Synthesis and Structure−Activity Relationships of Long-acting β₂ Adrenergic Receptor Agonists Incorporating Arylsulfonamide Groups

Abstract

A series of saligenin alkoxyalkylphenylsulfonamide beta(2) adrenoceptor agonists were prepared by reacting a protected saligenin oxazolidinone with alkynyloxyalkyl bromides, followed by Sonogashira reaction, hydrogenation, and deprotection. The meta-substituted primary sulfonamide was more potent than the para- and the ortho-analogues. Primary sulfonamides were more potent than the secondary and tertiary analogues. The onset and duration of action in vitro of selected compounds was assessed on isolated superfused guinea pig trachea. Sulfonamide 29b had the best profile of potency, selectivity, onset, and duration of action on both guinea pig trachea and human bronchus. Furthermore, 29b was found to have low oral bioavailability in rat and dog and also to have long duration of action in an in vivo model of bronchodilation. Crystalline salts of 29b were identified that had suitable properties for inhaled administration. A proposed binding mode for 29b to the beta(2)-receptor is presented.

Slow receptor dissociation is not a key factor in the duration of action of inhaled long‐acting β2‐adrenoceptor agonists

“…Salmeterol and salbutamol hemisulfate were obtained from Tocris Cookson Inc. (Bristol, UK). A related sulfonamide analogue of salmeterol 3‐[4‐[[6‐[[(2 R )‐2‐hydroxy‐2‐[4‐hydroxy‐3 (hydroxymethyl)phenyl]ethyl]amino]hexyl] oxy]butyl]benzenesulfonamide (Compound 1; Procopiou et al ., 2009; Rosethorne et al ., 2010) and indacaterol were synthesized by Global Discovery Chemistry (Novartis, Horsham, UK). All cell culture reagents including HBSS and HEPES were purchased from Gibco (Invitrogen, Paisley, UK).…”

Recent Advances in β2-Agonists for Treatment of Chronic Respiratory Diseases and Heart Failure

“…A number of novel β 2 -agonists have appeared in recent literature, but detailed information about their further development are hardly available. Procopiou et al have synthesized a series of LABAs incorporating an arylsulfonamide group . Compound 11 was identified as a candidate compound that possesses a high potency and a long duration of action.…”

“…Procopiou et al have synthesized a series of LABAs incorporating an arylsulfonamide group. 192 Compound 11 was identified as a candidate compound that possesses a high potency and a long duration of action. To search for new LABAs, chemists in Pfizer have designed and synthesized a series of saligenin analogues 193,194 including compounds 11, 12, 13, 14, and 15.…”

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

“…They would also explore key interactions with the predicted residues in the exosite binding pocket through the generation of a homology model to assist the understanding of the SAR for the aryl sulfona mide series of compounds (Figure 20.10). In their design concept [38], they chose to utilize the saligenin head group present in salmeterol, and explore sub stitution of the distal aryl group that had been proposed to extend to the exocite β 2 AR binding pocket with a variety of polar sulfonamide groups, such as shown in the generic structure 24, to increase polar surface area and the number of rotatable bonds to, therefore, limit oral absorption.…”