生物活性

• 描述TD-4208 (Revefenacin) is a potent mAChR antagonist; has a high affinity on M3 receptor with a Ki of 0.18 nM. At human recombinant mAChRs, revefenacin displayed high affinity (pKI = 8.2-9.8) and behaved as a competitive antagonist (pKI, apparent = 9.4-10.9) at the five human recombinant mAChRs. In isolated tracheal tissues from rat and guinea pig and isolated bronchial tissues from humans, revefenacin potently antagonized mAChR-mediated contractile responses. Furthermore, the antagonistic effects of revefenacin in rat, guinea pig, and human airway tissues were slowly reversible (t1/2 of 13.3, >16, and >10 hours, respectively) ^[1]. In anesthetized dogs, TD-4208, along with tiotropium and glycopyrronium, produced sustained inhibition of acetylcholine-induced bronchoconstriction for up to 24 hours. In anesthetized rats, inhaled TD-4208 exhibited dose-dependent 24-hour bronchoprotection against methacholine-induced bronchoconstriction. The calculated lung selectivity index (i.e., ratio of antisialagogue and bronchoprotective potency) of TD-4208 was superior to glycopyrronium after both single and repeat dosing regimens and was superior to tiotropium after repeat dosing^[2]. 88 and 175 μg revefenacin are appropriate doses for use in longer-term safety and efficacy trials. Revefenacin offers the potential for the first once-daily LAMA (long-acting muscarinic antagonist) for nebulization in patients with COPD (chronic obstructive pulmonary disease) who require or prefer a nebulized drug delivery option^[3].