Molecular hybridization yields triazole bronchodilators for the treatment of COPD

Lyn H Jones; Jane Burrows; Neil Feeder; Paul Glossop; Kim James; Rhys M Jones; Amy S Kenyon; Sheena Patel; Dannielle F Roberts; Matthew D Selby; Ross S Strang; Emilio F Stuart; Michael A Trevethick; Jessica Watson; Karen N Wright; Nick Clarke

doi:10.1016/j.bmcl.2015.10.008

Molecular hybridization yields triazole bronchodilators for the treatment of COPD

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

Authors

Affiliations

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.

PMID: 26471092
DOI: 10.1016/j.bmcl.2015.10.008

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.

MeSH terms

Adrenergic beta-2 Receptor Agonists / chemical synthesis*
Adrenergic beta-2 Receptor Agonists / pharmacokinetics
Adrenergic beta-2 Receptor Agonists / pharmacology
Animals
Biological Availability
Bronchoconstriction / drug effects
Bronchodilator Agents / chemical synthesis*
Bronchodilator Agents / pharmacokinetics
Bronchodilator Agents / pharmacology
CHO Cells
Cricetulus
Dogs
Humans
Ipratropium / pharmacology
Muscarinic Antagonists / chemical synthesis*
Muscarinic Antagonists / pharmacokinetics
Muscarinic Antagonists / pharmacology
Pulmonary Disease, Chronic Obstructive / drug therapy*
Rats
Receptor, Muscarinic M3 / antagonists & inhibitors
Salmeterol Xinafoate / pharmacology
Tiotropium Bromide / pharmacology
Triazoles / chemical synthesis*
Triazoles / pharmacokinetics
Triazoles / pharmacology

Substances

Adrenergic beta-2 Receptor Agonists
Bronchodilator Agents
Muscarinic Antagonists
PF-04810097
Receptor, Muscarinic M3
Triazoles
Salmeterol Xinafoate
Ipratropium
Tiotropium Bromide