- Compounds and methods of use
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Compounds are provided according to Formula (I): and pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof; wherein X1, X2, X3, X4, Y, A, L1, L2, R1, R2, R5, m and n are as defined herein. Compounds of the present invention are contemplated useful for the prevention and treatment of a variety of conditions.
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- Fragment-based Scaffold Hopping: Identification of Potent, Selective, and Highly Soluble Bromo and Extra Terminal Domain (BET) Second Bromodomain (BD2) Inhibitors
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The profound efficacy of pan-BET inhibitors is well documented, but these epigenetic agents have shown pharmacology-driven toxicity in oncology clinical trials. The opportunity to identify inhibitors with an improved safety profile by selective targeting of a subset of the eight bromodomains of the BET family has triggered extensive medicinal chemistry efforts. In this article, we disclose the identification of potent and selective drug-like pan-BD2 inhibitors such as pyrazole 23 (GSK809) and furan 24 (GSK743) that were derived from the pyrrole fragment 6. We transpose the key learnings from a previous pyridone series (GSK620 2 as a representative example) to this novel class of inhibitors, which are characterized by significantly improved solubility relative to our previous research.
- Seal, Jonathan T.,Atkinson, Stephen J.,Bamborough, Paul,Bassil, Anna,Chung, Chun-Wa,Foley, James,Gordon, Laurie,Grandi, Paola,Gray, James R. J.,Harrison, Lee A.,Kruger, Ryan G.,Matteo, Jeanne J.,McCabe, Michael T.,Messenger, Cassie,Mitchell, Darren,Phillipou, Alex,Preston, Alex,Prinjha, Rab K.,Rianjongdee, Francesco,Rioja, Inmaculada,Taylor, Simon,Wall, Ian D.,Watson, Robert J.,Woolven, James M.,Wyce, Anastasia,Zhang, Xi-Ping,Demont, Emmanuel H.
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p. 10772 - 10805
(2021/07/31)
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- BENZIMIDAZOLYL-METHYL UREA DERIVATIVES AS ALX RECEPTOR AGONISTS
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The present invention relates to benzimidazolyl-methyl urea derivatives of formula (I), wherein n, D, E, R1, R2, R3, R4, R6, R7, R8 and R9 are as defined in the description, their preparation and their use as pharmaceutically active compounds.
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Page/Page column 106
(2015/02/25)
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- TRI-SUBSTITUTED PYRIMIDINE COMPOUNDS AND THEIR USE AS PDE10 INHIBITORS
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The present invention provides a tri-substituted pyrimidine compound having an excellent PDE10 inhibitory activity. The present invention relates to a tri-substituted pyrimidine compound represented by the following formula [I0] or a pharmaceutically acceptable salt thereof, a method for preparing the same, and use of said compound for PDE10 inhibitor, and a pharmaceutical composition comprising said compounds as an active ingredient: wherein: either one of X1 and X2 is N, and the other of X1 and X2 is CH; A is *-CH═CH—, *-C(Alk)=CH—, *-CH2—CH2— or *-O—CH2— (* is a bond with R1); Alk is a lower alkyl group; Ring B is an optionally substituted nitrogen-containing aliphatic heterocyclic group; R1 is an optionally substituted quinoxalinyl or an optionally substituted quinolyl; Y0 is mono- or di-substituted amino group, or a pharmaceutically acceptable salt thereof.
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- BRADYKININ 1 RECEPTOR ANTAGONISTS
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The invention encompasses novel compounds and pharmaceutically acceptable derivatives thereof, pharmaceutical compositions and methods for treatment of diseases mediated by B1 bradykinin receptor.
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Page/Page column 63
(2008/06/13)
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