title: Functional and biochemical rationales for the 24-hour-long duration of action of olodaterol.
abstract: β(2)-Adrenoceptor (β(2)-AR) agonists are powerful bronchodilators and play a pivotal role in the management of pulmonary obstructive diseases, such as asthma and chronic obstructive pulmonary disease. Although these agents first were used many years ago, progress in drug development has resulted in better tolerated, long-acting β(2)-AR agonists (LABAs), such as formoterol and salmeterol. Although LABAs have been on the market for several years, relatively little is known on the rationale(s) behind their long duration of action. In this study, we focused on olodaterol (previously known as BI1744CL), a novel inhaled LABA, which provides a bronchodilating effect lasting 24 h and is currently in Phase III clinical trials. To understand the rationale behind its long duration of action, different aspects of olodaterol were analyzed (i.e., its lipophilicity and propensity to accumulate in the lipid bilayer as well as its tight binding to the β(2)-AR). In line with its physicochemical properties, olodaterol associated moderately with lipid bilayers. Instead, kinetic as well as equilibrium binding studies indicated the presence of a stable [(3)H]olodaterol/β(2)-AR complex with a dissociation half-life of 17.8 h due to ternary complex formation. The tight binding of olodaterol to the human β(2)-AR and stabilization of the ternary complex were confirmed in functional experiments monitoring adenylyl cyclase activity after extensive washout. Taken together, binding, kinetic, and functional data support the existence of a stable complex with the β(2)-AR that, with a dissociation half-life >17 h, might indeed be a rationale for the 24-h duration of action of olodaterol.
authors.affiliation: Department of Respiratory Diseases Research, Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorferstrasse 65, Biberach an der Riss, Germany. paola.casarosa@boehringer-ingelheim.com
authors.forename: Paola
authors.initials: P
authors.lastname: Casarosa
authors.forename: Ines
authors.initials: I
authors.lastname: Kollak
authors.forename: Tobias
authors.initials: T
authors.lastname: Kiechle
authors.forename: Angela
authors.initials: A
authors.lastname: Ostermann
authors.forename: Andreas
authors.initials: A
authors.lastname: Schnapp
authors.forename: Ralf
authors.initials: R
authors.lastname: Kiesling
authors.forename: Michael
authors.initials: M
authors.lastname: Pieper
authors.forename: Peter
authors.initials: P
authors.lastname: Sieger
authors.forename: Florian
authors.initials: F
authors.lastname: Gantner
mesh_terms: D000280:Administration, Inhalation; D058666:Adrenergic beta-2 Receptor Agonists / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology; D000420:Albuterol / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D001249:Asthma / Q000188:drug therapy*; D048588:Benzoxazines / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology; D001665:Binding Sites; D001993:Bronchodilator Agents / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology; D006224:Cricetinae; D004983:Ethanolamines / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D000068759:Formoterol Fumarate; D006207:Half-Life; D006801:Humans; D008051:Lipid Bilayers / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy* / Q000503:physiopathology; D018342:Receptors, Adrenergic, beta-1 / Q000378:metabolism; D018343:Receptors, Adrenergic, beta-2 / Q000378:metabolism*; D000068299:Salmeterol Xinafoate
chemical_list: D058666:Adrenergic beta-2 Receptor Agonists; D048588:Benzoxazines; D001993:Bronchodilator Agents; D004983:Ethanolamines; D008051:Lipid Bilayers; D018342:Receptors, Adrenergic, beta-1; D018343:Receptors, Adrenergic, beta-2; D000068299:Salmeterol Xinafoate; D000420:Albuterol; C549647:olodaterol; D000068759:Formoterol Fumarate