- Aiming to Miss a Moving Target: Bromo and Extra Terminal Domain (BET) Selectivity in Constrained ATAD2 Inhibitors
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ATAD2 is a cancer-associated protein whose bromodomain has been described as among the least druggable of its class. In our recent disclosure of the first chemical probe against this bromodomain, GSK8814 (6), we described the use of a conformationally constrained methoxy piperidine to gain selectivity over the BET bromodomains. Here we describe an orthogonal conformational restriction strategy of the piperidine ring to give potent and selective tropane inhibitors and show structural insights into why this was more challenging than expected. Greater understanding of why different rational approaches succeeded or failed should help in the future design of selectivity in the bromodomain family.
- Bamborough, Paul,Chung, Chun-Wa,Furze, Rebecca C.,Grandi, Paola,Michon, Anne-Marie,Watson, Robert J.,Mitchell, Darren J.,Barnett, Heather,Prinjha, Rab K.,Rau, Christina,Sheppard, Robert J.,Werner, Thilo,Demont, Emmanuel H.
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p. 8321 - 8336
(2018/09/27)
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- Dihydropyrrolopyridine inhibitors of ROR-gamma
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Provided are novel compounds of Formula (I): pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, which are useful in the treatment of diseases and disorders mediated by RORγ. Also provided are pharmaceutical compositions co
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Page/Page column 31; 32
(2016/11/21)
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- ARGININE METHYLTRANSFERASE INHIBITORS AND USES THEREOF
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Described herein are compounds of Formula (S-I), pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof. Compounds described herein are useful for inhibiting arginine methyltransferase activity. Methods of using the compounds for treating arginine methyltransferase-mediated disorders are also described.
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Paragraph 00485
(2016/04/20)
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- DIHYDROPYRROLOPYRIDINE INHIBITORS OF ROR-GAMMA
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Provided are novel compounds of Formula (I): pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, which are useful in the treatment of diseases and disorders mediated by RORy. Also provided are pharmaceutical compositions co
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Paragraph 00106
(2016/05/24)
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- EP1 RECEPTOR LIGANDS
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The present invention belongs to the field of EP1 receptor ligands. More specifically it refers to compounds of general formula (I) having great affinity and selectivity for the EP1 receptor. The invention also refers to the process for their preparation, to their use as medicament for the treatment and/or prophylaxis of diseases or disorders mediated by the EP1 receptor as well as to pharmaceutical compositions comprising them.
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Page/Page column 76
(2013/03/28)
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- AZAINDOLE GLUCOKINASE ACTIVATORS
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Provided herein are compounds of the formula (I): as well as pharmaceutically acceptable salts thereof, wherein the substituents are as those disclosed in the specification. These compounds, and the pharmaceutical compositions containing them, are useful for the treatment of metabolic diseases and disorders such as, for example, type II diabetes mellitus.
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Page/Page column 54-55
(2011/06/26)
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- Compounds Which Selectively Modulate The CB2 Receptor
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Compounds of formula (I) are disclosed. Compounds according to the invention bind to and are agonists, antagonists or inverse agonists of the CB2 receptor, and are useful for treating inflammation. Those compounds which are agonists are additionally useful for treating pain.
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Page/Page column 17-18
(2011/04/18)
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- TETRAZOLE COMPOUNDS WHICH SELECTIVELY MODULATE THE CB2 RECEPTOR
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Compounds of formula (I) are disclosed. Compounds according to the invention bind to and are agonists, antagonists or inverse agonists of the CB2 receptor, and are useful for treating inflammation. Those compounds which are agonists are additionally usefu
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Page/Page column 28
(2011/10/03)
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- PURINE DERIVATIVES AS IMMUNOMODULATORS
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The present invention includes novel compounds useful in the treatment of various disorders in particular infectious diseases, cancer, and allergic diseases and other inflammatory conditions for example allergic rhinitis and asthma, and as vaccine adjuvants
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Page/Page column 70
(2008/12/08)
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- Synthesis of bicyclic tertiary α-amino acids
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Novel bicyclic α-amino acids, exo and endo-1-azabicyclo-[2.2.1] heptane-2-carboxylic acid, 1-azabicyclo[2.2.1]heptane-7-carboxylic acid, and 1-azabicyclo[3.2.2]nonane-2-carboxylic acid have been readily synthesized for the generation of neuronal nicotinic receptor ligands. Alkylation of glycine-derived Schiff bases or nitroacetates with cyclic ether electrophiles, followed by acid-induced ring opening and cyclization in NH4OH, allowed for the preparation of substantial quantities of the three tertiary bicyclic α-amino acids.
