From libraries to candidate: The discovery of new ultra long-acting dibasic β2-adrenoceptor agonists

• Published in: Bioorganic & medicinal chemistry letters 2012-01, Vol.22 (1), p.689-695
• Main Authors: Alcaraz, Lilian, Bailey, Andrew, Cadogan, Elaine, Connolly, Stephen, Jewell, Robert, Jordan, Stephen, Kindon, Nicholas, Lister, Andrew, Lawson, Mandy, Mullen, Alexander, Dainty, Ian, Nicholls, David, Paine, Stuart, Pairaudeau, Garry, Stocks, Michael J., Thorne, Phillip, Young, Alan
• Format: Article
• Language: English
• Subjects: Adrenergic beta-Agonists - chemical synthesis; Adrenergic beta-Agonists - pharmacology; Adrenoceptor agonist; agonists; Animals; Asthma; Asthma - drug therapy; beta-adrenergic agonists; Biological and medical sciences; Bronchodilator Agents - pharmacology; Cell Line, Tumor; chemistry; Chemistry, Pharmaceutical - methods; COPD; Cyclic AMP - metabolism; Drug Design; Duration; Guinea Pigs; Humans; Inhaled; Inhibitory Concentration 50; LABA; Medical sciences; Models, Chemical; pharmacokinetics; Pharmacology. Drug treatments; Protein Binding; Pulmonary Disease, Chronic Obstructive - drug therapy; Thiazoles - pharmacology; Time Factors; β2-Agonist
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2011.10.049

Libraries of dibasic compounds designed around the molecular scaffold of the DA2/β2 dual agonist sibenadet (Viozan™) have yielded a number of promising starting points that have been further optimised into novel potent and selective target molecules with required pharmacokinetic properties. From a shortlist, 31 was discovered as a novel, high potency, and highly efficacious β2-agonist with high selectivity and a duration of action commensurable with once daily dosing.