The discovery of adamantyl-derived, inhaled, long acting β2-adrenoreceptor agonists

The many faces of the adamantyl group in drug design

“…The potency of 34 at human recombinant b adrenoreceptors in CHO cells was 60 pM, which compared well with the clinical b 2 -adrenoreceptor agonist salmeterol (70 pM) [153]. There was a 3-fold reduction in potency in the adamanyt-2-yl analogue, which underscores the specificity of interaction between the drug and receptor.…”

“…Adamantyl-based agents have been designed as b 2 -adrenoreceptor agonists (34) [153]. The potency of 34 at human recombinant b adrenoreceptors in CHO cells was 60 pM, which compared well with the clinical b 2 -adrenoreceptor agonist salmeterol (70 pM) [153].…”

“…There was a 3-fold reduction in potency in the adamanyt-2-yl analogue, which underscores the specificity of interaction between the drug and receptor. No significant affinity (<100 nM) of 34 was obtained for other receptors, enzymes or ion channels [153].…”

Lead Generation Approaches Delivering Inhaled β 2 ‐Adrenoreceptor Agonist Drug Candidates

“…This exercise led to the identification of 19 that had significantly longer duration of action than salmeterol in the ex vivo guinea pig trachea model (19 β 2 EC 50 0.030 nM, β 1 /β 2 6339, t 1/2 9.0 h, log D 2.6) while retaining pharmacokinetic properties similar to that of 17. Further efforts toward identifying a back-up compound presenting a similar overall profile to that of 19 as well as an efficient synthetic route amenable to scale-up yielded clinical candi date 20 in which an adamantyl group replaced the dichloro-benzyl amine moiety (20 β 2 EC 50 0.060 nM, β 1 /β 2 2211, t 1/2 similar to 19, log D 2.1) [30].…”

Emerging inhaled bronchodilators: an update

“…Evaluation of these analogues demonstrates that they have a salmeterol-like duration of action with the potential for long duration of action in humans. The discovery of adamantyl-derived inhaled LABAs that would exhibit low oral bioavailability compared to salmeterol in order to reduce systemic effects through the swallowed fraction after inhalation has also been discussed [48]. An amide derivative showed twice the duration of action of salmeterol at coefficient-ofvariation-tolerated doses and exhibited comparable lung absorption rates, with high clearance, a short half-life (1.6 h) and low oral bioavailability.…”