Department of Pharmacology, Theravance, Inc., South San Francisco, CA 94080, USA.
J Pharmacol Exp Ther. 2013 Aug;346(2):241-50. doi: 10.1124/jpet.113.203554. Epub 2013 May 17.
Tiotropium is currently the only once-daily, long-acting muscarinic antagonist (LAMA) approved in the United States and other countries for the treatment of chronic obstructive pulmonary disease (COPD). Glycopyrronium has shown promise as a LAMA and was recently approved for once-daily maintenance treatment of COPD in the European Union. Here, we describe the in vivo preclinical efficacy and lung selectivity of a novel inhaled muscarinic antagonist, TD-4208 (biphenyl-2-ylcarbamic acid 1-(2-{[4-(4-carbamoylpiperidin-1-ylmethyl)benzoyl]methylamino}ethyl)piperidin-4-yl ester) and compare its profile to tiotropium and glycopyrronium. 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 estimated 24-hour potency (expressed as concentration of dosing solution) was 45.0 µg/ml. The bronchoprotective potencies of TD-4208 and tiotropium were maintained after 7 days of once-daily dosing, whereas glycopyrronium showed a 6-fold loss in potency after repeat dosing. To assess systemic functional activity using a clinically relevant readout, the antisialagogue effect of compounds was also evaluated. 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. In conclusion, the in vivo preclinical profile suggests that TD-4208 has the potential to be a long-acting bronchodilator for once-daily treatment of respiratory diseases. Its greater functional selectivity for the lung in preclinical models may translate to an improved tolerability profile compared with marketed muscarinic receptor antagonists.
噻托溴铵是目前唯一一种在美国和其他国家获得批准的、每日一次的长效毒蕈碱拮抗剂（LAMA），用于治疗慢性阻塞性肺疾病（COPD）。 格隆溴铵作为一种 LAMA 显示出良好的前景，并于最近在欧盟获得批准，用于 COPD 的每日一次维持治疗。在这里，我们描述了一种新型吸入性毒蕈碱拮抗剂 TD-4208（联苯-2-基氨基甲酸 1-（2-[[4-（4-脒基哌啶-1-基甲基）苯甲酰基]甲基氨基]乙基）哌啶-4-基酯）的体内临床前疗效和肺选择性，并将其与噻托溴铵和格隆溴铵进行比较。 在麻醉犬中，TD-4208 与噻托溴铵和格隆溴铵一起，可长达 24 小时持续抑制乙酰胆碱诱导的支气管收缩。 在麻醉大鼠中，吸入 TD-4208 可对乙酰甲胆碱诱导的支气管收缩产生剂量依赖性的 24 小时支气管保护作用。 估计 24 小时的效价（以给药溶液的浓度表示）为 45.0µg/ml。 在每日一次给药 7 天后，TD-4208 和噻托溴铵的支气管保护效力得以维持，而格隆溴铵在重复给药后效力降低 6 倍。 为了使用临床相关的读出值评估系统功能活性，还评估了化合物的抗涎作用。 在单次和重复给药方案后，TD-4208 的计算肺选择性指数（即抗涎作用和支气管保护效力的比值）均优于格隆溴铵，且在重复给药后优于噻托溴铵。 总之，体内临床前研究结果表明，TD-4208 具有成为一种长效支气管扩张剂的潜力，可用于治疗呼吸道疾病的每日一次治疗。 在临床前模型中，其对肺的功能选择性更高，与市售的毒蕈碱受体拮抗剂相比，可能具有更好的耐受性。
