- Thiophene-Pyrazolourea Derivatives as Potent, Orally Bioavailable, and Isoform-Selective JNK3 Inhibitors
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Potent JNK3 isoform selective inhibitors were developed from a thiophenyl-pyrazolourea scaffold. Through structure activity relationship (SAR) studies utilizing enzymatic and cell-based assays, and in vitro and in vivo drug metabolism and pharmacokinetic (DMPK) studies, potent and highly selective JNK3 inhibitors with oral bioavailability and brain penetrant capability were developed. Inhibitor 17 was a potent and isoform selective JNK3 inhibitor (IC50 = 35 nM), had significant inhibition to only JNK3 in a panel profiling of 374 wild-type kinases, had high potency in functional cell-based assays, had high stability in human liver microsome (t1/2 = 66 min) and a clean CYP-450 inhibition profile, and was orally bioavailable and brain penetrant. Moreover, cocrystal structures of compounds 17 and 27 in human JNK3 were solved at 1.84 ?, which showed that these JNK3 isoform selective inhibitors bound to the ATP pocket, had interactions in both hydrophobic pocket-I and hydrophobic pocket-II.
- Feng, Yangbo,Park, Hajeung,Bauer, Luke,Ryu, Jae Cheon,Yoon, Sung Ok
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- Total synthesis of dimethyl sulfomycinamate
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Dimethyl sulfomycinamate (1), a methanolysis product from the natural antibiotic sulfomycin I, is synthesized in 11 steps. The chemistry of various pyridine, thiazole, and oxazole heterocycles and their coupling reactions under palladium catalysis are examined. The key transformations in the synthesis are the selective palladium-catalyzed coupling reactions on doubly activated pyridine 62 and the condensation reaction between bromo ketone 69 and amide 28 to form the oxazole moiety 76. The first preparation of oxazole triflates is described, as are some of their chemical properties.
- Kelly, T. Ross,Lang, Fengrui
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p. 4623 - 4633
(2007/10/03)
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- Total synthesis of dimethyl sulfomycinamate
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The first total synthesis of dimethyl sulfomycinamate (1) is described. Highlights of the synthesis include a selective palladium-catalyzed coupling reaction on the bromotriflate 21, and a condensation reaction to form the oxazole ring.
- Ross Kelly,Lang, Fengrui
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p. 5319 - 5322
(2007/10/02)
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