title: Boronic acid-containing aminopyridine- and aminopyrimidinecarboxamide CXCR1/2 antagonists: Optimization of aqueous solubility and oral bioavailability.
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.
authors.affiliation: Syntrix Biosystems, 215 Clay Street NW, Suite B-5, Auburn, WA 98001, United States. Electronic address: aschuler@syntrixbio.com.
authors.forename: Aaron D
authors.initials: AD
authors.lastname: Schuler
authors.affiliation: Syntrix Biosystems, 215 Clay Street NW, Suite B-5, Auburn, WA 98001, United States.
authors.forename: Courtney A
authors.initials: CA
authors.lastname: Engles
authors.affiliation: Syntrix Biosystems, 215 Clay Street NW, Suite B-5, Auburn, WA 98001, United States.
authors.forename: Dean Y
authors.initials: DY
authors.lastname: Maeda
authors.affiliation: Department of Microbiology and Immunology, Montana State University, 960 Technology Boulevard, Bozeman, MT 59717, United States.
authors.forename: Mark T
authors.initials: MT
authors.lastname: Quinn
authors.affiliation: Department of Microbiology and Immunology, Montana State University, 960 Technology Boulevard, Bozeman, MT 59717, United States.
authors.forename: Liliya N
authors.initials: LN
authors.lastname: Kirpotina
authors.affiliation: Infectious Disease Research Institute, 1616 Eastlake Avenue East, Seattle, WA 98102, United States.
authors.forename: Winston N
authors.initials: WN
authors.lastname: Wicomb
authors.affiliation: Department of Pediatrics (Neonatal Medicine), DUMC Box 3373, Duke University, Durham, NC 27710, United States.
authors.forename: S Nicholas
authors.initials: SN
authors.lastname: Mason
authors.affiliation: Department of Pediatrics (Neonatal Medicine), DUMC Box 3373, Duke University, Durham, NC 27710, United States.
authors.forename: Richard L
authors.initials: RL
authors.lastname: Auten
authors.affiliation: Syntrix Biosystems, 215 Clay Street NW, Suite B-5, Auburn, WA 98001, United States.
authors.forename: John A
authors.initials: JA
authors.lastname: Zebala
mesh_terms: D000284:Administration, Oral; D001682:Biological Availability; D001897:Boronic Acids / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D015394:Molecular Structure; D009536:Niacinamide / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D023062:Receptors, Interleukin-8A / Q000037:antagonists & inhibitors*; D023063:Receptors, Interleukin-8B / Q000037:antagonists & inhibitors*; D012995:Solubility; D013329:Structure-Activity Relationship; D014867:Water / Q000737:chemistry
chemical_list: C000597473:2-(5-(4-fluorophenylcarbamoyl)pyridin-2-ylsulfanylmethyl)phenylboronic acid; D001897:Boronic Acids; D023062:Receptors, Interleukin-8A; D023063:Receptors, Interleukin-8B; C000604939:SX-576; D014867:Water; D009536:Niacinamide
keywords: Antagonist; Asthma; COPD; CXCR1; CXCR2