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J Med Chem. 2014 Jun 12;57(11):4661-76. doi: 10.1021/jm5001216. Epub 2014 May 30.

Efficacious inhaled PDE4 inhibitors with low emetic potential and long duration of action for the treatment of COPD.

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1
AstraZeneca R&D Charnwood , Loughborough, Leicestershire, LE11 5RH, U.K.

Abstract

Oral phosphodiesterase 4 (PDE4) inhibitors, such as cilomilast and roflumilast, have been shown to be efficacious against chronic obstructive pulmonary disease (COPD). However, these drugs have been hampered by mechanism-related side effects such as nausea and emesis at high doses. Compounds administered by inhalation are delivered directly to the site of action and may improve the therapeutic index required to overcome side effects. This paper describes systematic and rational lead optimization to deliver highly potent, long-acting, and efficacious preclinical inhaled PDE4 inhibitors with low emetic potential.

PMID:
24785301
DOI:
10.1021/jm5001216
[Indexed for MEDLINE]

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