Characteristics of AZD9708, a novel, selective β2-adrenoceptor agonist with rapid onset and long duration of action.
Here we describe the pre-clinical pharmacological profile of AZD9708, a novel long-acting β(2)-adrenoceptor agonist that has potential as a once-daily therapy for asthma and chronic obstructive pulmonary disease (COPD). AZD9708 is a potent and selective agonist at the human β(2)-adrenoceptor, with selectivity over human β(1)- and β(3)-adrenoceptors of >500 and >24 fold, respectively. AZD9708 relaxes carbachol-induced contraction of human bronchial rings with a time to 90% of maximal relaxation of 13-20 min, similar to that seen with formoterol and quicker than salmeterol. In anesthetized guinea pigs, AZD9708 provides significant protection against histamine-induced airway constriction at 24 h after intratracheal and nebulized doses. This is longer than with intratracheal salmeterol, which is bronchoprotective for approximately 8 h, and formoterol, which is bronchoprotective for 8 and 12 h following nebulized and intratracheal dosing, respectively. AZD9708 also shows the potential for a greater therapeutic margin than widely used β(2)-adrenoceptor agonists such as formoterol. At a defined efficacy dose that provides 80% bronchoprotection (ED(80)), formoterol leads to a decrease in blood potassium levels in guinea pigs, whilst AZD9708 is not associated with significant reductions in potassium levels at doses up to 7 times the ED(80). [(14)C]AZD9708 is associated with extensive protein binding in both human (mean 1.0% free) and rat (mean 2.6% free) plasma. This pharmacological profile indicates the potential of AZD9708 to become an important addition to the range of bronchodilators available for the treatment of patients with obstructive airways disease.
AstraZeneca R&D Charnwood, Loughborough LE11 5RH, UK. david.nicholls@astrazeneca.com
D J
DJ
Nicholls
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Jordan
E
E
Cadogan
M
M
Lawson
R P
RP
Austin
S W
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Paine
P
P
Gardiner
R
R
Bonnert
S
S
Connolly
A
A
Young
D000249:Adenosine Monophosphate / Q000378:metabolism; D058666:Adrenergic beta-2 Receptor Agonists / Q000494:pharmacology*; D000420:Albuterol / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D001249:Asthma / Q000188:drug therapy / Q000503:physiopathology; D052160:Benzothiazoles / Q000494:pharmacology*; D001798:Blood Proteins / Q000378:metabolism; D001980:Bronchi / Q000187:drug effects; D001993:Bronchodilator Agents / Q000494:pharmacology; D004983:Ethanolamines / Q000494:pharmacology; D000068759:Formoterol Fumarate; D006168:Guinea Pigs; D006801:Humans; D008297:Male; D009126:Muscle Relaxation / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy / Q000503:physiopathology; D018343:Receptors, Adrenergic, beta-2 / Q000378:metabolism; D000068299:Salmeterol Xinafoate; D013997:Time Factors; D015091:beta-Alanine / Q000031:analogs & derivatives* / Q000494:pharmacology
D058666:Adrenergic beta-2 Receptor Agonists; D052160:Benzothiazoles; D001798:Blood Proteins; D001993:Bronchodilator Agents; D004983:Ethanolamines; C576735:N-cyclohexyl-N3-(2-(3-fluorophenyl)ethyl)-N-(2-((2-(4-hydroxy-2-oxo-2,3-dihydro-1,3-benzothiazol-7-yl)ethyl)amino)ethyl)-beta-alaninamide; D018343:Receptors, Adrenergic, beta-2; D015091:beta-Alanine; D000249:Adenosine Monophosphate; D000068299:Salmeterol Xinafoate; D000420:Albuterol; D000068759:Formoterol Fumarate