title: Inhalation by design: novel tertiary amine muscarinic M₃ receptor antagonists with slow off-rate binding kinetics for inhaled once-daily treatment of chronic obstructive pulmonary disease.
abstract: A novel tertiary amine series of potent muscarinic M(3) receptor antagonists are described that exhibit potential as inhaled long-acting bronchodilators for the treatment of chronic obstructive pulmonary disease. Geminal dimethyl functionality present in this series of compounds confers very long dissociative half-life (slow off-rate) from the M(3) receptor that mediates very long-lasting smooth muscle relaxation in guinea pig tracheal strips. Optimization of pharmacokinetic properties was achieved by combining rapid oxidative clearance with targeted introduction of a phenolic moiety to secure rapid glucuronidation. Together, these attributes minimize systemic exposure following inhalation, mitigate potential drug-drug interactions, and reduce systemically mediated adverse events. Compound 47 (PF-3635659) is identified as a Phase II clinical candidate from this series with in vivo duration of action studies confirming its potential for once-daily use in humans.
authors.affiliation: Department of Worldwide Medicinal Chemistry, Pfizer Global Research and Development, Sandwich Laboratories, Ramsgate Road, Kent CT13 9NJ, U.K. paglossop@gmail.com
authors.forename: Paul A
authors.initials: PA
authors.lastname: Glossop
authors.forename: Christine A L
authors.initials: CA
authors.lastname: Watson
authors.forename: David A
authors.initials: DA
authors.lastname: Price
authors.forename: Mark E
authors.initials: ME
authors.lastname: Bunnage
authors.forename: Donald S
authors.initials: DS
authors.lastname: Middleton
authors.forename: Anthony
authors.initials: A
authors.lastname: Wood
authors.forename: Kim
authors.initials: K
authors.lastname: James
authors.forename: Dannielle
authors.initials: D
authors.lastname: Roberts
authors.forename: Ross S
authors.initials: RS
authors.lastname: Strang
authors.forename: Michael
authors.initials: M
authors.lastname: Yeadon
authors.forename: Christelle
authors.initials: C
authors.lastname: Perros-Huguet
authors.forename: Nicholas P
authors.initials: NP
authors.lastname: Clarke
authors.forename: Michael A
authors.initials: MA
authors.lastname: Trevethick
authors.forename: Ian
authors.initials: I
authors.lastname: Machin
authors.forename: Emilio F
authors.initials: EF
authors.lastname: Stuart
authors.forename: Steven M
authors.initials: SM
authors.lastname: Evans
authors.forename: Anthony C
authors.initials: AC
authors.lastname: Harrison
authors.forename: David A
authors.initials: DA
authors.lastname: Fairman
authors.forename: Balaji
authors.initials: B
authors.lastname: Agoram
authors.forename: Jane L
authors.initials: JL
authors.lastname: Burrows
authors.forename: Neil
authors.initials: N
authors.lastname: Feeder
authors.forename: Craig K
authors.initials: CK
authors.lastname: Fulton
authors.forename: Barry R
authors.initials: BR
authors.lastname: Dillon
authors.forename: David A
authors.initials: DA
authors.lastname: Entwistle
authors.forename: Fiona J
authors.initials: FJ
authors.lastname: Spence
mesh_terms: D000280:Administration, Inhalation; D000818:Animals; D001384:Azetidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001993:Bronchodilator Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D016466:CHO Cells; D002460:Cell Line; D002463:Cell Membrane Permeability; D006224:Cricetinae; D003412:Cricetulus; D004158:Diphenylacetic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004285:Dogs; D005260:Female; D006168:Guinea Pigs; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D007700:Kinetics; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D009126:Muscle Relaxation / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy*; D011869:Radioligand Assay; D051381:Rats; D043587:Receptor, Muscarinic M3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014132:Trachea / Q000187:drug effects / Q000502:physiology
chemical_list: C568516:5-(3-(3-hydroxyphenoxy)azetidin-1-yl)-5-methyl-2,2-diphenylhexanamide; D001384:Azetidines; D001993:Bronchodilator Agents; D004158:Diphenylacetic Acids; D043587:Receptor, Muscarinic M3; D011994:Recombinant Proteins