Inhalation by design: Dual pharmacology β-2 agonists/M3 antagonists for the treatment of COPD

A Perspective on Synthetic and Solid-Form Enablement of Inhalation Candidates

“…Like MABA compounds, these consist of two pharmacophores connected by a linking group; either a bis-amide, an oxazole or a urea portion. The use of conventional bondforming chemistry (e.g., Suzuki reaction and amide formations) to assemble these molecules from the respective pharmacophoric fragments also echoes the approach that has been taken to combine LAMA and LABA activities [16][17][18][19].…”

“…Furthermore, dosing of a dual-pharmacology molecule would, potentially, allow co-dosing with another agent, giving a much coveted 'triple therapy' from a single dose. Currently, the most widely investigated class combines separate muscarinic antagonist-b 2 agonist (MABA) pharmacophores in a single molecule [16][17][18][19]. An early example of an alternate dual approach was sibenadet (FiguRe 2), combining b 2 and D 2 agonism within a single pharmacophore [20].…”

“…This initially isolated salt is then recrystallized to provide suitable quality material (93% yield). Pfizer have recently disclosed a summary of their efforts in developing a series of tolterodinederived MABA compounds [17,115], wherein known muscarinic antagonist tolterodine (39) is linked to a selection of known b 2 agonist motifs. Several of the examples disclosed are prepared from 39, a readily available commercial product.…”

“…This route was also used to prepare some of the aminoindanes used in [17,115,119,120,[122][123][124][125][126][127][128][129].…”

Pharmacology and Therapeutics of Bronchodilators

“…This would create larger molecules with high lipophilicity that are likely to possess high metabolism and low oral absorption to minimize potential systemically driven side effects from the swallowed component after inhalation (Jones et al, 2011b). This approach may offer several advantages over combination therapy of two separate drug entities.…”