Alkyne–quinuclidine derivatives as potent and selective muscarinic antagonists for the treatment of COPD Jean-Philippe Starck, Laurent Provins, * Bernard Christophe, Michel Gillard, Sophie Jadot, Patrick Lo Brutto, Luc Que ´re ´, Patrice Talaga and Michel Guyaux UCB, R&D, Chemin du Foriest, B-1420 Braine-L’Alleud, Belgium Received 24 January 2008; revised 5 March 2008; accepted 6 March 2008 Available online 18 March 2008 Abstract—SAR around alkyne–quinuclidine derivatives allowed the discovery of highly potent muscarinic antagonists displaying interesting preferential slow off-rates from the M3 receptor. Ó 2008 Elsevier Ltd. All rights reserved. Chronic obstructive pulmonary disease (COPD) is a ma- jor cause of morbidity and mortality worldwide. This pathology is foreseen to become the third leading cause of death and the fifth leading cause of morbidity over the next 10 years. Current treatments are essentially pal- liative, focusing on relieving symptoms, preventing acute disease exacerbations and improving quality of life. The understanding of the molecular and cellular mechanisms involved in COPD allowed the identifica- tion of many potential therapeutic approaches based on a variety of biological targets. For example, the b2- adrenergic or the cholinergic system, several phosphodi- esterases or the chemokines-interleukines pathways have been extensively investigated. 1–3 Anticholinergics drugs alone or in combination with b2 agonists are reported to be the preferred choice for the management of COPD, at all stages of the disease. Vag- ally-mediated reversible bronchoconstriction is an important component of airway obstruction in COPD patients. Three muscarinic receptors subtypes (M1R, M2R and M3R) have been identified in the respiratory system with each of these having been experimentally in- volved in specific effects and physiological responses. The M1 receptor is thought to facilitate the cholinergic neurotransmission in parasympathetic ganglia, the M2 receptor provides negative feedback modulation on ace- tylcholine release on postganglionic nerves whilst the M3 receptor mediates the contractile response in air- ways smooth muscles as well as secretion from submu- cosal glands. 4 The M1 and M3 receptors are the main receptor sub- types present in the human lungs. 5 The M2 receptor is also postulated to exist in bronchi 6 although it has not been autoradiographically visualized in human lungs. 5 Current anticholinergic drugs are non-selective musca- rinic antagonists. Their bronchorelaxing effects are thought to be mainly mediated by the blockade of M3 receptors on lung smooth muscles although an addi- tional contribution of M1 receptors is not excluded. A long duration of action is an important feature to treat chronic illnesses such as COPD. The measurement of kinetics of drug interaction to the target protein offers another approach to improve the duration of action of a drug besides pharmacokinetic factors. 7 This strategy has been used to discover Tiotropium bro- mide (Spiriva Ò ), the current gold standard anticholiner- gic drug for the treatment of COPD. Contrary to Ipratropium bromide (Atrovent Ò ), Tiotropium is characterized by a slow dissociation rate from the M3 (t 1/2off = 3308 min) and M1 receptors (t 1/2off = 876 min). Thanks to this remarkable property, this drug displays a very long duration of action allowing a once-a-day administration as an inhaled dry powder. 8,9 Interestingly, Tiotropium bromide also demonstrates a receptor-subtype kinetic selectivity with a far shorter 0960-894X/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmcl.2008.03.024 Keywords: Muscarinic receptor(s); COPD; Quinuclidine. * Corresponding author. Tel.: +32 2 3863217; fax: +32 2 3863669; e-mail: laurent.provins@ucb-group.com Available online at www.sciencedirect.com Bioorganic & Medicinal Chemistry Letters 18 (2008) 2675–2678