Ethenesulfonamide and ethanesulfonamide derivatives, a novel class of orally active endothelin-A receptor antagonists

Citation
H. Harada et al., Ethenesulfonamide and ethanesulfonamide derivatives, a novel class of orally active endothelin-A receptor antagonists, BIO MED CH, 9(11), 2001, pp. 2955-2968
Citations number
28
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Chemistry & Analysis
Journal title
BIOORGANIC & MEDICINAL CHEMISTRY
ISSN journal
0968-0896 → ACNP
Volume
9
Issue
11
Year of publication
2001
Pages
2955 - 2968
Database
ISI
SICI code
0968-0896(200111)9:11<2955:EAEDAN>2.0.ZU;2-3
Abstract
In the previous paper, we described a series of 2-phenylethenesulfonamide d erivatives, a novel class of ETA-selective endothelin (ET) receptor antagon ists, including the 2-methoxyethoxy derivative 2a and the 2-fluoroethoxy de rivative (2b). In this paper, we wish to report further details of structur e-activity relationships (SARs) of the two regions of the molecule in compo und 2b, which were the alkoxy region at the 6-position of the core pyrimidi ne ring and the 2-phenylethenesulfonamide region. In these modifications, r eplacement of the 2-fluoroethoxy group with a methoxy group (6e) and replac ement of the 2-phenylethenesulfonamide group with a 2-(pyridin-3-yl)ethenes ulfonamide group (61) or 2-phenylethanesulfonamide group (6q) were well tol erated both in the ETA binding affinity and ETA selectivity. Among them, co mpound 6e showed further improvement in oral activity compared to 2b. After oral administration, compound 6e inhibited the big ET-1 induced pressor re sponse in conscious rats at 0.3 mg/kg with a duration of >6.5 h. Compound 6 e also exhibited a potent antagonistic activity in the pithed rats. (C) 200 1 Elsevier Science Ltd. All rights reserved.