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.

Muscarinic receptor antagonists, from folklore to pharmacology; finding drugs that actually work in asthma and COPD

“…CHF 5407 appears more promising. Early trials show it is as potent and long‐acting antagonist of M3 receptors as tiotropium (with 54% still bound to M3 receptors at 32 h) with a significantly shorter half‐life at M2 receptors (21 min for CHF 5407 vs. 297 min for tiotropium)(Peretto et al ., 2007a,b; Cazzola and Matera, 2008). Studies are currently ongoing to determine the clinical effectiveness of CHF 5407.…”

Medicinal chemistry and therapeutic potential of muscarinic M3 antagonists

“…Imidazolidin-2-one derivatives have been recently described by Chiesi, 127,128 both as tertiary amine derivatives and quaternary ammonium salts, as potent and selective M3 antagonists (M3/M2 selectivity greater than 100-fold). In this series, two geminal aryl groups are present as in tiotropium analogues, while the imidazolidin-2-one structure represents the hydrogen-bond acceptor moiety in replacement of the hydroxyl-ester substructure.…”

Modifications to five-substituted 3,3-diethyl-4,5-dihydro-2(3H)-furanones en route to novel muscarinic receptor ligands

“…In general, the models propose that the pharmacophoric elements that should be present in muscarinic ligands include: (a) a quaternary ammonium group or its equivalent, (b) an unshared pair of electrons that can mediate a H-bond, (c) an appropriate distance between the H-bonding moiety and the center of the positive charge, and (d) the presence of a suitably located lipophilic/alkyl group (Beers and Reich, 1970;Marriott et al, 1999;Peretto et al, 2007). These fundamental requirements are useful when designing muscarinic ligands but have provided little guidance in the design of subtype selective compounds.…”