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.
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.
Glossop
Paul A
PA
Department of Worldwide Medicinal Chemistry, Pfizer Global Research and Development, Sandwich Laboratories, Ramsgate Road, Kent CT139NJ, UK. paul.glossop@pfizer.com
Lane
Charlotte A L
CA
Price
David A
DA
Bunnage
Mark E
ME
Lewthwaite
Russell A
RA
James
Kim
K
Brown
Alan D
AD
Yeadon
Michael
M
Perros-Huguet
Christelle
C
Trevethick
Michael A
MA
Clarke
Nicholas P
NP
Webster
Robert
R
Jones
Rhys M
RM
Burrows
Jane L
JL
Feeder
Neil
N
Taylor
Stefan C J
SC
Spence
Fiona J
FJ
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
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