Discovery of TD-4306, a long-acting β2-agonist for the treatment of asthma and COPD

McKinnell, R. Murray; Klein, Uwe; Linsell, Martin S.; Moran, Edmund J.; Nodwell, Matthew B.; Pfeiffer, Juergen; Thomas, Glyn; Yu, Cecile; Jacobsen, John R.

doi:10.1016/j.bmcl.2014.04.095

Cited by 13 publications

(7 citation statements)

References 28 publications

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“…McKinnel and co-workers (Theravance) investigated a new generation of long-lasting β 2 -agonists ( 168 ) for the treatment of respiratory disorders (Scheme a) . The target compounds were generated in a highly convergent synthetic route in which aryl bromide 166 and highly functionalized aniline 167 were coupled near the end of the sequence.…”

Section: Anilinesmentioning

confidence: 99%

Applications of Palladium-Catalyzed C–N Cross-Coupling Reactions

2016

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Pd-catalyzed cross-coupling reactions that form C–N bonds have become useful methods to synthesize anilines and aniline derivatives, an important class of compounds throughout chemical research. A key factor in the widespread adoption of these methods has been the continued development of reliable and versatile catalysts that function under operationally simple, user-friendly conditions. This review provides an overview of Pd-catalyzed N-arylation reactions found in both basic and applied chemical research from 2008 to the present. Selected examples of C–N cross-coupling reactions between nine classes of nitrogen-based coupling partners and (pseudo)aryl halides are described for the synthesis of heterocycles, medicinally relevant compounds, natural products, organic materials, and catalysts.

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Section: Anilinesmentioning

confidence: 99%

Applications of Palladium-Catalyzed C–N Cross-Coupling Reactions

2016

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“…Further evaluation and modification of milveterol and TD-5471 through the addition of amine moieties and scaffold modification led to the development of the dibasic β 2 agonist, TD-4306. 73 TD-4306 has a β 2 pED50 of 10.1, and 70% intrinsic activity in the BEAS endogenous cell line assay. In the in vivo guinea pig bronchoprovocation model, TD-4306 provided significantly greater, dosedependent bronchoprotection than salmeterol.…”

Section: Td-4306mentioning

confidence: 99%

<p>Ultra Long-Acting β-Agonists in Chronic Obstructive Pulmonary Disease</p>

Burkes¹,

Panos²

2020

JEP

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Introduction Inhaled β-agonists have been foundational medications for maintenance COPD management for decades. Through activation of cyclic adenosine monophosphate pathways, these agents relax airway smooth muscle and improve expiratory airflow by relieving bronchospasm and alleviating air trapping and dynamic hyperinflation improving breathlessness, exertional capabilities, and quality of life. β-agonist drug development has discovered drugs with increasing longer durations of action: short acting (SABA) (4–6 h), long acting (LABA) (6–12 h), and ultra-long acting (ULABA) (24 h). Three ULABAs, indacaterol, olodaterol, and vilanterol, are approved for clinical treatment of COPD. Purpose This article reviews both clinically approved ULABAs and ULABAs in development. Conclusion Indacaterol and olodaterol were originally approved for clinical use as monotherapies for COPD. Vilanterol is the first ULABA to be approved only in combination with other respiratory medications. Although there are many other ULABA’s in various stages of development, most clinical testing of these novel agents is suspended or proceeding slowly. The three approved ULABAs are being combined with antimuscarinic agents and corticosteroids as dual and triple agent treatments that are being tested for clinical use and efficacy. Increasingly, these clinical trials are using specific COPD clinical characteristics to define study populations and to begin to develop therapies that are trait-specific.

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“…Амины известны своей высокой аффинностью к легочной ткани (возможно, через лизосомальное секционирование), и их добавление к нейтральным вторично связанным группам в серии существующих β 2 -агонистов приводило к улучшению эффектив-ности in vivo, но одновременно сопровождалось образованием биологически активных альдегидных метаболитов [66]. Включение основных вторично связанных групп к сальметеролу приводило к блоки-рованию метаболизма, предотвращая образование альдегидов, образуемых при применении TD-4306 -β 2 -агониста с более высокой продолжительностью действия по сравнению с сальметеролом.…”

Section: обзорыunclassified

Progress and Prospects for Long-Acting Β 2 -Agonists in the Treatment of Chronic Obstructive Pulmonary Disease

Mario¹,

Ermanno²,

Ora³

et al. 2018

BCCM

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Статья итальянских авторов дает полное пред-ставление о развитии адреномиметиков ультрадли-тельного действия при ХОБЛ. Ценность статьи -во всесторонней оценке проблемы, отсутствии ангажированности и тенденциозности в изложении проблемы. Мы надеемся, что знакомство с русской версией статьи обогатит наших читателей новыми знаниями и расширит их мировоззрение. Реферат. Лечение хронической обструктивной болезни легких (ХОБЛ), как правило, предполагает назначение комбинации лекарственных препаратов, одним из которых зачастую является агонист β 2 -адренорецепторов. Цель данной статьи -представить информацию об агонистах β 2 -адренорецепторов длительного действия (ультра-ДДВА) -современную форму препаратов, обеспечивающую высокую приверженность пациентов к лечению, благодаря упрощенной схеме приема 1 раз в сут. Материал и методы. Проанализированы совре-менные литературные данные об агонистах β 2 -адренорецепторов. В частности, новейшие данные о применении ультра-ДДВА в лечении ХОБЛ, а также вопросы безопасности препарата для сердечно-сосудистой системы. Результаты и их обсуждение. Рассматривается инновационный метод назначения фиксированных доз ДДБА в комбинации с антихолинергическими препаратами длительного действия (ДДАХ) и/или с ингаляционными кор-тикостероидами, а также новейших препаратов ультра-ДДВА, находящихся на этапах клинического исследования и доклинической разработки. Выводы. Огромный интерес к разработке новых агонистов β 2 -адренорецепторов длительного действия значительно снизился за последние годы. Тем не менее ультра-ДДВА считаются одним из основных компонентов лечения ХОБЛ в комбинации с другими классами препаратов (ДДАХ и ингаляционные кортикостероиды), которые в настоящее время находятся на этапе внедрения для регулярного использования. Vergata, Via Montpellier,1, Italy, 00133, Rome, Abstract. Aim. The treatment of chronic obstructive pulmonary disease (COPD) is generally based on the assumption of drug combinations in which β 2 -agonists are commonly included. Ultra-LABAs were developed to induce a greater adherence to the treatment as a result of the simplification of treatment with the reduction of the daily dose to be taken. Material and methods. We analyzed the current literature data on β 2 -adrenergic agonists. The potential positioning of ultra-LABAs in the treatment of COPD and their cardiovascular safety is discussed according to the new information on the topics. Results and discussion. The novel fixed-dose combinations of ultra-LABAs with LAMAs and/or ICSs are examined, as well as the novel ultra-LABAs under clinical development and the ultra-LABAs in preclinical development. PROGRESS AND PROSPECTS FOR LONG-ACTING β 2 -AGONISTS IN THE TREATMENT OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE

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Discovery of TD-4306, a long-acting β2-agonist for the treatment of asthma and COPD

Cited by 13 publications

References 28 publications

Applications of Palladium-Catalyzed C–N Cross-Coupling Reactions

Applications of Palladium-Catalyzed C–N Cross-Coupling Reactions

<p>Ultra Long-Acting β-Agonists in Chronic Obstructive Pulmonary Disease</p>

Progress and Prospects for Long-Acting Β 2 -Agonists in the Treatment of Chronic Obstructive Pulmonary Disease

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