Source: Annual Congress 2010 - New treatments for asthma and COPD
Disease area: Airway diseases

Abstract

BACKGROUND: Nicotinic acetylcholine receptors are expressed on immune and structural cells and associated with immunological responses. ASM-024, a small synthetic nicotinic agonist with dual anti-inflammatory and bronchodilating properties, has thus far been administered either orally or by inhalation in two Phase I studies.
OBJECTIVES: To identify metabolites of ASM-024 in humans and assess their in vitro pharmacological activity.
METHODS: ASM-024 inhibition of cytochrome P450 (CYP) was evaluated in vitro using human liver microsomes and its metabolic profile assessed in vitro in microsomes and in urine from healthy subjects. Metabolite identification was performed by HPLC-MS and NMR. The identified metabolite was chemically synthesized and tested for its inhibitory potential of LPS-stimulated TNF release by human monocytes and its myorelaxing effect on methacholine pre-contracted mouse tracheas.
RESULTS: ASM-024 showed low to moderate inhibition of CYP2D6 (IC₅₀ =16 μM, Ki=36 μM). One metabolite was identified both in vitro and following oral administration as an oxidation product of the parent compound. High urinary excretion was observed. Relatively low levels were also detected in plasma. The metabolite displayed no myorelaxing effects (~2000 µM versus 71 µM for ASM-024) and induced a decline in TNF release associated with a decreased cellular viability at concentrations >10 µM.
CONCLUSION: ASM-024 administered orally undergoes extensive metabolism in humans, with a large percentage excreted in urine as an oxidized metabolite. The metabolic pattern of ASM-024 following inhalation is currently under investigation.

Rating:

Share or cite this content

Citations should be made in the following way:
Y. Cormier, E. Israël-Assayag, M. C. Pepin, L. Vachon (Quebec City, Canada). Metabolism of ASM-024, a novel nicotinic agonist being developed for the treatment of asthma. Eur Respir J 2010; 36: Suppl. 54, 1172

Member's Comments

No comment yet.

Related content which might interest you: A phase I inhalation study on ASM-024, a novel nicotinic agonist being developed for the treatment of asthma Source: Annual Congress 2010 - New treatments for asthma and COPD Year: 2010 Potential role of memantine in the prevention and treatment of COVID-19: its antagonism of nicotinic acetylcholine receptors and beyond Source: Eur Respir J, 56 (2) 2001610; 10.1183/13993003.01610-2020 Year: 2020 A novel dual-agonist challenge model in guinea pigs for assessment of individual and combined muscarinics antagonists and b2 adrenoceptor agonists bronchodilator efficacy Source: Annual Congress 2011 - Models of disease and drug actions Year: 2011 Long-acting muscarinic antagonists: a potential add-on therapy in the treatment of asthma? Source: Eur Respir Rev 2015; 25: 54-64 Year: 2016 In vitro pharmacological profile of CHF 5407, a potent, long-acting and selective muscarinic M3 receptor antagonist Source: Eur Respir J 2007; 30: Suppl. 51, 25s Year: 2007 Efficacy of UR-63325, a new H4 receptor antagonist, in two rodent asthma models Source: Annual Congress 2010 - Models of airways disease Year: 2010 The antitussive effects of alpha7 (a7) nicotinic receptor agonists Source: International Congress 2017 – Novel studies on bronchodilators and cough Year: 2017 A novel lung pharmacokinetic model predicts lung exposure and supports dose selection for clinical study of AZD2115, a dual muscarinic receptor antagonist/beta2 adrenoceptor agonist (MABA) Source: International Congress 2015 – Notable abstracts in exacerbations, mechanisms and biomarkers in COPD Year: 2015 Pharmacological profile of a novel, potent and oral TRPA1 antagonist. Characterization in a preclinical model of induced cough Source: International Congress 2015 – Novel treatments for cough, asthma, COPD and bronchiectasis Year: 2015 Nicotinic alpha-7 receptor stimulation (a7nAChR) inhibited NF-kB/STAT3/SOCS3 pathways in a murine model of asthma. Source: International Congress 2017 – Novel mechanisms and treatments for asthma Year: 2017 Characterising the cardiovascular safety profile of inhaled muscarinic receptor antagonists Source: Eur Respir Monogr 2020; 88: 238-250 Year: 2020 Effect of AVE5883, a dual NK1/NK2 receptor antagonist, on airway responsiveness to neurokinin A in asthma Source: Eur Respir J 2004; 24: Suppl. 48, 219s Year: 2004 Alpha-7 nicotinic receptor stimulation reduces airway inflammation in a murine model of asthma Source: International Congress 2016 – Airway pharmacology: drug targets and mode of action Year: 2016 The novel dual D2 dopamine receptor, β2-adrenoceptor agonist Viozan™ (AR-C68397AA) is well tolerated in a dog model Source: Eur Respir J 2001; 18: Suppl. 33, 406s Year: 2001 Repeated-dose pharmacokinetics of once-daily TD-4208, a long-acting muscarinic receptor antagonist (LAMA), in subjects with COPD Source: International Congress 2014 – Bronchodilators for asthma and COPD Year: 2014 Pharmacological treatment of asthma today Source: Eur Respir J 2001; 18: 34S-40S Year: 2001 An oral selective M3 cholinergic receptor antagonist in COPD Source: Eur Respir J 2006 Oct 01;28(4):772-780 Year: 2006 Rate of onset of action of aclidinium bromide, a novel, long-acting, muscarinic antagonist Source: Annual Congress 2009 - Next generation bronchodilators Year: 2009 The in vitro profile of ADC3680, a potent and selective CRTh2 antagonist for the treatment of inadequately controlled asthma Source: Annual Congress 2013 –Novel drugs and biomarkers in respiratory medicine Year: 2013 In vivo potent and long-lasting bronchodilator activity of muscarinic M3 receptor antagonist CHF5407 Source: Eur Respir J 2007; 30: Suppl. 51, 26s Year: 2007