The design of a novel series of muscarinic receptor antagonists leading to AZD8683, a potential inhaled treatment for COPD

Emerging therapeutic strategies in COPD

“…AZD8683 (AstraZeneca, UK), after rigorous preclinical evaluation for onset of action, efficacy and safety, was selected for formal assessment in clinical studies [19]. Phase I studies reported no safety concerns (NCT00979849) and, more recently, Phase II studies in COPD subjects (NCT01205269, NCT01708057) at various doses of AZD8683 versus placebo and tiotropium have been conducted and results are awaited.…”

Discovery of novel quaternary ammonium derivatives of (3 R )-quinuclidinyl amides as potent and long acting muscarinic antagonists

“…However, as quaternary compounds, their predicted low absorption could minimize undesired effects due to systemic availability and lack of selectivity. 17,19 Studies of human plasma stability and metabolism in human microsomes were performed to evaluate the potential of these compounds to be able to show minimized anticholinergic side effects upon systemic exposure. The results obtained for the representative compound 4a are reported.…”

“…The quaternization of the tertiary amino group is widely used in this class of compounds to limit their absorption across membranes, which results in low oral bioavailability and low blood-brain barrier permeability, consequently minimizing typical anticholinergic side effects associated with the binding of systemically available compound to muscarinic receptors outside the respiratory tract. [15][16][17] Aclidinium bromide has also demonstrated low potential for systemic class-related side effects due to its rapid human plasma hydrolysis. 18 During the progress of the Almirall research program to discover novel long acting muscarinic antagonists (LAMA) for the inhaled treatment of COPD 18,19 with low potential for systemic class-related effects, that has delivered aclidinium bromide, 20 novel (3R)-quinuclidinyl amides and their quaternary ammonium derivatives were identified as potent antimuscarinic compounds.…”

Discovery and optimization of 3-(4-aryl/heteroarylsulfonyl)piperazin-1-yl)-6-(piperidin-1-yl)pyridazines as novel, CNS penetrant pan-muscarinic antagonists

“…1–4 However, the development of small molecule ligands that are selective for M 4 , or any of the individual mAChRs, has proven to be challenging due to the high sequence homology amongst the receptor subtypes. 5–8 Historically, mAChR antagonists possessed somewhat conserved chemotypes, exemplified by a basic tertiary or quaternary amine, and compounds with these functional groups represent the bulk of high-throughput screening (HTS) hits (the ‘usual suspects’) and marketed drugs 1 - 4 (Figure 1). 9–11 Thus, we were delighted to identify fundamentally new chemotypes in an M 4 functional HTS campaign, which was subsequently optimized to deliver potent and CNS penetrant antagonists such as 5 ; however, despite the absence of the classical pharmacophore, 5 proved to be a pan -muscarinic antagonist that bound to the orthosteric (ACh) site.…”