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Bioorg Med Chem Lett. 2015 Sep 15;25(18):3793-7. doi: 10.1016/j.bmcl.2015.07.090. Epub 2015 Jul 30.

Boronic acid-containing aminopyridine- and aminopyrimidinecarboxamide CXCR1/2 antagonists: Optimization of aqueous solubility and oral bioavailability.

Author information

1
Syntrix Biosystems, 215 Clay Street NW, Suite B-5, Auburn, WA 98001, United States. Electronic address: aschuler@syntrixbio.com.
2
Syntrix Biosystems, 215 Clay Street NW, Suite B-5, 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
Department of Pediatrics (Neonatal Medicine), DUMC Box 3373, Duke University, Durham, NC 27710, United States.

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.

KEYWORDS:

Antagonist; Asthma; COPD; CXCR1; CXCR2

PMID:
26248802
PMCID:
PMC4564001
DOI:
10.1016/j.bmcl.2015.07.090
[Indexed for MEDLINE]
Free PMC Article

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