The Identification of Indacaterol as an Ultralong-Acting Inhaled β₂-Adrenoceptor Agonist

Abstract

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.

Observed Drug-Receptor Association Rates Are Governed by Membrane Affinity: The Importance of Establishing “Micro-Pharmacokinetic/Pharmacodynamic Relationships” at the β2-Adrenoceptor

“…The interaction of drugs with membrane phospholipids is multifaceted, driven not only by lipophilicity (logD) but also electrostatic interactions with both acidic and basic moieties on the phosphate head groups. We therefore used an artificial immobilized phospholipid column (Baur et al, 2010) to derive a macroscopic membrane partition coefficient (logK IAM ) that encapsulates all the different ligand-phospholipid interactions into a single coefficient for each drug. This partition coefficient was then used to estimate the local concentration of drug in the membrane.…”

Pharmacology and Therapeutics of Bronchodilators

“…Within a series of 8-hydroxyquinoline 2-aminoindan-derived ␤ 2 -agonists, the 5,6-diethyl substituted indan analog indacaterol was selected using lipophilicity as the basis for the design and rationalization of their onset and duration of action profiles, as assessed by a guinea pig tracheal-strip assay. In addition to lipophilicity, potency and intrinsic efficacy have also been shown to be contributing factors in regulating these in vitro time course profiles (Baur et al, 2010). Extensive preclinical studies involving indacaterol have been performed both in vitro and in vivo and have documented that it demonstrates a unique rapid onset of action and a bronchodilating effect that lasts for 24 h (Cazzola et al, 2010d).…”

The identification of 7-[(R)-2-((1S,2S)-2-benzyloxycyclopentylamino)-1-hydroxyethyl]-4-hydroxybenzothiazolone as an inhaled long-acting β2-adrenoceptor agonist

“…We have previously described in detail the targeted LABA preclinical profile that was put in place for the identification of indacaterol, and the goal for the backup project was also to fulfil these criteria as closely as possible. 7,13 To achieve the desired onset and duration of action profiles the lipophilicity of the potential targets were estimated prior to synthesis. To select suitable R-substituents, to introduce into the series 5 and 6, calculated log D 7.4 values were used to make this assessment.…”

“…As described previously maintaining the lipophilicity close to that which had been targeted during the lead-generation phase was implemented (within the c log D 7.4 window of 2.4 to 3.5). 8,12,13 To assess the biological profiles of the compounds: affinities for the human b 1 AR and b 2 AR were initially assessed using radio-ligand binding assays.…”

“…20 In terms of the pharmacokinetic profiles, comparable plasma protein binding and rat clearance and volume of distribution data provided further confidence that 2 would exhibit a comparable LABA profile to indacaterol, based upon the previously hypothesised roles of these parameters in satisfying the targeted profile. 13 The similar profile of 2 in comparison with indacaterol led to the compound entering into in vivo profiling to assess DoA and tolerability. Previously we have shown an anti-bronchoconstrictor model in the rhesus monkey to be a good predictor of intrinsic DoA and tolerability using clinically established b 2 AR agonists, and also as a key model in the selection of indacaterol.…”