ABSTRACT
A series of dibasic des-hydroxy ß2 receptor agonists has been prepared and evaluated for potential as inhaled ultralong acting bronchodilators. Determination of activities at the human ß-adrenoreceptors demonstrated a series of highly potent and selective ß2 receptor agonists that were progressed to further study in a guinea pig histamine-induced bronchoconstriction model. Following further assessment by onset studies in guinea pig tracheal rings and human bronchial rings contracted with methacholine (guinea pigs) or carbachol (humans), duration of action studies in guinea pigs after intratracheal (i.t.) administration and further selectivity and safety profiling AZD3199 was shown to have an excellent over all profile and was progressed into clinical evaluation as a new ultralong acting inhaled ß2 receptor agonist with rapid onset of action.
ABSTRACT
Starting with the molecular scaffold of the DA(2)/ß(2) dual agonist sibenadet (Viozan™), a number of molecular changes were incorporated, which were designed to increase the potency and selectivity of the target molecule, and improve its pharmacokinetics. Through this process a novel, high potency, full ß(2)-agonist with high selectivity and long duration capable of being dosed once daily has been discovered.
Subject(s)
Adrenergic beta-2 Receptor Agonists/chemistry , Bronchodilator Agents/chemistry , Receptors, Adrenergic, beta-2/chemistry , Thiazoles/chemistry , Adrenergic beta-2 Receptor Agonists/chemical synthesis , Adrenergic beta-2 Receptor Agonists/pharmacokinetics , Animals , Bronchodilator Agents/chemical synthesis , Bronchodilator Agents/pharmacokinetics , Drug Design , Drug Evaluation, Preclinical , Guinea Pigs , Receptors, Adrenergic, beta-2/metabolism , Structure-Activity Relationship , Thiazoles/chemical synthesis , Thiazoles/pharmacokineticsABSTRACT
The design and synthesis of a new series of high efficacy ß(2)-agonists devoid of the key benzylic alcohol present in previously described highly efficacious ß(2)-agonists is reported. A hypothesis for the unprecedented level of efficacy is proposed based on considerations of ß(2)-adrenoceptor crystal structure, other biophysical data and modeling studies.
Subject(s)
Adrenergic beta-2 Receptor Agonists/chemical synthesis , Drug Design , Adrenergic beta-2 Receptor Agonists/chemistry , Animals , Bronchi/cytology , Cell Line , Crystallography, X-Ray , Humans , Models, Molecular , Molecular Structure , Structure-Activity RelationshipABSTRACT
The identification of two novel series of formyl peptide receptor 1 (FPR1) antagonists are reported, represented by methionine benzimidazole 6 and diamide 7. Both series specifically inhibited the binding of labelled fMLF to hrFPR1 and selectively antagonized FPR1 function in human neutrophils, making them useful in vitro validation tools for the target.
Subject(s)
Drug Discovery , Receptors, Formyl Peptide/antagonists & inhibitors , Receptors, Formyl Peptide/chemistry , Humans , Molecular StructureABSTRACT
As part of a Lead Optimisation programme to identify small molecule antagonists of the human CXCR2 receptor, a series of substituted thiazolo[4,5-d]pyrimidines was prepared via the application of a novel tandem displacement reaction.
