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 K i = 1141 nM. Functional in vitro studies on selected compounds confirmed the antagonist activity toward the M3 receptor and functional selectivity toward the M2 receptor.
Discovery of diaryl imidazolidin-2-one derivatives, a novel class of muscarinic M3 selective antagonists (Part 1) / I. Peretto, R. Forlani, C. Fossati, G.A.M. Giardina, A. Giardini, M. Guala, E. La Porta, P. Petrillo, S. Radaelli, L. Radice, L.F. Raveglia, E. Santoro, R. Scudellaro, F. Scarpitta, C. Bigogno, P. Misiano, G.M. Dondio, A. Rizzi, E. Armani, G. Amari, M. Civelli, G. Villetti, R. Patacchini, M. Bergamaschi, M. Delcanale, C. Salcedo, A.G. Fernández, B.P. Imbimbo. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0022-2623. - 50:7(2007), pp. 1571-1583.
|Titolo:||Discovery of diaryl imidazolidin-2-one derivatives, a novel class of muscarinic M3 selective antagonists (Part 1)|
|Parole Chiave:||administration, oral ; animals ; atrial function ; CHO cells ; caco-2 cells ; cell membrane permeability ; cricetinae ; cricetulus ; female ; humans ; imidazolidines ; male; mice; microsomes; models, molecular ; muscle contraction ; muscle, smooth ; radioligand assay ; rats; receptor, muscarinic M2 ; receptor, muscarinic M3 ; structure-activity relationship ; urinary bladder ; organic chemistry|
|Settore Scientifico Disciplinare:||Settore CHIM/08 - Chimica Farmaceutica|
Settore BIO/10 - Biochimica
|Data di pubblicazione:||2007|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1021/jm061159a|
|Appare nelle tipologie:||01 - Articolo su periodico|