ABSTRACT
The synthesis of a series of indacaterol analogues in which each of the three structural regions of indacaterol are modified in a systematic manner is described. Evaluation of the affinity of these analogues for the ß(2)-adrenoceptor identified the 3,4-dihydroquinolinone and 5-n-butylindanyl analogues to demonstrate the most similar profiles to indacaterol. An α-methyl aminoindane analogue was discovered to be 25-fold more potent than indacaterol, and functional studies revealed an atypical ß(2)-adrenoceptor activation profile for this compound consistent with that of a slowly dissociating 'super agonist'.
Subject(s)
Adrenergic beta-2 Receptor Agonists/pharmacology , Indans/pharmacology , Quinolones/pharmacology , Receptors, Adrenergic, beta-2/metabolism , Adrenergic beta-2 Receptor Agonists/chemical synthesis , Adrenergic beta-2 Receptor Agonists/chemistry , Dose-Response Relationship, Drug , Humans , Indans/chemical synthesis , Indans/chemistry , Molecular Structure , Quinolones/chemical synthesis , Quinolones/chemistry , Structure-Activity RelationshipABSTRACT
Following a lipophilicity-based hypothesis, an 8-hydroxyquinolinone 2-aminoindan derived series of beta(2)-adrenoceptor agonists have been prepared and evaluated for their potential as inhaled ultralong-acting bronchodilators. Determination of their activities at the human beta(2)-adrenoceptor receptor showed symmetrical substitution of the 2-aminoindan moiety at the 5- and 6-positions delivered the targeted intermediate potency and intrinsic-efficacy profiles relative to a series of clinical reference beta(2)-adrenoceptor agonists. Further assessment with an in vitro superfused electrically stimulated guinea-pig tracheal-strip assay established the onset and duration of action time courses, which could be rationalized by considering the lipophilicity, potency, and intrinsic efficacy of the compounds. From these studies the 5,6-diethylindan analogue indacaterol 1c was shown to possess a unique profile of combining a rapid onset of action with a long duration of action. Further in vivo profiling of 1c supported the long duration of action and a wide therapeutic index following administration to the lung, which led to the compound being selected as a development candidate.
Subject(s)
Adrenergic beta-2 Receptor Agonists , Bronchodilator Agents/chemistry , Indans/pharmacology , Quinolones/pharmacology , Administration, Inhalation , Animals , Guinea Pigs , Humans , Hydrophobic and Hydrophilic Interactions , Indans/administration & dosage , Indans/pharmacokinetics , Quinolones/administration & dosage , Quinolones/pharmacokinetics , Structure-Activity RelationshipABSTRACT
The synthesis of a series of long-chain formoterol analogues in which the terminal ether residue of the beta-phenethyl-amino-substituent has been extended beyond the methyl ether residue present in the parent compound are described. Evaluation of these analogues as beta(2)-adrenoceptor agonists was used to provide an insight into the factors controlling the magnitude and duration of receptor activation.
