The identification of 7-[(R)-2-((1S,2S)-2-benzyloxycyclopentylamino)-1-hydroxyethyl]-4-hydroxybenzothiazolone as an inhaled long-acting β2-adrenoceptor agonist |
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| Institution: | 1. Discovery Chemistry, Merck Research Laboratory, Kenilworth, NJ 07033, United States;2. Department of Medicinal Chemistry, Albany Molecular Research, Inc. (AMRI), Albany, NY 12203, United States;3. In Vivo Pharmacology Group, Merck Research Laboratory, Kenilworth, NJ 07033, United States;4. Cardiorenal Group, Merck Research Laboratory, Kenilworth, NJ 07033, United States;5. Neuroscience, Merck Research Laboratory, West Point, PA 19486, United States;6. Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck Research Laboratory, Kenilworth, NJ 07033, United States;1. Medicinal Chemistry, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA;2. In Vitro Pharmacology, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA |
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| 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. |
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| Keywords: | Bronchodilator Chronic obstructive pulmonary disease |
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