title: Discovery of diaryl imidazolidin-2-one derivatives, a novel class of muscarinic M3 selective antagonists (Part 1).
abstract: Pharmacophore-based structural identification, synthesis, and structure-activity relationships of a new class of muscarinic M3 receptor antagonists, the diaryl imidazolidin-2-one derivatives, are described. The versatility of the discovered scaffold allowed for several structural modifications that resulted in the discovery of two distinct classes of compounds, specifically a class of tertiary amine derivatives (potentially useful for the treatment of overactive bladder by oral administration) and a class of quaternary ammonium salt derivatives (potentially useful for the treatment of respiratory diseases by the inhalation route of administration). In this paper, we describe the synthesis and biological activity of tertiary amine derivatives. For these compounds, selectivity for the M3 receptor toward the M2 receptor was crucial, because the M2 receptor subtype is mainly responsible for adverse systemic side effects of currently marketed muscarinic antagonists. Compound 50 showed the highest selectivity versus M2 receptor, with binding affinity for M3 receptor Ki = 4.8 nM and for M2 receptor Ki = 1141 nM. Functional in vitro studies on selected compounds confirmed the antagonist activity toward the M3 receptor and functional selectivity toward the M2 receptor.
authors.affiliation: NiKem Research, Via Zambeletti 25, 20021 Baranzate, Milan, Italy. ilaria.peretto@nikemresearch.com
authors.forename: Ilaria
authors.initials: I
authors.lastname: Peretto
authors.forename: Roberto
authors.initials: R
authors.lastname: Forlani
authors.forename: Claudia
authors.initials: C
authors.lastname: Fossati
authors.forename: Giuseppe A M
authors.initials: GA
authors.lastname: Giardina
authors.forename: Alessandra
authors.initials: A
authors.lastname: Giardini
authors.forename: Matilde
authors.initials: M
authors.lastname: Guala
authors.forename: Elena
authors.initials: E
authors.lastname: La Porta
authors.forename: Paola
authors.initials: P
authors.lastname: Petrillo
authors.forename: Stefano
authors.initials: S
authors.lastname: Radaelli
authors.forename: Luigi
authors.initials: L
authors.lastname: Radice
authors.forename: Luca F
authors.initials: LF
authors.lastname: Raveglia
authors.forename: Enza
authors.initials: E
authors.lastname: Santoro
authors.forename: Roberta
authors.initials: R
authors.lastname: Scudellaro
authors.forename: Francesca
authors.initials: F
authors.lastname: Scarpitta
authors.forename: Chiara
authors.initials: C
authors.lastname: Bigogno
authors.forename: Paola
authors.initials: P
authors.lastname: Misiano
authors.forename: Giulio M
authors.initials: GM
authors.lastname: Dondio
authors.forename: Andrea
authors.initials: A
authors.lastname: Rizzi
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Armani
authors.forename: Gabriele
authors.initials: G
authors.lastname: Amari
authors.forename: Maurizio
authors.initials: M
authors.lastname: Civelli
authors.forename: Gino
authors.initials: G
authors.lastname: Villetti
authors.forename: Riccardo
authors.initials: R
authors.lastname: Patacchini
authors.forename: Marco
authors.initials: M
authors.lastname: Bergamaschi
authors.forename: Maurizio
authors.initials: M
authors.lastname: Delcanale
authors.forename: Carolina
authors.initials: C
authors.lastname: Salcedo
authors.forename: Andrés G
authors.initials: AG
authors.lastname: Fernández
authors.forename: Bruno P
authors.initials: BP
authors.lastname: Imbimbo
mesh_terms: D000284:Administration, Oral; D000818:Animals; D016275:Atrial Function / Q000187:drug effects; D016466:CHO Cells; D018938:Caco-2 Cells; D002463:Cell Membrane Permeability; D006224:Cricetinae; D003412:Cricetulus; D005260:Female; D006801:Humans; D048289:Imidazolidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008861:Microsomes / Q000378:metabolism; D008958:Models, Molecular; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D011869:Radioligand Assay; D051381:Rats; D043585:Receptor, Muscarinic M2 / Q000037:antagonists & inhibitors; D043587:Receptor, Muscarinic M3 / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D001743:Urinary Bladder / Q000187:drug effects / Q000502:physiology
chemical_list: D048289:Imidazolidines; D043585:Receptor, Muscarinic M2; D043587:Receptor, Muscarinic M3