- Discovery of Novel 1-Cyclopentenyl-3-phenylureas as Selective, Brain Penetrant, and Orally Bioavailable CXCR2 Antagonists
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CXCR2 has emerged as a therapeutic target for not only peripheral inflammatory diseases but also neurological abnormalities in the central nervous system (CNS). Herein, we describe the discovery of a novel 1-cyclopentenyl-3-phenylurea series as potent and CNS penetrant CXCR2 antagonists. Extensive SAR studies, wherein molecules' property forecast index (PFI) was carefully optimized for overall balanced developability profiles, led to the discovery of the advanced lead compound 68 with a desirable PFI. Compound 68 demonstrated good in vitro pharmacology with excellent selectivity over CXCR1 and other chemokine receptors. Rat and dog pharmacokinetics (PK) revealed good oral bioavailability, high oral exposure, and desirable elimination half-life of the compound in both species. In addition, the compound demonstrated dose-dependent efficacy in the in vivo pharmacology neutrophil infiltration "air pouch" model in rodents after oral administration. Further, compound 68 is a CNS penetrant molecule with high unbound fraction in brain tissue.
- Lu, Hongfu,Yang, Ting,Xu, Zhongmiao,Lin, Xichen,Ding, Qian,Zhang, Yueting,Cai, Xin,Dong, Kelly,Gong, Sophie,Zhang, Wei,Patel, Metul,Copley, Royston C. B.,Xiang, Jianing,Guan, Xiaoming,Wren, Paul,Ren, Feng
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supporting information
p. 2518 - 2532
(2018/03/26)
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- 1,3-THIAZOL-2-YL SUBSTITUTED BENZAMIDES
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The present invention relates to 1,3-thiazol-2-yl substituted benzamide compounds of general formula (I) as described and defined herein, to pharmaceutical compositions and combinations comprising said compounds and to the use of said compounds for manufacturing a pharmaceutical composition for the treatment or prophylaxis of a disease, in particular of neurogenic disorder, as a sole agent or in combination with other active ingredients.
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Page/Page column 276
(2016/07/05)
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- 1 -(CYCLOPENT-2-EN-1 -YL)-3-(2-HYDROXY-3-(ARYLSULFONYL)PHENYL)UREA DERIVATIVES AS CXCR2 INHIBITORS
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The invention relates to 1-(3-sulfonylphenyl)-3-(cyclopent-2-en-1-yl)urea derivatives, and their use in treating or preventing diseases and conditions mediated by the CXCR2 receptor. In addition, the invention relates to compositions containing the derivatives and processes for their preparation.
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Page/Page column 112
(2015/12/18)
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- RING INVERSION EQUILIBRIA IN 4-CHLORO-, 4-BROMO-, AND 4-METHOXY-1-ALKYLPIPERIDINES IN A NON-POLAR SOLVENT
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The position of ring inversion equilibrium (axial Requuatorial R) in 4-R-N-alkylpiperidines (R = Cl, Br, or OMe), dissolved in CFCl3-CDCl3, has been determined by (13)C n.m.r. spectroscopy at low temperatures.In all three series, change of NH to NMe produces a marked increase in the proportion of conformation with axial R.When R is OMe, further alterations in the N-substituent from Me to Et, Pri, and CH2CF3 do not affect the equilibrium significantly, but the signifficant changes observed when R is halogen can be related to the inductive effect of the N-substituent. (13)C Chemical shifts, proportions of conformations, and conformational free energy differences are recorded for all systems studied.
- Bailey, Judith M.,Booth, Harold,Al-Shirayda, Hatif A.R.Y.,Trimble, Mary L.
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p. 737 - 744
(2007/10/02)
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