- PYRIMIDINES AND USE THEREOF
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The present disclosure provides pyrimidines of Formula I: and pharmaceutically acceptable salts and solvates thereof, wherein A1, X, A2, G, Y, n, R2a, R2b, and R3 are defined as set forth in the specification. The present disclosure is also directed to the use of compounds of Formula I and the pharmaceutically acceptable salts and solvates thereof to treat a disorder responsive to the blockade of one or more sodium channels. In one embodiment, compounds of the present disclosure are useful for treating pain.
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Page/Page column 61; 62
(2015/07/07)
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- Discovery, synthesis, and optimization of antimalarial 4(1 H)-quinolone-3-diarylethers
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The historical antimalarial compound endochin served as a structural lead for optimization. Endochin-like quinolones (ELQ) were prepared by a novel chemical route and assessed for in vitro activity against multidrug resistant strains of Plasmodium falciparum and against malaria infections in mice. Here we describe the pathway to discovery of a potent class of orally active antimalarial 4(1H)-quinolone-3-diarylethers. The initial prototype, ELQ-233, exhibited low nanomolar IC50 values against all tested strains including clinical isolates harboring resistance to atovaquone. ELQ-271 represented the next critical step in the iterative optimization process, as it was stable to metabolism and highly effective in vivo. Continued analoging revealed that the substitution pattern on the benzenoid ring of the quinolone core significantly influenced reactivity with the host enzyme. This finding led to the rational design of highly selective ELQs with outstanding oral efficacy against murine malaria that is superior to established antimalarials chloroquine and atovaquone.
- Nilsen, Aaron,Miley, Galen P.,Forquer, Isaac P.,Mather, Michael W.,Katneni, Kasiram,Li, Yuexin,Pou, Sovitj,Pershing, April M.,Stickles, Allison M.,Ryan, Eileen,Kelly, Jane Xu,Doggett, J. Stone,White, Karen L.,Hinrichs, David J.,Winter, Rolf W.,Charman, Susan A.,Zakharov, Lev N.,Bathurst, Ian,Burrows, Jeremy N.,Vaidya, Akhil B.,Riscoe, Michael K.
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p. 3818 - 3834
(2014/05/20)
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- TRIAZINE CARBOXAMIDES AS SODIUM CHANNEL BLOCKERS
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The present disclosure provides substituted triazine carboxamides of Formula I: and the pharmaceutically acceptable salts and solvates thereof, wherein A1, X, A2, E, and Z are defined as set forth in the specification. The present di
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Paragraph 0285; 0286
(2014/09/16)
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- HETEROARYL COMPOUNDS AS SODIUM CHANNEL BLOCKERS
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The invention relates to aryl substituted compounds of Formula (I) : and pharmaceutically acceptable salts, prodrugs, or solvates thereof, wherein Het, G, A, R, and n are defined as set forth in the specification. The invention is also directed to the use
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Paragraph 0342; 0343; 0344; 0345
(2013/05/22)
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- PYRIDINE COMPOUNDS AND THE USES THEREOF
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The invention relates to substituted pyridine compounds of Formula (I) and the pharmaceutically acceptable salts, prodrugs, and solvates thereof, wherein R1a, A1, A2, E, G, Z1, and Z2 are defined as set forth in the specification. The invention is also directed to the use of compounds of Formula I to treat a disorder responsive to the blockade of sodium channels. Compounds of the present invention are especially useful for treating pain.
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Page/Page column 246
(2012/04/04)
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- PYRIDINE COMPOUNDS AS SODIUM CHANNEL BLOCKERS
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The invention relates to substituted pyridine compounds of Formula I: (I) or a pharmaceutically acceptable salt, prodrug, or solvate thereof, wherein A1, X, A2, R1a, R1b, R1c, G, and z are defined as
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Page/Page column 117
(2012/02/02)
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