- Discovery of Isoxazole Amides as Potent and Selective SMYD3 Inhibitors
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We report herein the discovery of isoxazole amides as potent and selective SET and MYND Domain-Containing Protein 3 (SMYD3) inhibitors. Elucidation of the structure-activity relationship of the high-throughput screening (HTS) lead compound 1 provided potent and selective SMYD3 inhibitors. The SAR optimization, cocrystal structures of small molecules with SMYD3, and mode of inhibition (MOI) characterization of compounds are described. The synthesis and biological and pharmacokinetic profiles of compounds are also presented.
- Blackledge, Chuck W.,Bonnette, William,Burgess, Joelle,Carson, Jeffrey D.,Creasy, Caretha L.,Elkins, Patricia,Graves, Alan P.,Heerding, Dirk A.,Knapp-Reed, Beth,Kruger, Ryan,Luengo, Juan,McHugh, Charles,Mohammad, Helai,Nagarajan, Raman,Pappalardi, Melissa Baker,Qu, Junya,Reif, Alexander,Schulz, Mark,Stern, Melissa,Su, Dai-Shi,Wang, Liping,Wong, Kristen,Yu, Hongyi,Zeng, Jenny
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- Substituted imidazo[1,2-b]pyridazines as protein kinase inhibitors
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The present invention provides protein kinase having one of the following structures (I), (II) or (III): or a stereoisomer, prodrug, tautomer or pharmaceutically acceptable salt thereof, wherein R, R1, R2 and X are as defined herein. Compositions and methods for using the same in the treatment of cancer, autoimmune, inflammatory and other Pim kinase-associated conditions are also disclosed.
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- HETEROCYCLIC PROTEIN KINASE INHIBITORS
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The present invention provides protein kinase having one of the following structures (I), (II) or (III): or a stereoisomer, prodrug, tautomer or pharmaceutically acceptable salt thereof, wherein R, R1, R2 and X are as defined herein. Compositions and methods for using the same in the treatment of cancer, autoimmune, inflammatory and other Pim kinase-associated conditions are also disclosed.
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- Novel Compounds for the Treatment of Diseases Associated with Amyloid or Amyloid-Like Proteins
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The present invention relates to novel compounds that can be employed in the treatment of a group of disorders and abnormalities associated with amyloid protein, such as Alzheimer's disease, and of diseases or conditions associated with amyloid-like proteins. The compounds of the present invention can also be used in the treatment of ocular diseases associated with pathological abnormalities/changes in the tissues of the visual system. The present invention further relates to pharmaceutical compositions comprising these compounds and to the use of these compounds for the preparation of medicaments for treating or preventing diseases or conditions associated with amyloid and/or amyloid-like proteins. A method of treating or preventing diseases or conditions associated with amyloid and/or amyloid-like proteins is also disclosed.
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Page/Page column 62
(2011/11/30)
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- Tetrahydroindole and Tetrahydroindazole Derivatives
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The invention provides indole and indazole compounds of Formula (I) or pharmaceutically acceptable salts thereof which are useful for treating and/or preventing diseases and/or disorders ameliorated by the inhibition of Heat-Shock Protein 90. The invention further provides pharmaceutical compositions comprising compounds of Formula (I) and methods of preparing compounds of Formula (I).
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Page/Page column 33
(2008/12/04)
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- 11β-HYDROXYSTEROID DEHYDROGENASE TYPE 1 ACTIVE COMPOUNDS
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A novel class of compounds of the general formula (I), their use in therapy, pharmaceutical compositions comprising the compounds, as well as their use in the manufacture of medicaments are described. The present compounds modulate the activity of 11β-hydroxy-steroid dehydrogenase type 1 (11βHSD1) and are accordingly useful in the treatment of diseases in which such a modulation is beneficial, e.g. the metabolic syndrome.
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Page/Page column 61
(2008/06/13)
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- IMPROVED PROCESS FOR THE PREPARATION OF BIOLOGICALLY ACTIVE TETRAHYDROBENZTHIAZOLE DERIVATIVE
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Improved process for the preparation of the intermediate compound of formula II for formation pramipezole of formula (I) as well as the biological active tetrahydrobenzothiazole compound of formula (I) and/or its pharmaceutically acceptable salts or solvates.
