<i>In Vitro</i>Characterization of TD-4208, a Lung-Selective and Long-Acting Muscarinic Antagonist Bronchodilator.

Steinfeld, Tod; Pulido-Rios, MT; Chin, Kay H.; King, Keith D.; Jx, Huang; Tw, Lee; Jasper, JR; Ji, Yuhua; Hegde, Sharath S.; Mammen, Mathai

doi:10.1164/ajrccm-conference.2009.179.1_meetingabstracts.a4553

Cited by 6 publications

(5 citation statements)

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“…By contrast, the bronchoprotective potency of glycopyrronium decreased by 6-fold after repeat dosing. The loss in potency of glycopyrronium was unexpected since the pharmacological and kinetic binding selectivity profiles for muscarinic M 2 and M 3 receptors are similar for the three compounds (Haddad et al, 1994(Haddad et al, , 1999Steinfeld et al, 2009). This phenomenon may be either species-specific for glycopyrronium activity in the rat or a consequence of negative feedback mechanisms from blockade of M 2 autoreceptors at the highest dose tested (Aas and Fig.…”

Section: Pharmacology Of Lung-selective Muscarinic Antagonist Td-4208mentioning

confidence: 99%

In Vivo Pharmacological Characterization of TD-4208, a Novel Lung-Selective Inhaled Muscarinic Antagonist with Sustained Bronchoprotective Effect in Experimental Animal Models

Pulido‐Rios¹,

McNamara²,

Obedencio³

et al. 2013

J Pharmacol Exp Ther

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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 dosedependent 24-hour bronchoprotection against methacholineinduced bronchoconstriction. The estimated 24-hour potency (expressed as concentration of dosing solution) was 45.0 mg/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.

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Section: Pharmacology Of Lung-selective Muscarinic Antagonist Td-4208mentioning

confidence: 99%

In Vivo Pharmacological Characterization of TD-4208, a Novel Lung-Selective Inhaled Muscarinic Antagonist with Sustained Bronchoprotective Effect in Experimental Animal Models

Pulido‐Rios¹,

McNamara²,

Obedencio³

et al. 2013

J Pharmacol Exp Ther

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“…Revefenacin (TD-4208) (Chart ) is a novel LAMA that differs from other LAMAs in its chemical structure. It has a high affinity for the human M3 receptor with a K i value of 0.18 nM. , A 28-day, randomized, double-blind, placebo-controlled, parallel group phase II study of nebulized revefenacin (88, 175, or 350 μg) in 355 patients with COPD demonstrated that revefenacin significantly improved D28 through FEV 1 at a dose ≥88 μg, and in the first 4 h post dose, an increase in FEV 1 of at least 100 mL from baseline was observed in more than 80% of patients; further, the bronchodilation was sustained for 24 h. The 350 μg dose did not give additional efficacy compared with the 175 μg dose, which indicates that 88 and 175 μg doses are appropriate. In addition, patients were tolerant to a high dose (350 μg) of revefenacin, and no safety issues were found .…”

Section: Lmwds For the Treatment Of Copdmentioning

confidence: 99%

Targeted Treatments for Chronic Obstructive Pulmonary Disease (COPD) Using Low-Molecular-Weight Drugs (LMWDs)

Zhou

et al. 2019

J. Med. Chem.

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Chronic obstructive pulmonary disease (COPD) is a very common and frequently fatal airway disease. Current therapies for COPD depend mainly on long-acting bronchodilators, which cannot target the pathogenic mechanisms of chronic inflammation in COPD. New pharmaceutical therapies for the inflammatory processes of COPD are urgently needed. Several anti-inflammatory targets have been identified based on increased understanding of the pathogenesis of COPD, which raises new hopes for targeted treatment of this fatal respiratory disease. In this review, we discuss the recent advances in bioactive low-molecular-weight drugs (LMWDs) for the treatment of COPD and, in addition to the first-line drug bronchodilators, focus particularly on low-molecular-weight anti-inflammatory agents, including modulators of inflammatory mediators, inflammasome inhibitors, protease inhibitors, antioxidants, PDE4 inhibitors, kinase inhibitors, and other agents. We also provide new insights into targeted COPD treatments using LMWDs, particularly small-molecule agents.

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“…Preclinical data have shown enhanced affinity for the M 3 compared with M 2 receptors, and a prolonged duration of action of >16 h with no safety concerns [14,15]. In preclinical studies, TD-4208 has shown greater functional selectivity for the lung.…”

Section: Anticholinergicsmentioning

confidence: 99%

Emerging therapeutic strategies in COPD

Babu

Morjaria

2015

Drug Discovery Today

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In VitroCharacterization of TD-4208, a Lung-Selective and Long-Acting Muscarinic Antagonist Bronchodilator.

Cited by 6 publications

References 0 publications

In Vivo Pharmacological Characterization of TD-4208, a Novel Lung-Selective Inhaled Muscarinic Antagonist with Sustained Bronchoprotective Effect in Experimental Animal Models

In Vivo Pharmacological Characterization of TD-4208, a Novel Lung-Selective Inhaled Muscarinic Antagonist with Sustained Bronchoprotective Effect in Experimental Animal Models

Targeted Treatments for Chronic Obstructive Pulmonary Disease (COPD) Using Low-Molecular-Weight Drugs (LMWDs)

Emerging therapeutic strategies in COPD

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