Discovery of AZD3199, An Inhaled Ultralong Acting β2 Receptor Agonist with Rapid Onset of Action

Abstract

A series of dibasic des-hydroxy β2 receptor agonists has been prepared and evaluated for potential as inhaled ultralong acting bronchodilators. Determination of activities at the human β-adrenoreceptors demonstrated a series of highly potent and selective β2 receptor agonists that were progressed to further study in a guinea pig histamine-induced bronchoconstriction model. Following further assessment by onset studies in guinea pig tracheal rings and human bronchial rings contracted with methacholine (guinea pigs) or carbachol (humans), duration of action studies in guinea pigs after intratracheal (i.t.) administration and further selectivity and safety profiling AZD3199 was shown to have an excellent over all profile and was progressed into clinical evaluation as a new ultralong acting inhaled β2 receptor agonist with rapid onset of action.

Keywords: AZD3199; COPD; adrenoreceptor agonist; asthma; inhaled; uLABA; β2 receptor agonist.

Figure 1

Selection of known β₂AR agonists and sibenadet (a dual D₂ dopamine receptor, β₂-AR agonist).

Chart 1. Binding selectivity for AZD3199 vs. β₁ and β₃a

Chart 2. Onset of Relaxation of AZD3199 As Measured Using Guinea Pig Tracheal Rings Contracted with 1 μM Methacholine

Chart 3. Plot of Guinea Pig Onset Time vs. cLogP for a Selection of Monobasic or Dibasic Compounds

Chart 4. Duration of Action Studies in Guinea Pigs for AZD3199 and a Selection of Standard Compounds

Scheme 1. Chemical synthesis of AZD3199

Reagents and conditions: (a) 18 + (COCl)₂ (1.1 mol equiv), dimethyl formamide (cat.), CH₂Cl₂, rt, 15 h, concentrate and add to 17, Hunig’s base (2 mol equiv), CH₂Cl₂, rt, 20 h (75%). (b) (i) dimethyl sulfoxide (2.2 mol equiv), CH₂Cl₂, −78 °C, add (COCl)₂ (1.1 mol equiv), stir 15 min; (ii) add 19, stir 15 min; (iii) add triethylamine (5 mol equiv) and warm to rt 90 min; (iv) 20 in CH₂Cl₂, sodium triacetoxyborohydride (2 mol equiv), rt (27%).