- Strachan, Jon-Paul,Whitaker, Regina C.,Miller, Craig H.,Bhatti, Balwinder S.
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p. 9909 - 9911
(2007/10/03)
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- 3-CYCLOALKYLCARBONYL INDOLES AS CANNABINOID RECEPTOR LIGANDS
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The present invention provides novel compounds of Formula (I), which are CB2 selective ligands useful for the treatment of pain.
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Page/Page column 39
(2008/06/13)
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- New high affinity H3 receptor agonists without a basic side chain
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In this study, we replaced the basic amine function of the known histamine H3 receptor agonists imbutamine or immepip with non-basic alcohol or hydrocarbon moieties. All compounds in this study show a moderate to high affinity for the cloned human H3 receptor and, unexpectedly, almost all of them act as potent agonists. Moreover, in the alcohol series, we consistently observed an increased selectivity for the human H3 receptor over the human H4 receptor, but none of the compounds in this series possess increased affinity and functional activity compared to their alkylamine congeners. In this new series of compounds VUF5657, 5-(1H-imidazol-4-yl)-pentan-1-ol, is the most potent histamine H3 receptor agonist (pKi = 8.0 and pEC50 = 8.1) with a 320-fold selectivity at the human H3 receptor over the human H 4 receptor.
- Kitbunnadaj, Ruengwit,Hoffmann, Marcel,Fratantoni, Silvina A.,Bongers, Gerold,Bakker, Remko A.,Wieland, Kerstin,El Jilali, Ahmed,De Esch, Iwan J. P.,Menge, Wiro M. P. B.,Timmerman, Henk,Leurs, Rob
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p. 6309 - 6323
(2007/10/03)
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- Pharmaceutical compositions and methods for effecting dopamine release
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Patients susceptible to or suffering from disorders, such as central nervous system disorders, which are characterized by an alteration in normal neurotransmitter release, such as dopamine release (e.g., Parkinsonism, Parkinson's Disease, Tourette's Syndrome, attention deficient disorder, or schizophrenia), are treated by administering a 1-aza-2-(3-pyridyl)bicyclo[2.2.1]heptane, a 1-aza-2-(3-pyridyl)bicyclo[2.2.2]octane, a 1-aza-2-(3-pyridyl)bicyclo[3.2.1]octane, a 1-aza-2-(3-pyridyl)bicyclo[3.2.2]nonane, a 1-aza-7-(3-pyridyl) bicyclo[2.2.1]heptane, a 1-aza-3-(3-pyridyl)bicyclo[3.2.2]nonane, or a 1-aza-7-(3-pyridyl)bicyclo[3.2.2]nonane. The compounds can exist as individual stereoisomers, racemic mixtures, diastereomers and the like.
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- BENZIMIDAZOLE DERIVATIVES
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This invention relates to the compounds represented by a general formula [I]: ???[in which A1 and A2 represent optionally fluorine-substituted methine or the like; B represents halogen, cyano, lower alkyl or the like; D represents optionally substituted heterocyclic group or the like; and G represents C3-C20 aliphatic group such as alicyclic group]. These compounds inhibit nociceptin activities due to their high affinity to nociceptin receptor, and are useful as analgesic, antiobestic, corebral function improver, drugs for treatment of alzheimer's disease and dementia, remedies for schizophrenia and neurodegenerative diseases, antidepressant, remedies for diabetes insipidus, polyuria, hypotension and so on.
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