is a bond, C═O, (C═O)O, (C═O)NRp1 or S(O)xNRp1; x is 1 or 2; Rp1 is hydrogen or a an optionally substituted C1-25 hydrocarbyl group containing 0, 1 or 2 carbocyclic rings and 0, 1, 2, 3, 4, 5 or 6 carbon-carbon multiple bonds, provided that Rp1 is not hydrogen when Lp is a bond, C═O or (C═O)O; and provided also that O—Rz does not contain an O—O moiety; and excluding compounds wherein R1 is hydroxy and R2a is methoxy; Rp2 and Rp3 are the same or different and each is a group Rp1; and R3, R4a, R8 and R10 are defined in the claims. The compounds of formula (VI0) are pro-drugs of parent compounds wherein R1 and/or R2a are hydroxy, wherein the parent compounds have Hsp90 inhibiting activity.
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Page/Page column 100
(2010/06/22)
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- A new method for halogenation of aromatic compounds by using dimethyldioxirane and tetrabutylammonium halides
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In this presentation the novel regioselective halogenation of arenes or phenols with dimethyldioxirane and Bu4NX is described. The results showed that a new, versatile and mild method can be utilized for preparation of aryl halides starting with arenes or phenols. Finally, this aryl halide forming methodology is applicable to structurally more complex flavonoids.
- Lee, Yean-Jang,Wu, Huan-Ting,Lin, Chia-Ning
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experimental part
p. 585 - 587
(2010/04/23)
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- METHOD FOR PRODUCING 4-OXOQUINOLINE COMPOUND
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The present invention provides a compound useful as a synthetic intermediate for an anti-HIV agent having an integrase inhibitory activity, and a production method thereof, and a production method of an anti-HIV agent using the synthetic intermediate. Spe
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Page/Page column 79-80
(2008/12/09)
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- PHARMACEUTICAL COMBINATIONS
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The invention provides combinations comprising (or consisting essentially of) one or more ancillary compound(s) and a compound of the formula (I): or salts, tautomers, solvates and N-oxides thereof; wherein R1 is hydroxy or hydrogen; R2 is hydroxy; methoxy or hydrogen; provided that at least one of R1 and R2 is hydroxy; R3 is selected from hydrogen; halogen; cyano; optionally substituted C1-5 hydrocarbyl and optionally substituted C1- 5 hydrocarbyloxy; R4 is selected from hydrogen; a group -(O)n-R7 where n is 0 or 1 and R7 is an optionally substituted acyclic C1-5 hydrocarbyl group or a monocyclic carbocyclic or heterocyclic group having 3 to 7 ring members; halogen; cyano; hydroxy; amino; and optionally substituted mono- or di-C1-5 hydrocarbyl-amino; or R3 and R4 together form a monocyclic carbocyclic or heterocyclic ring of 5 to 7 ring members; and NR5R6 forms an optionally substituted bicyclic heterocyclic group having 8 to 12 ring members of which up to 5 ring members are heteroatoms selected from oxygen, nitrogen and sulphur. The combinations have activity as Hsp90 inhibitors.
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Page/Page column 239
(2008/06/13)
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- PHARMACEUTICAL COMBINATIONS
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The invention provides combinations comprising (or consisting essentially of) one or more ancillary compound(s) and a compound of the formula (I): or salts, tautomers, solvates and N-oxides thereof; wherein R1 is hydroxy or hydrogen; R2 is hydroxy; methoxy or hydrogen; provided that at least one of R1 and R2 is hydroxy; R3 is selected from hydrogen; halogen; cyano; optionally substituted C1-5 hydrocarbyl and optionally substituted C1-5 hydrocarbyloxy; R4 is selected from hydrogen; a group -(O)n-R7 where n is 0 or 1 and R7 is an optionally substituted acyclic C1-5 hydrocarbyl group or a monocyclic carbocyclic or heterocyclic group having 3 to 7 ring members; halogen; cyano; hydroxy; amino; and optionally substituted mono- or di-C1-5 hydrocarbyl-amino; or R3 and R4 together form a monocyclic carbocyclic or heterocyclic ring of 5 to 7 ring members; and NR5R6 forms an optionally substituted bicyclic heterocyclic group having 8 to 12 ring members of which up to 5 ring members are heteroatoms selected from oxygen, nitrogen and sulphur. The combinations have activity as Hsp90 and/or glycogen synthase kinase-3 and/or cyclin dependent kinase inhibitors.
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Page/Page column 261
(2008/06/13)
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- PHARMACEUTICAL COMBINATIONS
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The invention provides combinations comprising (or consisting essentially of) one or more ancillary compound(s) and a compound of the formula (I): or salts, tautomers, solvates and N-oxides thereof; wherein R1 is hydroxy or hydrogen; R2 is hydroxy; methoxy or hydrogen; provided that at least one of R1 and R2 is hydroxy; R3 is selected from hydrogen; halogen; cyano; optionally substituted C1-5 hydrocarbyl and optionally substituted C1-5 hydrocarbyloxy; R4 is selected from hydrogen; a group -(O)n-R7 where n is 0 or 1 and R7 is an optionally substituted acyclic C1-5 hydrocarbyl group or a monocyclic carbocyclic or heterocyclic group having 3 to 7 ring members; halogen; cyano; hydroxy; amino; and optionally substituted mono- or di-C1-5 hydrocarbyl-amino; or R3 and R4 together form a monocyclic carbocyclic or heterocyclic ring of 5 to 7 ring members; and NR5R6 forms an optionally substituted bicyclic heterocyclic group having 8 to 12 ring members of which up to 5 ring members are heteroatoms selected from oxygen, nitrogen and sulphur. The combinations have activity as Hsp90 and/or glycogen synthase kinase-3 and/or cyclin dependent kinase and/or aurora kinase inhibitors.
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Page/Page column 314
(2008/06/13)
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- PHARMACEUTICAL COMPOUNDS
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The invention provides the use of a compound for the manufacture of a medicament for the treatment of pain, wherein the compound is a compound of the formula (Vl): or a salt, solvate, tautomer or N-oxide thereof; wherein the bicydic group: is selected from the structures C1, C5 and C6: wherein n, R1, R2a, R3, R4a, R8 and R10 are as defined in the claims. The invention also provides the use of a compound of the formula (Vl) for the manufacture of a medicament for the prophylaxis or treatment of a fungal, protozoal, viral or parasitic disease state or condition (other than a disease state or condition due to Plasmodium falciparum) or for use in the prophylaxis or treatment of Ewing's sarcoma, atherosclerosis or lupus erythematosus
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Page/Page column 158
(2008/06/13)
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- N-(3-pyrrolidinyl) benzamide derivative
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N-(3-Pyrrodinyl)benzamide derivatives represented by the following general formula (I) which have potent and selective antagonism against dopamine D3 and/or D4 receptor and are useful as a psychotropic, a schizophrenia-treating agent and the like, or a pharmaceutically acceptable salt thereof or a pharmaceutical preparation thereof. STR1
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