Discovery of diaryl imidazolidin-2-one derivatives, a novel class of muscarinic M3 selective antagonists (Part 1).
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.
Peretto
Ilaria
I
NiKem Research, Via Zambeletti 25, 20021 Baranzate, Milan, Italy. ilaria.peretto@nikemresearch.com
Forlani
Roberto
R
Fossati
Claudia
C
Giardina
Giuseppe A M
GA
Giardini
Alessandra
A
Guala
Matilde
M
La Porta
Elena
E
Petrillo
Paola
P
Radaelli
Stefano
S
Radice
Luigi
L
Raveglia
Luca F
LF
Santoro
Enza
E
Scudellaro
Roberta
R
Scarpitta
Francesca
F
Bigogno
Chiara
C
Misiano
Paola
P
Dondio
Giulio M
GM
Rizzi
Andrea
A
Armani
Elisabetta
E
Amari
Gabriele
G
Civelli
Maurizio
M
Villetti
Gino
G
Patacchini
Riccardo
R
Bergamaschi
Marco
M
Delcanale
Maurizio
M
Salcedo
Carolina
C
Fernández
Andrés G
AG
Imbimbo
Bruno P
BP
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
D048289:Imidazolidines; D043585:Receptor, Muscarinic M2; D043587:Receptor, Muscarinic M3