title: Structure Activity Relationships of αv Integrin Antagonists for Pulmonary Fibrosis by Variation in Aryl Substituents.
abstract: Antagonism of αvβ6 is emerging as a potential treatment of idiopathic pulmonary fibrosis based on strong target validation. Starting from an αvβ3 antagonist lead and through simple variation in the nature and position of the aryl substituent, the discovery of compounds with improved αvβ6 activity is described. The compounds also have physicochemical properties commensurate with oral bioavailability and are high quality starting points for a drug discovery program. Compounds 33S and 43E1 are pan αv antagonists having ca. 100 nM potency against αvβ3, αvβ5, αvβ6, and αvβ8 in cell adhesion assays. Detailed structure activity relationships with these integrins are described which also reveal substituents providing partial selectivity (defined as at least a 0.7 log difference in pIC50 values between the integrins in question) for αvβ3 and αvβ5.
authors.affiliation: University of Nottingham, School of Chemistry, University of Nottingham , University Park, Nottingham NG7 2RD, U.K.
authors.forename: James
authors.initials: J
authors.lastname: Adams
authors.affiliation: University of Nottingham, School of Chemistry, University of Nottingham , University Park, Nottingham NG7 2RD, U.K.
authors.forename: Edward C
authors.initials: EC
authors.lastname: Anderson
authors.affiliation: University of Nottingham, School of Chemistry, University of Nottingham , University Park, Nottingham NG7 2RD, U.K.
authors.forename: Emma E
authors.initials: EE
authors.lastname: Blackham
authors.affiliation: University of Nottingham, School of Chemistry, University of Nottingham , University Park, Nottingham NG7 2RD, U.K.
authors.forename: Yin Wa Ryan
authors.initials: YW
authors.lastname: Chiu
authors.affiliation: University of Nottingham, School of Chemistry, University of Nottingham , University Park, Nottingham NG7 2RD, U.K.
authors.forename: Thomas
authors.initials: T
authors.lastname: Clarke
authors.affiliation: University of Nottingham, School of Chemistry, University of Nottingham , University Park, Nottingham NG7 2RD, U.K.
authors.forename: Natasha
authors.initials: N
authors.lastname: Eccles
authors.affiliation: University of Nottingham, School of Chemistry, University of Nottingham , University Park, Nottingham NG7 2RD, U.K.
authors.forename: Luke A
authors.initials: LA
authors.lastname: Gill
authors.affiliation: University of Nottingham, School of Chemistry, University of Nottingham , University Park, Nottingham NG7 2RD, U.K.
authors.forename: Joshua J
authors.initials: JJ
authors.lastname: Haye
authors.affiliation: University of Nottingham, School of Chemistry, University of Nottingham , University Park, Nottingham NG7 2RD, U.K.
authors.forename: Harvey T
authors.initials: HT
authors.lastname: Haywood
authors.affiliation: University of Nottingham, School of Chemistry, University of Nottingham , University Park, Nottingham NG7 2RD, U.K.
authors.forename: Christian R
authors.initials: CR
authors.lastname: Hoenig
authors.affiliation: GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage SG1 2NY, U.K.
authors.forename: Marius
authors.initials: M
authors.lastname: Kausas
authors.affiliation: GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage SG1 2NY, U.K.
authors.forename: Joelle
authors.initials: J
authors.lastname: Le
authors.affiliation: University of Nottingham, School of Chemistry, University of Nottingham , University Park, Nottingham NG7 2RD, U.K.
authors.forename: Hannah L
authors.initials: HL
authors.lastname: Russell
authors.affiliation: University of Nottingham, School of Chemistry, University of Nottingham , University Park, Nottingham NG7 2RD, U.K.
authors.forename: Christopher
authors.initials: C
authors.lastname: Smedley
authors.affiliation: University of Nottingham, School of Chemistry, University of Nottingham , University Park, Nottingham NG7 2RD, U.K.
authors.forename: William J
authors.initials: WJ
authors.lastname: Tipping
authors.affiliation: University of Nottingham, School of Chemistry, University of Nottingham , University Park, Nottingham NG7 2RD, U.K.
authors.forename: Tom
authors.initials: T
authors.lastname: Tongue
authors.affiliation: University of Nottingham, School of Chemistry, University of Nottingham , University Park, Nottingham NG7 2RD, U.K.
authors.forename: Charlotte C
authors.initials: CC
authors.lastname: Wood
authors.affiliation: University of Nottingham, School of Chemistry, University of Nottingham , University Park, Nottingham NG7 2RD, U.K.
authors.forename: Jason
authors.initials: J
authors.lastname: Yeung
authors.affiliation: GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage SG1 2NY, U.K.
authors.forename: James E
authors.initials: JE
authors.lastname: Rowedder
authors.affiliation: University of Nottingham, School of Chemistry, University of Nottingham , University Park, Nottingham NG7 2RD, U.K.
authors.forename: M Jonathan
authors.initials: MJ
authors.lastname: Fray
authors.affiliation: University of Nottingham, School of Chemistry, University of Nottingham , University Park, Nottingham NG7 2RD, U.K.
authors.forename: Thomas
authors.initials: T
authors.lastname: McInally
authors.affiliation: GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage SG1 2NY, U.K.
authors.forename: Simon J F
authors.initials: SJ
authors.lastname: Macdonald
keywords: Integrins; antagonist; fibrosis; pulmonary; αvβ3; αvβ6; β-amino acids