Boronic acid-containing CXCR1/2 antagonists: Optimization of metabolic stability, in vivo evaluation, and a proposed receptor binding model.
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.
Syntrix Biosystems, 215 Clay Street Northwest, Suite B5, Auburn, WA 98001, United States. Electronic address: dmaeda@syntrixbio.com.
Dean Y
DY
Maeda
Syntrix Biosystems, 215 Clay Street Northwest, Suite B5, Auburn, WA 98001, United States.
Angela M
AM
Peck
Syntrix Biosystems, 215 Clay Street Northwest, Suite B5, Auburn, WA 98001, United States.
Aaron D
AD
Schuler
Department of Microbiology and Immunology, Montana State University, 960 Technology Boulevard, Bozeman, MT 59717, United States.
Mark T
MT
Quinn
Department of Microbiology and Immunology, Montana State University, 960 Technology Boulevard, Bozeman, MT 59717, United States.
Liliya N
LN
Kirpotina
Infectious Disease Research Institute, 1616 Eastlake Avenue East, Seattle, WA 98102, United States.
Winston N
WN
Wicomb
Division of Neonatal Medicine, Department of Pediatrics, Duke University Medical Center, 366 Sands Research Drive, Durham, NC 27710, United States.
Richard L
RL
Auten
Integrated Drug Discovery Services, GVK Biosciences Private Limited, IDA Nacharam, Hyderabad 500 076, India.
Rambabu
R
Gundla
Syntrix Biosystems, 215 Clay Street Northwest, Suite B5, Auburn, WA 98001, United States.
John A
JA
Zebala
D000818:Animals; D001897:Boronic Acids / Q000737:chemistry* / Q000627:therapeutic use; D019295:Computational Biology; D015195:Drug Design; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy; D008171:Lung Diseases / Q000139:chemically induced / Q000188:drug therapy; D015394:Molecular Structure; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000737:chemistry / Q000627:therapeutic use; D010126:Ozone / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D023062:Receptors, Interleukin-8A / Q000037:antagonists & inhibitors*; D023063:Receptors, Interleukin-8B / Q000037:antagonists & inhibitors* / Q000737:chemistry
D001897:Boronic Acids; D023062:Receptors, Interleukin-8A; D023063:Receptors, Interleukin-8B; C000604939:SX-576; D009536:Niacinamide; D010126:Ozone
Antagonist; Asthma; COPD; CXCR2; Thionicotinamide