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Bioorg Med Chem Lett. 2014 Sep 1;24(17):4341-7. doi: 10.1016/j.bmcl.2014.06.014. Epub 2014 Jun 26.

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

Author information

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

PMID:
25065493
DOI:
10.1016/j.bmcl.2014.06.014
[Indexed for MEDLINE]

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