Discovery of 2-hydroxy-N,N-dimethyl-3-{2-[[(R)-1-(5-methylfuran-2-yl) propyl]amino]-3,4-dioxocyclobut-1-enylamino}benzamide (SCH 527123): A potent, orally bioavailable CXCR2/CXCR1 receptor antagonist

Journal of Medicinal Chemistry

Volumn 49, Issue 26, 2006, Pages 7603-7606

  Dwyer, Michael P ^a   Yu, Younong ^a   Chao, Jianping ^a   Aki, Cynthia ^a   Chao, Jianhua ^a   Biju, Purakkattle ^a   Girijavallabhan, Viyyoor ^a   Rindgen, Diane ^a   Bond, Richard ^a   Mayer Ezel, Rosemary ^a   Jakway, James ^a   Hipkin, R William ^a   Fossetta, James ^a   Gonsiorek, Waldemar ^a   Bian, Hong ^a   Fan, Xuedong ^a   Terminelli, Carol ^a   Fine, Jay ^a   Lundell, Daniel ^a   Merritt, J Robert ^b   Rokosz, Laura L ^b   Kaiser, Bernd ^b   Li, Ge ^b   Wang, Wei ^b   Stauffer, Tara ^b   Ozgur, Lynne ^b   Baldwin, John ^b   Taveras, Arthur G ^a,c   more..

^a MERCK RESEARCH LABORATORIES   (United States)

^b PHARMACOPEIA INC   (United States)

^c Alantos Pharmaceuticals Inc   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

2 HYDROXY N,N DIMETHYL 3 [2 [1 (5 METHYLFURAN 2 YL)PROPYL]AMINO 3,4 DIOXOCYCLOBUT 1 ENYLAMINO]BENZAMIDE; CHEMOKINE RECEPTOR CXCR2 CXCR1 ANTAGONIST; RECEPTOR BLOCKING AGENT; SCH 527123; UNCLASSIFIED DRUG;

ANIMAL EXPERIMENT; ARTICLE; CELL CULTURE; CHIRALITY; CULTURE MEDIUM; DRUG BIOAVAILABILITY; DRUG POTENCY; DRUG SCREENING; DRUG STRUCTURE; DRUG SYNTHESIS; HUMAN; HUMAN CELL; INFLAMMATION; NEUTROPHIL; NONHUMAN; RAT; STRUCTURE ACTIVITY RELATION; STRUCTURE ANALYSIS;

ADMINISTRATION, ORAL; ANIMALS; BENZAMIDES; BIOLOGICAL AVAILABILITY; CYCLOBUTANES; MOLECULAR STRUCTURE; RATS; RECEPTORS, INTERLEUKIN-8A; RECEPTORS, INTERLEUKIN-8B; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 33845963398     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm0609622     Document Type: Article

References (28)

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21. 1H NMR analysis of the corresponding β-amino alcohol in accordance with ref 14.
22. The CXCR2 binding data for 3 depicted in Table 1 is 3-fold higher than the reported value in ref 11. Different assay conditions were employed for the compounds in Tables 1 and 2 leading to subtle differences in the binding affinities. The complete assay conditions are found in Supporting Information.
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24. Full experimental details for this assay and subsequent data analysis can be found in Supporting Information.
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26. Rats (n = 2) were orally administered with 10 mg/kg of compound in 20% HPBCD. Blood was drawn at intervals over a 6 h period. Plasma from the two animals was pooled at each sampled time point. AUC was calculated over a 0-6 h period. See ref 19 for a detailed description of this protocol.
27. Dwyer, M. P.; Yu, Y.; Chao, J.; Aki, C.; Chao, J.; Purakkattle, B.; Taveras, A. G. Unpublished results.
28. A detailed description of the pharmacology and in vivo properties of 4 will be reported in due course.