Novel benzo[1,4]diazepin-2-one derivatives as endothelin receptor antagonists.
Since its discovery in 1988 by Yanagisawa et al., endothelin (ET), a potent vasoconstrictor, has been widely implicated in the pathophysiology of cardiovascular, cerebrovascular, and renal diseases. Many research groups have embarked on the discovery and development of ET receptor antagonists for the treatment of such diseases. While several compounds, e.g., ambrisentan 2, are in late clinical trials for various indications, one compound (bosentan, Tracleer) is being marketed to treat pulmonary arterial hypertension. Inspired by the structure of ambrisentan 2, we designed a novel class of ET receptor antagonists based on a 1,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-2-one scaffold. Here, we report on the preparation as well as the in vitro and in vivo structure-activity relationships of these derivatives. Potent dual ET(A)/ET(B) receptor antagonists with affinities in the low nanomolar range have been identified. In addition, several compounds efficiently reduced arterial blood pressure after oral administration to Dahl salt sensitive rats. In this animal model, the efficacy of the benzo[e][1,4]diazepin-2-one derivative rac-39au was superior to that of racemic ambrisentan, rac-2.
Bolli
Martin H
MH
Drug Discovery Chemistry and Preclinical Research, Actelion Pharmaceuticals Ltd., Gewerbestrasse 16, CH-4123 Allschwil, Switzerland. martin.bolli@actelion.com
Marfurt
Judith
J
Grisostomi
Corinna
C
Boss
Christoph
C
Binkert
Christoph
C
Hess
Patrick
P
Treiber
Alexander
A
Thorin
Eric
E
Morrison
Keith
K
Buchmann
Stephan
S
Bur
Daniel
D
Ramuz
Henri
H
Clozel
Martine
M
Fischli
Walter
W
Weller
Thomas
T
D000818:Animals; D000959:Antihypertensive Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001569:Benzodiazepines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001682:Biological Availability; D001794:Blood Pressure / Q000187:drug effects; D065607:Cytochrome P-450 Enzyme Inhibitors; D065130:Endothelin A Receptor Antagonists; D065131:