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

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

  • Bioorg Med Chem Lett. 2014 Sep 1;24(17):4341-7. doi: 10.1016/j.bmcl.2014.06.014.
Nicola Arnold 1 David Beattie 1 Michelle Bradley 1 Andrew Brearley 1 Lyndon Brown 1 Steven J Charlton 1 Robin A Fairhurst 2 David Farr 1 John Fozard 1 Joe Fullerton 1 Martin Gosling 1 Julia Hatto 1 Diana Janus 1 Darryl Jones 1 Lynne Jordan 1 Christine Lewis 1 Janet Maas 1 Clive McCarthy 1 Mark Mercer 1 Helen Oakman 1 Neil Press 1 Rachel Profit 1 Friedrich Schuerch 1 David Sykes 1 Roger J Taylor 1 Alexandre Trifilieff 1 Andrew Tuffnell 1
Affiliations

Affiliations

  • 1 Novartis Institutes for BioMedical Research, Respiratory Diseases Area, Horsham, United Kingdom; Novartis Institutes for BioMedical Research, Respiratory Diseases Area, Basel, Switzerland.
  • 2 Novartis Institutes for BioMedical Research, Respiratory Diseases Area, Horsham, United Kingdom; Novartis Institutes for BioMedical Research, Respiratory Diseases Area, Basel, Switzerland. Electronic address: robin.fairhurst@novartis.com.
Abstract

The optimisation of two series of 4-hydroxybenzothiazolone derived β2-adrenoceptor agonists, bearing α-substituted cyclopentyl and β-phenethyl amino-substituents, as inhaled long-acting bronchodilators is described. Analogues were selected for synthesis using a lipophilicity based hypothesis to achieve the targeted rapid onset of action in combination with a long duration of action. The profiling of the two series led to identification of the α-substituted cyclopentyl analogue 2 as the optimal compound with a comparable profile to the inhaled once-daily long-acting β2-adrenoceptor agonist indacaterol. On the basis of these data 2 was promoted as the backup development candidate to indacaterol from the Novartis LABA project.

Keywords

Bronchodilator; Chronic obstructive pulmonary disease; β(2)-Adrenoceptor agonist.

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