1-(3-Cyanobenzylpiperidin-4-yl)-5-methyl-4-phenyl-1,3-dihydroimidazol-2-one:  A Selective High-Affinity Antagonist for the Human Dopamine D₄Receptor with Excellent Selectivity over Ion Channels

Abstract

After the requirement of pseudocycle formation in the ureas 3 and 7 for hD(4) binding and selectivity was confirmed, structural hybridization with the known hD(4) ligand 2 led to the design and identification of the lead 4-(2-oxo-1, 3-dihydroimidazol-2-yl)piperidine 8. Optimization studies were carried out on 8 with the aim of achieving 1000-fold selectivity for hD(4) over all other receptors while retaining the good pharmacokinetic properties of the lead. After initial preparation of 8 as a minor component in a low-yielding reaction, a novel and regioselective "four-step/one-pot" procedure was developed which proved to be applicable to rapid investigation of the SAR of the 1, 3-dihydroimidazol-2-one ring. Various changes to substituents attached to the 3-, 4-, or 5-position of the 1, 3-dihydroimidazol-2-one core of 8 did not significantly improve selectivity for hD(4) over hD(2) and hD(3). Greater selectivity (>1000-fold) was ultimately achieved by meta substitution of the benzyl group of 8 with various substituents. Compounds 28, 31, and 32 all possess the required selectivity for hD(4) over the other dopamine subtypes, but only 32 has >1000-fold selectivity over all the key counterscreens we tested against. Compound 32 is an antagonist at hD(4) and has a good pharmacokinetic profile in the rat, with excellent estimated in vivo receptor occupancy, thus making it a potentially useful pharmacological tool to investigate the role of the D(4) receptor.

One-Pot, Three-Step Copper-Catalyzed Five-/Four-Component Reaction Constructs Polysubstituted Oxa(Thia)zolidin-2-imines

“…12 This scaffold structurally resembles the biologically active 2-iminoimidazolines 13 and 2-imidazolones. 14 The compounds containing this scaffold are also known to possess various therapeutic activities. 15 These results incited us to further explore the one-pot synthesis.…”

A simple synthesis of 4-aroyl-5-methyl-1H-imidazol-2(3H)-one derivatives (Enoxymone analogues) from aryl methyl ketones via enaminones

“…MHz for 1 H and 126 MHz for 13 C, using DMSO-d 6 and CDCl 3 with TMS as the internal standard, as solvents. Mass spectra were recorded on an AutoSpecQ spectrometer and Agilent 6224 Accurate Mass TOF LC/MS, IR spectra on a Perkin-Elmer Spectrum BX FTIR spectrophotometer.…”

Synthesis of a Small Library of Imidazolidin-2-ones using Gold Catalysis on Solid Phase

“…[27][28][29][30] As part of our research program concerning the application of organometallic chemistry to the solid-phase synthesis, [31][32][33][34] herein we report the synthesis of a small library of imidazolidin-2-ones using gold catalysis on propargylureas bonded to solid support. Imidazolidin-2-ones possess a variety of biological activities, including antileishmanil activity, 35 MurB enzyme inhibitors possessing antibacterial activity, 36 antiviral activity, 37 antiarrhythmic, 38 selective high-affinity antagonists for the human dopamine D4 receptor, 39 and anticancer agents. 40,41,42 There are several studies on the cycloisomerization of alkynylureas in solution phase, some of them involving the synthesis of bicyclic heterocycles starting from (ortho-arylalkynyl)ureas 43,44 and others describing the formation of monocyclic heterocycles from in situ generated propargylureas.…”