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

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

  • Bioorg Med Chem Lett. 2015 Jun 1;25(11):2280-4. doi: 10.1016/j.bmcl.2015.04.041.
Dean Y Maeda 1,  Angela M Peck 2,  Aaron D Schuler 2,  Mark T Quinn 3,  Liliya N Kirpotina 3,  Winston N Wicomb 4,  Richard L Auten 5,  Rambabu Gundla 6,  John A Zebala 2
Affiliations

Affiliations

  • 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.
PMID: 25933594 DOI: 10.1016/j.bmcl.2015.04.041
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.

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