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Bioorg Med Chem Lett. 2015 Jun 1;25(11):2280-4. doi: 10.1016/j.bmcl.2015.04.041. Epub 2015 Apr 23.

Boronic acid-containing CXCR1/2 antagonists: Optimization of metabolic stability, in vivo evaluation, and a proposed receptor binding model.

Author information

1
Syntrix Biosystems, 215 Clay Street Northwest, Suite B5, Auburn, WA 98001, United States. Electronic address: dmaeda@syntrixbio.com.
2
Syntrix Biosystems, 215 Clay Street Northwest, Suite B5, Auburn, WA 98001, United States.
3
Department of Microbiology and Immunology, Montana State University, 960 Technology Boulevard, Bozeman, MT 59717, United States.
4
Infectious Disease Research Institute, 1616 Eastlake Avenue East, Seattle, WA 98102, United States.
5
Division of Neonatal Medicine, Department of Pediatrics, Duke University Medical Center, 366 Sands Research Drive, Durham, NC 27710, United States.
6
Integrated Drug Discovery Services, GVK Biosciences Private Limited, IDA Nacharam, Hyderabad 500 076, India.

Abstract

Blockade of undesired neutrophil migration to sites of inflammation remains an area of substantial pharmaceutical interest. To effect this blockade, a validated therapeutic target is antagonism of the chemokine receptor CXCR2. Herein we report the discovery of 6-(2-boronic acid-5-trifluoromethoxy-benzylsulfanyl)-N-(4-fluoro-phenyl)-nicotinamide 6, an antagonist with activity at both CXCR1 and CXCR2 receptors (IC50 values 31 and 21 nM, respectively). Compound 6 exhibited potent inhibition of neutrophil influx in a rat model of pulmonary inflammation, and is hypothesized to interact with a unique intracellular binding site on CXCR2. Compound 6 (SX-576) is undergoing further investigation as a potential therapy for pulmonary inflammation.

KEYWORDS:

Antagonist; Asthma; COPD; CXCR2; Thionicotinamide

PMID:
25933594
PMCID:
PMC4430358
DOI:
10.1016/j.bmcl.2015.04.041
[Indexed for MEDLINE]
Free PMC Article

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