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Discovery of TD-4306, a long-acting β2-agonist for the treatment of asthma and COPD.

Abstract：

:A multivalent approach focused on amine-based secondary binding groups was applied to the discovery of long-acting inhaled β2-agonists. Addition of amine moieties to the neutral secondary binding group of an existing β2-agonist series was found to provide improved in vivo efficacy, but also led to the formation of biologically active aldehyde metabolites which were viewed as a risk for the development of these compounds. Structural simplification of the scaffold and blocking the site of metabolism to prevent aldehyde formation afforded a potent series of dibasic β2-agonists with improved duration of action relative to their monobasic analogs. Additional optimization led to the discovery of 29 (TD-4306), a potent and selective β2-agonist with potential for once-daily dosing.

journal_name

Bioorg Med Chem Lett

journal_title

Bioorganic & medicinal chemistry letters

authors

McKinnell RM,Klein U,Linsell MS,Moran EJ,Nodwell MB,Pfeiffer JW,Thomas GR,Yu C,Jacobsen JR

doi

10.1016/j.bmcl.2014.04.095

subject

Has Abstract

pub_date

2014-07-01 00:00:00

pages

2871-6

issue

13

eissn

0960-894X

issn

1464-3405

pii

S0960-894X(14)00452-1

journal_volume

24

pub_type

杂志文章

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