1-(3-Cyanobenzylpiperidin-4-yl)-5-methyl-4-phenyl-1, 3-dihydroimidazol-2-one: a selective high-affinity antagonist for the human dopamine D(4) receptor with excellent selectivity over ion channels.
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.
Carling
R W
RW
Departments of Medicinal Chemistry, Biochemistry, and Pharmacology, Merck Sharp and Dohme Research Laboratories, Neuroscience Research Centre, Terlings Park, Eastwick Road, Harlow, Essex CM20 2QR, U.K.
Moore
K W
KW
Moyes
C R
CR
Jones
E A
EA
Bonner
K
K
Emms
F
F
Marwood
R
R
Patel
S
S
Patel
S
S
Fletcher
A E
AE
Beer
M
M
Sohal
B
B
Pike
A
A
Leeson
P D
PD
D000818:Animals; D001667:Binding, Competitive; D016466:CHO Cells; D002460:Cell Line; D006224:Cricetinae; D018492:Dopamine Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D007473:Ion Channels / Q000187:drug effects*; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D017448:Receptors, Dopamine D2 / Q000187:drug effects* / Q000378:metabolism; D050638:Receptors, Dopamine D4; D013329:Structure-Activity Relationship
C120318:1-(3-cyanobenzylpiperidin-4-yl)-5-methyl-4-phenyl-1,3-dihydroimidazol-2-one; C493599:DRD4 protein, human; D018492:Dopamine Antagonists; C493601:Drd4 protein, rat; D007093:Imidazoles; D007473:Ion Channels; D010880:Piperidines; D017448:Receptors, Dopamine D2; D050638:Receptors, Dopamine D4