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Bioorg Med Chem Lett. 2015 Nov 15;25(22):5121-6. doi: 10.1016/j.bmcl.2015.10.008. Epub 2015 Oct 8.

Molecular hybridization yields triazole bronchodilators for the treatment of COPD.

Author information

1
WorldWide Medicinal Chemistry, 610 Main Street, Cambridge, MA 02139, USA. Electronic address: lyn.jones@pfizer.com.
2
Pharmaceutical Sciences, Pfizer, Ramsgate Road, Sandwich CT13 9NJ, UK.
3
WorldWide Medicinal Chemistry, Pfizer, Ramsgate Road, Sandwich CT13 9NJ, UK.
4
Pharmacokinetics, Dynamics and Metabolism, 610 Main Street, Cambridge, MA 02139, USA.
5
Allergy and Respiratory Biology, Pfizer, Ramsgate Road, Sandwich CT13 9NJ, UK; CVMED Research Unit, Pfizer, Cambridge, MA 02139, USA.
6
Allergy and Respiratory Biology, Pfizer, Ramsgate Road, Sandwich CT13 9NJ, UK.
7
Allergy and Respiratory Biology, Pfizer, Ramsgate Road, Sandwich CT13 9NJ, UK; Inflammation and Immunology Research Unit, Pfizer, 610 Main Street, Cambridge, MA 02139, USA.

Abstract

A 1,2,4-triazole motif was employed as a bioisostere for the ester commonly used in muscarinic antagonists, and subsequent integrative conjugation to a β2 agonist quinolinone furnished a new class of bifunctional MABAs for the treatment of COPD. Medicinal chemistry optimization using the principles of 'inhalation by design' furnished a clinical candidate with desirable pharmacological, pharmacokinetic and biopharmaceutical properties.

KEYWORDS:

Bifunctional; Bronchodilator; COPD; Inhalation by design; MABA

PMID:
26471092
DOI:
10.1016/j.bmcl.2015.10.008
[Indexed for MEDLINE]

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