3 - ENDOTHELIN ANTAGONISTS - DISCOVERY OF EMD-122946, A HIGHLY POTENTAND ORALLY-ACTIVE ETA SELECTIVE ANTAGONIST

Authors
MEDERSKI WWKR DORSCH D OSSWALD M ANZALI S CHRISTADLER M SCHMITGES CJ SCHELLING P WILM C FLUCK M
Citation
Wwkr. Mederski et al., 3 - ENDOTHELIN ANTAGONISTS - DISCOVERY OF EMD-122946, A HIGHLY POTENTAND ORALLY-ACTIVE ETA SELECTIVE ANTAGONIST, Bioorganic & medicinal chemistry letters, 8(13), 1998, pp. 1771-1776
Citations number
19
Categorie Soggetti
Chemistry Inorganic & Nuclear","Chemistry Medicinal
Journal title
Bioorganic & medicinal chemistry letters → ACNP
ISSN journal
0960894X
Volume
8
Issue
13
Year of publication
1998
Pages
1771 - 1776
Database
ISI
SICI code
0960-894X(1998)8:13<1771:3-EA-D>2.0.ZU;2-H
Abstract
The discovery, in vitro and in vivo studies of the highly potent ETA a ntagonist EMD 122946 are presented. This compound displayed high bindi ng affinity and functional antagonism [ IC50 = 3.2 x 10(-11) M, pA(2) = 9.5 (ETA)] and inhibited the ET-1 induced presser response in pithed rats with an ED50 of 0.3 mg/kg. In conscious spontaneously hypertensi ve rats and in DOCA-salt hypertensive rats the compound lowered mean b lood pressure with an ED50 of 0.06 mg/kg. EMD 122946 exhibited high bi oavailability in rats and monkeys. (C) 1998 Elsevier Science Ltd. All rights reserved.