- Discovery of Highly Potent Liver X Receptor β Agonists
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Introducing a uniquely substituted phenyl sulfone into a series of biphenyl imidazole liver X receptor (LXR) agonists afforded a dramatic potency improvement for induction of ATP binding cassette transporters, ABCA1 and ABCG1, in human whole blood. The ag
- Kick, Ellen K.,Busch, Brett B.,Martin, Richard,Stevens, William C.,Bollu, Venkataiah,Xie, Yinong,Boren, Brant C.,Nyman, Michael C.,Nanao, Max H.,Nguyen, Lam,Plonowski, Artur,Schulman, Ira G.,Yan, Grace,Zhang, Huiping,Hou, Xiaoping,Valente, Meriah N.,Narayanan, Rangaraj,Behnia, Kamelia,Rodrigues, A. David,Brock, Barry,Smalley, James,Cantor, Glenn H.,Lupisella, John,Sleph, Paul,Grimm, Denise,Ostrowski, Jacek,Wexler, Ruth R.,Kirchgessner, Todd,Mohan, Raju
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supporting information
p. 1207 - 1212
(2016/12/18)
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- Discovery of a new 2-aminobenzhydrol template for highly potent squalene synthase inhibitors
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To obtain small and efficient squalene synthase inhibitors, a flexible 2-aminobenzhydrol open form structure was designed and showed potent inhibitory activity comparable to 4,1-benzoxazepin compounds. Further chemical modification led to the discovery of a novel template with a strong squalene synthase inhibitory activity, and its basic structure-activity relationship was revealed. The X-ray crystallographic data of compound 12 bound to the active site of squalene synthase provided an important insight into the binding mode of this alternative template that formed 11-membered ring conformations with an intramolecular hydrogen bond.
- Ichikawa, Masanori,Yokomizo, Aki,Itoh, Masao,Sugita, Kazuyuki,Usui, Hiroyuki,Shimizu, Hironari,Suzuki, Makoto,Terayama, Koji,Kanda, Akira
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experimental part
p. 1930 - 1949
(2011/05/03)
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- Quinolone carboxylic acids as a novel monoketo acid class of human immunodeficiency virus type 1 integrase inhibitors
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Human immunodeficiency virus type 1 (HIV-1) integrase is a crucial target for antiretroviral drugs, and several keto - enol acid class (often referred to as diketo acid class) inhibitors have clinically exhibited-marked antiretroviral activity. Here, we show the synthesis and the detailed structure - activity relationship of the quinolone carboxylic acids as a novel monoketo acid class of integrase inhibitors. 6-(3-Chloro-2-fluorobenzyl)-1-((2S)-1-hydroxy-3,3- dimethylbutan-2-yl)-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid 51, which showed an IC50 of 5.8 nMin the strand transfer assay and an ED50 of 0.6 nMin the antiviral assay, and 6-(3-chloro-2-fluorobenzyl) -1-((2S)-1-hydroxy-3-methylbutan-2-yl)-7-methoxy-4-oxo-1,4-dihydroquinoline-3- carboxylic acid 49, which had an IC50 of 7.2 nMand an ED50 of 0.9 nM, were the most potent compounds in this class. The monoketo acid 49 was much more potent at inhibiting integrasecatalyzed strand transfer processes than 3′-processing reactions, as is the case with the keto - enol acids. Elvitegravir 49 was chosen as a candidate for further studies and is currently in phase 3 clinical trials.
- Sato, Motohide,Kawakami, Hiroshi,Motomura, Takahisa,Aramaki, Hisateru,Matsuda, Takashi,Yamashita, Masaki,Ito, Yoshiharu,Matsuzaki, Yuji,Yamataka, Kazunobu,Ikeda, Satoru,Shinkai, Hisashi
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supporting information; experimental part
p. 4869 - 4882
(2010/03/02)
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