- CARBOXAMIDES AS UBIQUITIN-SPECIFIC PROTEASE INHIBITORS
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The present disclosure relates to modulators, such as inhibitors, of at least one pathway chosen from USP28 and USP25, pharmaceutical compositions comprising the inhibitors, and methods of using the inhibitors. The modulators, such as inhibitors, of at least one pathway chosen from USP28 and USP25 can be useful in the treatment of cancers, among other ailments.
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- Structure-activity relationships of privileged structures lead to the discovery of novel biased ligands at the dopamine D2 receptor
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Biased agonism at GPCRs highlights the potential for the discovery and design of pathway-selective ligands and may confer therapeutic advantages to ligands targeting the dopamine D2 receptor (D2R). We investigated the determinants of efficacy, affinity, and bias for three privileged structures for the D2R, exploring changes to linker length and incorporation of a heterocyclic unit. Profiling the compounds in two signaling assays (cAMP and pERK1/2) allowed us to identify and quantify determinants of biased agonism at the D2R. Substitution on the phenylpiperazine privileged structures (2-methoxy vs 2,3-dichloro) influenced bias when the thienopyridine heterocycle was absent. Upon inclusion of the thienopyridine unit, the substitution pattern (4,6-dimethyl vs 5-chloro-6-methoxy-4-methyl) had a significant effect on bias that overruled the effect of the phenylpiperazine substitution pattern. This latter observation could be reconciled with an extended binding mode for these compounds, whereby the interaction of the heterocycle with a secondary binding pocket may engender bias.
- Szabo, Monika,Klein Herenbrink, Carmen,Christopoulos, Arthur,Lane, J. Robert,Capuano, Ben
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p. 4924 - 4939
(2014/07/07)
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- Synthesis of some new pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidin-4(3H)-ones and pyrido[3′,2′: 4,5]thieno[2,3-e]-1,2,4-triazolo[1,5-c]pyrimidine derivatives
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2,3-Disubstituted-pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidin-4( 3H) -ones 8a-8c, 9a-9c were obtained by treatment of pyrido[3′,2′:4,5]thieno[3,2-d][1,3]oxazin-4(3H)-one derivative 3, 3-diacetylamino-thieno[2,3-b]pyridine derivative 5 and 3-ethoxymethyleneaminothieno[2,3-b]pyridine derivative 7a with appropriate amines, respectively. Condensation of compounds 8b, 9b with appropriate α-chlorocarbonyl compounds gave the corresponding 3-substituted carbonylmethylene-pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidin-4(3H)-one derivatives 13a-d. 3-N-Substituted-pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidin-4(3H)-ones 15a,b, 16a,b and 18a,b were also obtained by cyclization of carbohydrazide 14 with different reagents under a variety of conditions. On the other hand, cyclization of 3-amino-4-imino-pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidin-4(3H)-ones 21a,b with appropriate orthoesters afforded the corresponding 3,5-dialkyl-pyrido[3′,2′:4,5]thieno[2,3-e]-1,2,4-triazolo[1,5-c] pyrimidines 22a-f.
- Ho, Yuh-Wen
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p. 1163 - 1174
(2007/10/03)
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