title: Discovery and evaluation of a novel monocyclic series of CXCR2 antagonists.
abstract: Antagonism of the chemokine receptor CXCR2 has been proposed as a strategy for the treatment of inflammatory diseases such as arthritis, chronic obstructive pulmonary disease and asthma. Earlier series of bicyclic CXCR2 antagonists discovered at AstraZeneca were shown to have low solubility and poor oral bioavailability. In this Letter we describe the design, synthesis and characterisation of a new series of monocyclic CXCR2 antagonists with improved solubility and good pharmacokinetic profiles.
authors.affiliation: AstraZeneca R&D Charnwood, Bakewell Road, Loughborough, Leicestershire, LE11 5RH, UK.
authors.forename: Rupert P
authors.initials: RP
authors.lastname: Austin
authors.affiliation: AstraZeneca R&D Charnwood, Bakewell Road, Loughborough, Leicestershire, LE11 5RH, UK.
authors.forename: Colin
authors.initials: C
authors.lastname: Bennion
authors.affiliation: AstraZeneca R&D Charnwood, Bakewell Road, Loughborough, Leicestershire, LE11 5RH, UK.
authors.forename: Roger V
authors.initials: RV
authors.lastname: Bonnert
authors.affiliation: AstraZeneca R&D Charnwood, Bakewell Road, Loughborough, Leicestershire, LE11 5RH, UK.
authors.forename: Lal
authors.initials: L
authors.lastname: Cheema
authors.affiliation: AstraZeneca R&D Charnwood, Bakewell Road, Loughborough, Leicestershire, LE11 5RH, UK.
authors.forename: Anthony R
authors.initials: AR
authors.lastname: Cook
authors.affiliation: AstraZeneca R&D Charnwood, Bakewell Road, Loughborough, Leicestershire, LE11 5RH, UK; Respiratory, Inflammation & Autoimmunity iMed, AstraZeneca R&D Mölndal, Pepparedsleden, 431 83 Mölndal, Sweden. Electronic address: rhona.cox@astrazeneca.com.
authors.forename: Rhona J
authors.initials: RJ
authors.lastname: Cox
authors.affiliation: AstraZeneca R&D Charnwood, Bakewell Road, Loughborough, Leicestershire, LE11 5RH, UK.
authors.forename: Mark R
authors.initials: MR
authors.lastname: Ebden
authors.affiliation: AstraZeneca R&D Charnwood, Bakewell Road, Loughborough, Leicestershire, LE11 5RH, UK.
authors.forename: Alasdair
authors.initials: A
authors.lastname: Gaw
authors.affiliation: AstraZeneca R&D Charnwood, Bakewell Road, Loughborough, Leicestershire, LE11 5RH, UK; Respiratory, Inflammation & Autoimmunity iMed, AstraZeneca R&D Mölndal, Pepparedsleden, 431 83 Mölndal, Sweden.
authors.forename: Ken
authors.initials: K
authors.lastname: Grime
authors.affiliation: AstraZeneca R&D Charnwood, Bakewell Road, Loughborough, Leicestershire, LE11 5RH, UK.
authors.forename: Premji
authors.initials: P
authors.lastname: Meghani
authors.affiliation: AstraZeneca R&D Charnwood, Bakewell Road, Loughborough, Leicestershire, LE11 5RH, UK; AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire, SK10 4TG, UK.
authors.forename: David
authors.initials: D
authors.lastname: Nicholls
authors.affiliation: AstraZeneca R&D Charnwood, Bakewell Road, Loughborough, Leicestershire, LE11 5RH, UK; AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire, SK10 4TG, UK.
authors.forename: Caroline
authors.initials: C
authors.lastname: Phillips
authors.affiliation: AstraZeneca R&D Charnwood, Bakewell Road, Loughborough, Leicestershire, LE11 5RH, UK.
authors.forename: Neal
authors.initials: N
authors.lastname: Smith
authors.affiliation: AstraZeneca R&D Charnwood, Bakewell Road, Loughborough, Leicestershire, LE11 5RH, UK; Respiratory, Inflammation & Autoimmunity iMed, AstraZeneca R&D Mölndal, Pepparedsleden, 431 83 Mölndal, Sweden.
authors.forename: John
authors.initials: J
authors.lastname: Steele
authors.affiliation: AstraZeneca R&D Charnwood, Bakewell Road, Loughborough, Leicestershire, LE11 5RH, UK.
authors.forename: Jeffrey P
authors.initials: JP
authors.lastname: Stonehouse
mesh_terms: D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D001682:Biological Availability; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D006801:Humans; D008968:Molecular Conformation; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D023063:Receptors, Interleukin-8B / Q000037:antagonists & inhibitors*; D012995:Solubility; D013329:Structure-Activity Relationship
chemical_list: D000577:Amides; D011743:Pyrimidines; D023063:Receptors, Interleukin-8B; C030986:pyrimidine
keywords: CXCR2; Chemokine antagonism; Inflammatory disease; Solubility