A physical properties based approach for the exploration of a 4-hydroxybenzothiazolone series of beta2-adrenoceptor agonists as inhaled long-acting bronchodilators.
The chiral synthesis of a 4-hydroxybenzothiazolone based series of beta(2)-adrenoceptor agonists is described. Using this methodology a library of N-substituted analogues were prepared for the rapid identification of leads with the potential to be fast onset and long-acting inhaled bronchodilators with improved therapeutic margins. The design of the library to achieve the targeted profile was based upon lipophilicity and metabolism based hypotheses. This approach identified beta-phenethyl, alpha-substituted cyclopentyl and monoterpene N-substituents to be of particular interest for further evaluation, as exemplified by structures 19, 29 and 33, respectively.
Beattie
David
D
Novartis Institutes for BioMedical Research, Respiratory Diseases Area, Horsham, United Kingdom.
Bradley
Michelle
M
Brearley
Andrew
A
Charlton
Steven J
SJ
Cuenoud
Bernard M
BM
Fairhurst
Robin A
RA
Gedeck
Peter
P
Gosling
Martin
M
Janus
Diana
D
Jones
Darryl
D
Lewis
Christine
C
McCarthy
Clive
C
Oakman
Helen
H
Stringer
Rowan
R
Taylor
Roger J
RJ
Tuffnell
Andrew
A
D000280:Administration, Inhalation; D058672:Adrenergic beta-2 Receptor Antagonists / Q000494:pharmacology / Q000627:therapeutic use*; D001993:Bronchodilator Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D013844:Thiazoles / Q000494:pharmacology / Q000627:therapeutic use*
D058672:Adrenergic beta-2 Receptor Antagonists; D001993:Bronchodilator Agents; D013844:Thiazoles