- Discovery of a Series of 5,11-Dihydro-6H-benzo[e]pyrimido[5,4-b][1,4]diazepin-6-ones as Selective PI3K-δ/γ Inhibitors
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Dual inhibition of PI3K-δ and PI3K-γ is an established therapeutic strategy for treatment of hematological malignancies. Reported molecules targeting PI3K-δ/γ selectively are chemically similar and based upon isoquinolin-1(2H)-one or quinazolin-4(3H)-one scaffolds. Here we report a chemically distinct series of potent, selective PI3K-δ/γ inhibitors based on a 5,11-dihydro-6H-benzo[e]pyrimido[5,4-b][1,4]diazepin-6-one scaffold with comparable biochemical potency and cellular effects on PI3K signaling. We envisage these molecules will provide useful leads for development of next-generation PI3K-δ/γ targeting therapeutics.
- Ferguson, Fleur M.,Ni, Jing,Zhang, Tinghu,Tesar, Bethany,Sim, Taebo,Kim, Nam Doo,Deng, Xianming,Brown, Jennifer R.,Zhao, Jean J.,Gray, Nathanael S.
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supporting information
p. 908 - 912
(2016/10/22)
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- Pyrrole inhibitors of S-nitrosoglutathione reductase as therapeutic agents
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The present invention is directed to inhibitors of S-nitrosoglutathione reductase (GSNOR), pharmaceutical compositions comprising such GSNOR inhibitors, and methods of making and using the same.
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Page/Page column 304
(2015/11/16)
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- Structure-activity relationship of pyrrole based S-nitrosoglutathione reductase inhibitors: Carboxamide modification
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The enzyme S-nitrosoglutathione reductase (GSNOR) is a member of the alcohol dehydrogenase family (ADH) that regulates the levels of S-nitrosothiols (SNOs) through catabolism of S-nitrosoglutathione (GSNO). GSNO and SNOs are implicated in the pathogenesis of many diseases including those in respiratory, gastrointestinal, and cardiovascular systems. The pyrrole based N6022 was recently identified as a potent, selective, reversible, and efficacious GSNOR inhibitor which is currently in clinical development for acute asthma. We describe here the synthesis and structure-activity relationships (SAR) of novel pyrrole based analogs of N6022 focusing on carboxamide modifications on the pendant N-phenyl moiety. We have identified potent and novel GSNOR inhibitors that demonstrate efficacy in an ovalbumin (OVA) induced asthma model in mice.
- Sun, Xicheng,Qiu, Jian,Strong, Sarah A.,Green, Louis S.,Wasley, Jan W.F.,Blonder, Joan P.,Colagiovanni, Dorothy B.,Stout, Adam M.,Mutka, Sarah C.,Richards, Jane P.,Rosenthal, Gary J.
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supporting information; experimental part
p. 2338 - 2342
(2012/04/18)
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- BENZOPHENONES AS INHIBITORS OF REVERSE TRANSCRIPTASE
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The present invention includes benzophenone compounds (I) which are useful in the treatment of HIV infections.
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Page/Page column 8; 21
(2010/11/08)
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- Process for preparing reverse transcriptase inhibitors
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The present invention is directed to processes for the synthesis of intermediates useful in the preparation of non-nucleoside reverse transcriptase inhibitors.
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Page/Page column 4
(2008/06/13)
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- Novel Benzophenones as Non-nucleoside Reverse Transcriptase Inhibitors of HIV-1
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GW4511, GW4751, and GW3011 showed IC50 values ≤2 nM against wild type HIV-1 and 10 nM against 16 mutants. They were particularly potent against NNRTI-resistant viruses containing Y181C-, K103N-, and K103N-based double mutations, which account for a significant proportion of the clinical failure of the three currently marketed NNRTIs. The antiviral data together with the favorable pharmacokinetic data of GW4511 suggested that these benzophenones possess attributes of a new NNRTI drug candidate.
- Chan, Joseph H.,Freeman, George A.,Tidwell, Jeffrey H.,Romines, Karen R.,Schaller, Lee T.,Cowan, Jill R.,Gonzales, Steve S.,Lowell, Gina S.,Andrews III,Reynolds, David J.,St. Clair, Marty,Hazen, Richard J.,Ferris, Rob G.,Creech, Katrina L.,Roberts, Grace B.,Short, Steven A.,Weaver, Kurt,Koszalka, George W.,Boone, Lawrence R.
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p. 1175 - 1182
(2007/10/03)
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