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Page/Page column 10; 15
(2008/06/13)
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- Arylsulphonyl substituted-tetrahydro- and hexahydro-carbazoles
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The invention provides compounds of formula I for use in treating conditions in which 5-HT6 receptors are involved such as in anxiety, depression, schizophrenia, Alzheimer's disease, stress-related disease, panic, a phobia, obsessive compulsive disorder, obesity, post-traumatic stress syndrome, epilepsy, and other CNS disorders.
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- Medicaments 1,2,3,4-tetrahydrocarbazoles and 5-HT1 agonist use thereof
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Use of a compound of general formula (I): STR1 wherein R1 represents hydrogen, halogen, trifluoromethyl, nitro, hydroxy, C1-6 alkyl, C1-6 alkoxy, arylC1-6 alkoxy, --CO2 R4, --(CH2)n CN, --(CH2)n CONR5 R6, --(CH2)n SO2 NR5 R6, C1-6 alkanoylamino(CH2)n, or C1-6 alkylsulphonylamino(CH2)n ; R4 represents hydrogen, C1-6 alkyl or arylC1-6 alkyl; R5 and R6 each independently represent hydrogen or C1-6 alkyl, or R5 and R6 together with the nitrogen atom to which they are attached form a ring; n represents 0, 1 or 2; and R2 and R3 each independently represent hydrogen, C1-6 alkyl or benzyl or together with the nitrogen atom to which they are attached form a pyrrolidino, piperidino or hexahydroazepino ring; or a physiologically acceptable salt thereof, in the manufacture of a medicament for the treatment of a condition where a 5-HT1 -like agonist is indicated, for example migraine. Novel compounds of formula (I), processes for preparing them and pharmaceutical compositions containing them are also described.
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- Tetrahydrocarbazole derivatives for the manufacture of a medicament for the treatment of a disease where a 5-HT1-like agonist is indicated
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Use of a compound of general formula (I): wherein : R1represents hydrogen, halogen, trifluoromethyl, nitro, hydroxy, C1 6alkyl, C1 6alkoxy, arylC1 6alkoxy, -CO2R4, -(CH2)nCN, -(CH2)nCONR5R6,-(CH2)nSO2NR5R6,C1 6alkanoylamino(CH2)n, or C1 6alkylsulphonylamino (CH2)n; R4represents hydrogen, C1 6alkyl or arylC1 6alkyl; R5 and R6each independently represent hydrogen or C1 6alkyl, or R5 and R6 together with the nitrogen atom to which they are attached form a ring; nrepresents 0, 1 or 2; and R2 and R3each independently represent hydrogen, C1 6alkyl or benzyl or together with the nitrogen atom to which they are attached form a pyrrolidino, piperidino or hexahydroazepino ring; or a physiologically acceptable salt thereof, in the manufacture of a medicament for the treatment of a condition where a 5-HT1-like agonist is indicated, for example migraine. Novel compounds of formula (I), processes for preparing them and pharmaceutical compositions containing them are also described.
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- Tetrahydro-benzthiazoles, the preparation thereof and their use as intermediate products or as pharmaceuticals
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This invention relates to new tetrahydrobenzthiazoles of general formula STR1 wherein R1 represents a hydrogen atom, an alkyl group, an alkenyl or alkynylk group, an alkanoyl group, a phenyl alkyl or phenyl alkanoyl group, while the above mentioned phenyl nuclei may each be substituted by 1 or 2 halogen atoms, R2 represents a hydrogen atom or an alkyl group, R3 represents a hydrogen atom, an alkyl group a cycloalkyl group, an alkenyl or alkynyl group, an alkanoyl group, a phenyl alkyl or phenyl alkanoyl group, while the phenyl nucleus may be substituted by flurorine, chlorine or bromine atoms, R4 represents a hydrogen atom, an alkyl group, an alkyl or alkenyl group, or R3 and R4 together with the nitrogen atom between them represent a pyrrolidino, piperidino, hexamethyleneimino or morpholino group, the enantiomers and the acid addition salts thereof. The compounds of general formula I above in which one of the groups R1 or R3 or both groups R1 and R3 represent an acyl group are valuable intermediate products for preparing the other compounds of general formula I which have valuable pharmacological properties. The new compounds may be prepared using methods known per se.
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