The In-Vitro Pharmacology Of PF-4348235 At Recombinant Receptors - A Novel Inhaled Dual Antimuscarinic/Beta2 Adrenoceptor Agonist

Optimized glucuronidation of dual pharmacology β-2 agonists/M3 antagonists for the treatment of COPD

“…Next, we attempted to enhance/switch on glucuronidation of the MABA through the introduction of halogen atoms to increase the acidity of the phenol (and similarly through the incorporation of a nitrile group in compound 10). 9 Although this strategy was unsuccessful for the ortho-and metaphenols (8-12), a breakthrough for the project was realized when this approach was applied to the para-substituted phenol as this provided a significant increase in glucuronidation rates, whilst maintaining the desirable dual pharmacology (13,14,15). Indeed, the substitution pattern of the chloro-phenol 15 seemed an optimal balance of metabolic vulnerability and dual pharmacology and this group was retained for further work.…”

“…12 Pleasingly, values were indicative of long residency at both receptors (Table 2). 13 We then assessed the potency of 15 in the guinea-pig trachea (GPT) model using electric field stimulation to release endogenous acetylcholine. 14 The drive for bronchoconstriction in this model operates through both b-2 and M3 mechanisms and therefore values here reflect combined bronchodilatory effects.…”