- Boronic acid-containing aminopyridine- and aminopyrimidinecarboxamide CXCR1/2 antagonists: Optimization of aqueous solubility and oral bioavailability
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Abstract The chemokine receptors CXCR1 and CXCR2 are important pharmaceutical targets due to their key roles in inflammatory diseases and cancer progression. We have previously identified 2-[5-(4-fluoro-phenylcarbamoyl)-pyridin-2-ylsulfanylmethyl]-phenylboronic acid (SX-517) and 6-(2-boronic acid-5-trifluoromethoxy-benzylsulfanyl)-N-(4-fluoro-phenyl)-nicotinamide (SX-576) as potent non-competitive boronic acid-containing CXCR1/2 antagonists. Herein we report the synthesis and evaluation of aminopyridine and aminopyrimidine analogs of SX-517 and SX-576, identifying (2-{(benzyl)[(5-boronic acid-2-pyridyl)methyl]amino}-5-pyrimidinyl)(4-fluorophenylamino)formaldehyde as a potent chemokine antagonist with improved aqueous solubility and oral bioavailability.
- Schuler, Aaron D.,Engles, Courtney A.,Maeda, Dean Y.,Quinn, Mark T.,Kirpotina, Liliya N.,Wicomb, Winston N.,Mason, S. Nicholas,Auten, Richard L.,Zebala, John A.
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p. 3793 - 3797
(2015/08/24)
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- Structure-based optimization of arylamides as inhibitors of soluble epoxide hydrolase
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Inhibition of soluble epoxide hydrolase (sEH) is hypothesized to lead to an increase in circulating levels of epoxyeicosatrienoic acids, resulting in the potentiation of their in vivo pharmacological properties. As part of an effort to identify inhibitors
- Eldrup, Anne B.,Soleymanzadeh, Fariba,Taylor, Steven J.,Muegge, Ingo,Farrow, Neil A.,Joseph, David,McKellop, Keith,Man, Chuk C.,Kukulka, Alison,De Lombaert, Stéphane
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experimental part
p. 5880 - 5895
(2010/03/24)
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- 6-SUBSTITUTED- 2,3,4,5-TETRAHYDRO-1H-BENZO[D]AZEPINES AS 5-HT2C RECEPTOR AGONISTS
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The present invention provides 6-substituted 2,3,4,5-tetrahydro-lH- benzo[d]azepines of Formula (I) as selective 5-HT2C receptor agonists for the treatment of 5-HT2c associated disorders including obesity, obsessive/compulsive disorder, depression, and anxiety: R6 D R? N-R" R* where R6 is -(CrC3)alkyl-S-(C0-C3)alkyl-R10, -(C1-C3)alkyl-NR11R12, -(CrC3)alkyl-O- R 13. and other substituents are as defined in the specification.
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Page/Page column 65
(2008/06/13)
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- (+)-(2R,5S)-4-[4-cyano-3-(trifluoromethyl)phenyl]-2,5-dimethyl-N-[6- (trifluoromethyl)pyridin-3-yl]piperazine-1-carboxamide (YM580) as an orally potent and peripherally selective nonsteroidal androgen receptor antagonist
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A novel series of trans-N-aryl-2,5-dimethylpiperazine-1-carboxamide derivatives was synthesized and their androgen receptor (AR) antagonist activities and in vivo antiandrogenic effects were evaluated. Pharmacological assays indicated that compound 33 was a potent AR antagonist, and subsequent optical resolution provided (+)-(2R,5S)4-[4-cyano-3-(trifluoromethyl)phenyl]-2, 5-dimethyl-N-[6(triflouromethyl)pyridin-3-yl]piperazine-1-carboxamide (33a, YM580) which exhibited the most potent antiandrogenic activity. Unlike bicalutamide, compound 33a decreased the weight of rat ventral prostate in a dose-dependent manner (ED50 = 2.2 mg/kg/day), and induced the maximum antiandrogenic effect, comparable to that of surgical castration, without significantly affecting serum testosterone levels. Compound 33a is a promising clinical candidate for prostate cancer monotherapy.
- Kinoyama, Isao,Taniguchi, Nobuaki,Toyoshima, Akira,Nozawa, Eisuke,Kamikubo, Takashi,Imamura, Masakazu,Matsuhisa, Akira,Samizu, Kiyohiro,Kawanimani, Eiji,Niimi, Tatsuya,Hamada, Noritaka,Koutoku, Hiroshi,Furutani, Takashi,Kudoh, Masafumi,Okada, Minoru,Ohta, Mitsuaki,Tsukamoto, Shin-Ichi
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p. 716 - 726
(2007/10/03)
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- NOVEL CYANOGUANIDINE COMPOUNDS
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Novel pyridyl cyanoguanidien compounds of general formula I (I) wherein R1, X, R2 and R3 are as defined herein, exhibit a high antiproliferative activity and may be used in the treatment of hyperproliferative and neoplastic diseases.
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Page/Page column 20
(2008/06/13)
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- Soluble Epoxide Hydrolase Inhibitors and Methods of Using Same
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Disclosed are compounds active against soluble epoxide hydrolase (sEH), compositions thereof and methods of using and making same.
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Page/Page column 49
(2010/11/25)
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- PREPERATION OF 1,6-DISUBSTITUTED AZABENZIMIDAZOLES AS KINASE INHIBITORS
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Novel inhibitors of Rho-kinases are disclosed.
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Page/Page column 116-117
(2008/06/13)
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- Synthesis of the Coenzyme Metabolite 1,6-Dihydro-6-oxo-1-(β-D-ribofuranosyl)-3-pyridinecarboxamide
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The NAD(P) coenzyme metabolite 1,6-dihydro-6-oxo-1-(β-D-ribofuranosyl)-3-pyridinecarboxamide (9) which is excreted in human urine and its 3-carboxylic acid 8 were synthesized by condensation of silylated 6-oxo-3-pyridinecarboxamide 4 and the corresponding silylated 3-carboxylic acid 2 with 1,2,3,5-tetra-O-acetyl-β-D-ribofuranose in acetonitrile in the presence of tin tetrachloride.The ribosidation site in 8 and 9 was assigned by 1H and 13C NMR spectroscopy.
- Frister, Hermann,Kemper, Klaus,Boos, Karl-Siegfried,Schlimme, Eckhard
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p. 510 - 516
(2007/10/02)
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