title: Inhalation by design: novel ultra-long-acting β(2)-adrenoreceptor agonists for inhaled once-daily treatment of asthma and chronic obstructive pulmonary disease that utilize a sulfonamide agonist headgroup.
abstract: A novel series of potent and selective sulfonamide derived β(2)-adrenoreceptor agonists are described that exhibit potential as inhaled ultra-long-acting bronchodilators for the treatment of asthma and chronic obstructive pulmonary disease. Analogues from this series mediate very long-lasting smooth muscle relaxation in guinea pig tracheal strips. The sulfonamide agonist headgroup confers high levels of intrinsic crystallinity that could relate to the acidic sulfonamide motif supporting a zwitterionic form in the solid state. Optimization of pharmacokinetic properties was achieved through targeted introduction of a phenolic moiety to support rapid phase II clearance, thereby minimizing systemic exposure following inhalation and reducing systemically mediated adverse events. Compound 38 (PF-610355) is identified as a clinical candidate from this series, with in vivo duration of action studies confirming its potential for once-daily use in humans. Compound 38 is currently in advanced phase II clinical studies.
authors.affiliation: Department of Worldwide Medicinal Chemistry, Pfizer Global Research and Development, Sandwich Laboratories, Ramsgate Road, Kent CT139NJ, UK. paul.glossop@pfizer.com
authors.forename: Paul A
authors.initials: PA
authors.lastname: Glossop
authors.forename: Charlotte A L
authors.initials: CA
authors.lastname: Lane
authors.forename: David A
authors.initials: DA
authors.lastname: Price
authors.forename: Mark E
authors.initials: ME
authors.lastname: Bunnage
authors.forename: Russell A
authors.initials: RA
authors.lastname: Lewthwaite
authors.forename: Kim
authors.initials: K
authors.lastname: James
authors.forename: Alan D
authors.initials: AD
authors.lastname: Brown
authors.forename: Michael
authors.initials: M
authors.lastname: Yeadon
authors.forename: Christelle
authors.initials: C
authors.lastname: Perros-Huguet
authors.forename: Michael A
authors.initials: MA
authors.lastname: Trevethick
authors.forename: Nicholas P
authors.initials: NP
authors.lastname: Clarke
authors.forename: Robert
authors.initials: R
authors.lastname: Webster
authors.forename: Rhys M
authors.initials: RM
authors.lastname: Jones
authors.forename: Jane L
authors.initials: JL
authors.lastname: Burrows
authors.forename: Neil
authors.initials: N
authors.lastname: Feeder
authors.forename: Stefan C J
authors.initials: SC
authors.lastname: Taylor
authors.forename: Fiona J
authors.initials: FJ
authors.lastname: Spence
mesh_terms: D000280:Administration, Inhalation; D058666:Adrenergic beta-2 Receptor Agonists; D000318:Adrenergic beta-Agonists / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D001249:Asthma / Q000188:drug therapy*; D044482:Benzeneacetamides / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D016084:Bronchoconstriction / Q000187:drug effects; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D018360:Crystallography, X-Ray; D004285:Dogs; D005260:Female; D006168:Guinea Pigs; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D008099:Liver / Q000378:metabolism; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure; D009130:Muscle, Smooth / Q000187:drug effects / Q000503:physiopathology; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy*; D051381:Rats; D013237:Stereoisomerism; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D014132:Trachea / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D001713:Biphenyl Compounds
chemical_list: D058666:Adrenergic beta-2 Receptor Agonists; D000318:Adrenergic beta-Agonists; D044482:Benzeneacetamides; D013449:Sulfonamides; C552705:N-((4'-hydroxybiphenyl-3-yl)methyl)-2-(3-(2-((-2-hydroxy-2-(4-hydroxy-3-((methylsulfonyl)amino)phenyl)ethyl)amino)-2-methylpropyl)phenyl)acetamide; D001713:Biphenyl Compounds