title: Synthesis and structure-activity relationships of long-acting beta2 adrenergic receptor agonists incorporating arylsulfonamide groups.
abstract: A series of saligenin alkoxyalkylphenylsulfonamide beta(2) adrenoceptor agonists were prepared by reacting a protected saligenin oxazolidinone with alkynyloxyalkyl bromides, followed by Sonogashira reaction, hydrogenation, and deprotection. The meta-substituted primary sulfonamide was more potent than the para- and the ortho-analogues. Primary sulfonamides were more potent than the secondary and tertiary analogues. The onset and duration of action in vitro of selected compounds was assessed on isolated superfused guinea pig trachea. Sulfonamide 29b had the best profile of potency, selectivity, onset, and duration of action on both guinea pig trachea and human bronchus. Furthermore, 29b was found to have low oral bioavailability in rat and dog and also to have long duration of action in an in vivo model of bronchodilation. Crystalline salts of 29b were identified that had suitable properties for inhaled administration. A proposed binding mode for 29b to the beta(2)-receptor is presented.
authors.affiliation: Department of Medicinal Chemistry, GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, United Kingdom. pan.a.procopiou@gsk.com
authors.forename: Panayiotis A
authors.initials: PA
authors.lastname: Procopiou
authors.forename: Victoria J
authors.initials: VJ
authors.lastname: Barrett
authors.forename: Nicola J
authors.initials: NJ
authors.lastname: Bevan
authors.forename: Keith
authors.initials: K
authors.lastname: Biggadike
authors.forename: Peter R
authors.initials: PR
authors.lastname: Butchers
authors.forename: Diane M
authors.initials: DM
authors.lastname: Coe
authors.forename: Richard
authors.initials: R
authors.lastname: Conroy
authors.forename: Dean D
authors.initials: DD
authors.lastname: Edney
authors.forename: Rita N
authors.initials: RN
authors.lastname: Field
authors.forename: Alison J
authors.initials: AJ
authors.lastname: Ford
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Guntrip
authors.forename: Brian E
authors.initials: BE
authors.lastname: Looker
authors.forename: Iain M
authors.initials: IM
authors.lastname: McLay
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Monteith
authors.forename: Valerie S
authors.initials: VS
authors.lastname: Morrison
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Mutch
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Richards
authors.forename: Rosemary
authors.initials: R
authors.lastname: Sasse
authors.forename: Claire E
authors.initials: CE
authors.lastname: Smith