3.: Endothelin antagonists:: Discovery of EMD 122946, a highly potent and orally active ETA selective antagonist

被引：13

作者：

Mederski, WWKR ^{[1
]}

Dorsch, D

Osswald, M

Anzali, S

Christadler, M

Schmitges, CJ

Schelling, P

Wilm, C

Fluck, M

机构：

[1] Merck KGaA, Preclin Pharmaceut Res, D-64271 Darmstadt, Germany

[2] Inst Pharmacokinet & Metab, D-85567 Grafing, Germany

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 1998年 / 8卷 / 13期

关键词：

D O I：

10.1016/S0960-894X(98)00301-1

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The discovery, in vitro and in vivo studies of the highly potent ETA antagonist EMD 122946 are presented. This compound displayed high binding 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 hypertensive rats and in DOCA-salt hypertensive rats the compound lowered mean blood pressure with an ED50 of 0.06 mg/kg. EMD 122946 exhibited high bioavailability in rats and monkeys. (C) 1998 Elsevier Science Ltd. All rights reserved.

引用

页码：1771 / 1776

页数：6

共 19 条

[1] 1. Endothelin antagonists: Search for surrogates of methylendioxyphenyl by means of a Kohonen neural network
Anzali, S
Mederski, WWKR
Osswald, M
Dorsch, D
[J]. BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 1998, 8 (01) : 11 - 16
[2] ANTIHYPERTENSIVE EFFECTS OF A NOVEL ENDOTHELIN-A RECEPTOR ANTAGONIST IN RATS
BIRD, JE
MORELAND, S
WALDRON, TL
POWELL, JR
[J]. HYPERTENSION, 1995, 25 (06) : 1191 - 1195
[3] A NEW METHOD FOR CONTINUOUS CHRONIC MEASUREMENT AND RECORDING OF BLOOD-PRESSURE, HEART-RATE AND ACTIVITY IN THE RAT VIA RADIOTELEMETRY
BROCKWAY, BP
MILLS, PA
AZAR, SH
[J]. CLINICAL AND EXPERIMENTAL HYPERTENSION PART A-THEORY AND PRACTICE, 1991, 13 (05) : 885 - 895
[4] CLOZEL M, 1994, J PHARMACOL EXP THER, V270, P228
[5] DENG LY, 1992, AM J PHYSIOL, V262, pH1782
[6] HOIDA G, 1976, DRUG RES, V26, P2003
[7] Pyrrolidine-3-carboxylic acids as endothelin antagonists .2. Sulfonamide-based ETA/ETB mixed antagonists
Jae, HS
Winn, M
Dixon, DB
Marsh, KC
Nguyen, B
Opgenorth, TJ
vonGeldern, TW
[J]. JOURNAL OF MEDICINAL CHEMISTRY, 1997, 40 (20) : 3217 - 3227
[8] Kohonen T., 1995, SELF ORG MAPS
[9] INCREASED EXPRESSION OF ENDOTHELIN-1 GENE IN BLOOD-VESSELS OF DEOXYCORTICOSTERONE ACETATE SALT HYPERTENSIVE RATS
LARIVIERE, R
DAY, R
SCHIFFRIN, EL
[J]. HYPERTENSION, 1993, 21 (06) : 916 - 920
[10] EFFECT OF PHOSPHORAMIDON (ENDOTHELIN-CONVERTING ENZYME-INHIBITOR) AND BQ-123 (ENDOTHELIN RECEPTOR SUBTYPE-A ANTAGONIST) ON BLOOD-PRESSURE IN HYPERTENSIVE RATS
MCMAHON, EG
PALOMO, MA
BROWN, MA
BERTENSHAW, SR
CARTER, JS
[J]. AMERICAN JOURNAL OF HYPERTENSION, 1993, 6 (08) : 667 - 673

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