- Discovery and structural modification of 1-phenyl-3-(1-phenylethyl)urea derivatives as inhibitors of complement
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A series of 1-phenyl-3-(1-phenylethyl)urea derivatives were identified as novel and potent complement inhibitors through structural modification of the original compound from high-throughput screening. Various analogues (7 and 13-15) were synthesized and identified as complement inhibitors, with the introduction of a five- or six-carbon chain (7c, 7d, 7k, 7l, and 7o) greatly improving their activity. Optimized compound 7l has an excellent inhibition activity with IC50 values as low as 13 nM. We demonstrated that the compound 7l inhibited C9 deposition through the classical, the lectin, and the alternative pathways but had no influence on C3 and C4 depositions.
- Zhang, Mei,Yang, Xiao-Ying,Tang, Wei,Groeneveld, Tom W. L.,He, Pei-Lan,Zhu, Feng-Hua,Li, Jia,Lu, Wei,Blom, Anna M.,Zuo, Jian-Ping,Nan, Fa-Jun
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supporting information; experimental part
p. 317 - 321
(2012/05/20)
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- 7[4′-trifluoromethyl-biphenyl-2-carbonyl)amino]-quinoline-3-carboxylic acid amides, and method of inhibiting the secretion of apolipoprotein B
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This invention relates to compounds of Formula I that inhibit the secretion of apolipoprotein B, to pharmaceutical compositions comprising the compounds, and to methods of treating and/or preventing atherosclerosis, obesity, diabetes, hyperlipidemia, hyperliproproteinemia, hypercholesterolemia, hypertriglyceridemia, hypoalphalipoproteinemia, pancreatitis, myocardial infarction, stroke, restenosis, or Syndrome X. This invention also relates to methods of reducing the secretion of apolipoprotein B and/or inhibiting microsomal triglyceride transfer protein.
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- Cyclic Nucleotide Phosphodiesterase Inhibition by Imidazopyridines: Analogues of Sulmazole and Isomazole as Inhibitors of the cGMP Specific Phosphodiesterase
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The synthesis and phosphodiesterase (PDE) inhibitory profile of a series of imidazopyridines, including sulmazole and isomazole, on separated PDE isoenzymes are described.The results show that both sulmazole and isomazole are weak inhibitors of PDE III, and their inotropic activity is unlikely to be due to PDE III inhibition alone.Surprisingly, both compounds were found to be significant inhibitors of the cGMP specific isoenzyme, PDE V, and a series of simple 2-substituted phenylimidazopyridines have been made to investigate the SAR of PDE activity.This has been shown to be sensitive to chain length, polarity, and the nature of the heteroatom linking group.Potent PDE V inhibitors, many of which are also significant inhibitors of PDE IV, have been identified.
- Coates, William J.,Connolly, Brendan,Dhanak, Dashyant,Flynn, Sean T.,Worby, Angela
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p. 1387 - 1392
(2007/10/02)
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- New potent antagonists of leukotrienes C4 and D4. 1. Synthesis and structure-activity relationships
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(p-Amylcinnamoyl)anthranilic acid (3a) had moderate antagonist activities against LTD4-induced smooth muscle contraction on guinea pig ileum and LTC4-induced bronchoconstriction in anesthetized guinea pigs. Modifications were made in the hydrophobic part (cinnamoyl moiety) and the hydrophilic part (anthranilate moiety) of 3a. A series of 8-(benzoylamino)-2-tetrazol-5-yl-1,4-benzodioxans and 8-(benzoylamino)-2-tetrazol-5-yl-4-oxo-4H-1-benzopyrans were revealed to be potent antagonists of leukotrienes C4 and D4. Among both series, ONO-RS-347 (18k) and ONO-RS411 (19h) were the most potent and orally active antagonists, respectively. Structure-activity relationships are discussed.
- Nakai,Konno,Kosuge,Sakuyama,Toda,Arai,Obata,Katsube,Miyamoto,Okegawa,Kawasaki
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