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Titolo:
4,4-DISUBSTITUTED PIPERIDINE HIGH-AFFINITY NK1 ANTAGONISTS - STRUCTURE-ACTIVITY-RELATIONSHIPS AND IN-VIVO ACTIVITY
Autore:
STEVENSON GI; HUSCROFT I; MACLEOD AM; SWAIN CJ; CASCIERI MA; CHICCHI GG; GRAHAM MI; HARRISON T; KELLEHER FJ; KURTZ M; LADDUWAHETTY T; MERCHANT KJ; METZGER JM; MACINTYRE DE; SADOWSKI S; SOHAL B; OWENS AP;
Indirizzi:
MERCK SHARP & DOHME RES LABS,NEUROSCI RES CTR,DEPT MED CHEM,TERLINGS PK,EASTWICK RD HARLOW CM20 2QR ESSEX ENGLAND MERCK RES LABS,DEPT PHARMACOL RAHWAY NJ 07065 MERCK RES LABS,DEPT MOL PHARMACOL RAHWAY NJ 07065 MERCK RES LABS,DEPT BIOCHEM RAHWAY NJ 07065
Titolo Testata:
Journal of medicinal chemistry
fascicolo: 23, volume: 41, anno: 1998,
pagine: 4623 - 4635
SICI:
0022-2623(1998)41:23<4623:4PHNA->2.0.ZU;2-9
Fonte:
ISI
Lingua:
ENG
Soggetto:
SUBSTANCE-P RECEPTOR; HUMAN NEUROKININ-1 RECEPTOR; TACHYKININ NK(1) RECEPTOR; NONPEPTIDE ANTAGONIST; PLASMA EXTRAVASATION; HNK(1) ANTAGONISTS; DURA-MATER; POTENT; CP-99,994; CP-96,345;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Citazioni:
39
Recensione:
Indirizzi per estratti:
Citazione:
G.I. Stevenson et al., "4,4-DISUBSTITUTED PIPERIDINE HIGH-AFFINITY NK1 ANTAGONISTS - STRUCTURE-ACTIVITY-RELATIONSHIPS AND IN-VIVO ACTIVITY", Journal of medicinal chemistry, 41(23), 1998, pp. 4623-4635

Abstract

Previously reported studies from these laboratories described the design of a novel series of high-affinity NK1 antagonists based on the 4,4-disubstituted piperidine ring system. Further structure-activity studies have now established that for high NK1 affinity the benzyl ether side chain must be 3,5-disubstituted and highly Lipophilic, the optimal side chain being the 3,5-bis(trifluoromethyl)benzyl ether, 12 (kNK(1) IC50 = 0.95 nM). Additional studies have shown that this class of NK1 antagonist tolerates a wider range of substituents on the piperidinenitrogen, including acyl (38) (hNK(1) IC50 = 5.3 nM) and sulfonyl (39) (hNK(1) IC50 = 5.7 nM) derivatives. Following preliminary pharmacokinetic analysis, two compounds (32 and 43) were selected for in vivo study in the resiniferotoxin-induced vascular leakage model, both showing excellent profiles (ID50 = 0.22 and 0.28 mg/kg, respectively).

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 28/11/20 alle ore 01:00:31