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

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Abstract

Libraries of dibasic compounds designed around the molecular scaffold of the DA22 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.

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      Finally, other work identified compound c (Fig. 8) to be potent and efficacious at the β2-adrenoceptor, to have good selectivity over closely related receptors and long duration of action in a bronchoconstriction guinea pig model, which is superior to that of both formoterol and salmeterol, and similar to that of indacaterol. Due to its promising profile, compound c of Fig. 8 (as the bis-malonate salt) was progressed into further development [90]. The research interest in the pharmaceutical industry has been currently directed to the development of Ultra-LABAs with improved duration of action over the most used LABAs, salmeterol and formoterol.

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