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Titolo:
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 receptorwith excellent selectivity over ion channels
Autore:
Carling, RW; Moore, KW; Moyes, CR; Jones, EA; Bonner, K; Emms, F; Marwood, R; Patel, S; Patel, S; Fletcher, AE; Beer, M; Sohal, B; Pike, A; Leeson, PD;
Indirizzi:
Merck Sharp & Dohme Res Labs, Dept Med Chem, Neurosci Res Ctr, Harlow CM202QR, Essex, England Merck Sharp & Dohme Res Labs Harlow Essex England CM202QR Essex, England Merck Sharp & Dohme Res Labs, Dept Biochem, Neurosci Res Ctr, Harlow CM20 2QR, Essex, England Merck Sharp & Dohme Res Labs Harlow Essex England CM202QR Essex, England Merck Sharp & Dohme Res Labs, Dept Pharmacol, Neurosci Res Ctr, Harlow CM20 2QR, Essex, England Merck Sharp & Dohme Res Labs Harlow Essex England CM20 2QR Essex, England
Titolo Testata:
JOURNAL OF MEDICINAL CHEMISTRY
fascicolo: 14, volume: 42, anno: 1999,
pagine: 2706 - 2715
SICI:
0022-2623(19990715)42:14<2706:1>2.0.ZU;2-B
Fonte:
ISI
Lingua:
ENG
Soggetto:
D4 RECEPTORS; SCHIZOPHRENIA; LIGANDS; CLONING; GENE; BINDING; POTENT; EXPRESSION; L-745,870; AGENTS;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
52
Recensione:
Indirizzi per estratti:
Indirizzo: Carling, RW Merck Sharp & Dohme Res Labs, Dept Med Chem, Neurosci Res Ctr,Terlings Pk,Eastwick Rd, Harlow CM20 2QR, Essex, England Merck Sharp & Dohme Res Labs Terlings Pk,Eastwick Rd Harlow Essex England CM20 2QR
Citazione:
R.W. Carling et al., "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 receptorwith excellent selectivity over ion channels", J MED CHEM, 42(14), 1999, pp. 2706-2715

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 . 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 SARof the 1,3-dihydroimidazol-2-one ring. Various changes to substituents attached to the 3-, 4-, or B-position of the 1,3-dihydroimidazol-2-one core of8 did not significantly improve selectivity for hD(4) over hD(2) and hD(3). Greater Selectivity( > 1000-foId) 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 hasa 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.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 19/01/20 alle ore 05:59:13