1-(3-Cyanobenzylpiperidin-4-yl)-5-methyl-4-phenyl-1,3-dihydroimidazol-2-one:  A Selective High-Affinity Antagonist for the Human Dopamine D4 Receptor with Excellent Selectivity over Ion Channels

• Published in: Journal of medicinal chemistry Vol. 42; no. 14; pp. 2706 - 2715
• Main Authors: Carling, Robert W, Moore, Kevin W, Moyes, Christopher R, Jones, Elizabeth A, Bonner, Katrine, Emms, Frances, Marwood, Rosemary, Patel, Shil, Patel, Smita, Fletcher, Alan E, Beer, Margaret, Sohal, Bindi, Pike, Andrew, Leeson, Paul D
• Format: Journal Article
• Language: English
• Published: American Chemical Society 15.07.1999
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm991029k

After the requirement of pseudocycle formation in the ureas 3 and 7 for hD4 binding and selectivity was confirmed, structural hybridization with the known hD4 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 hD4 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 hD4 over hD2 and hD3. 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 hD4 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 hD4 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 D4 receptor.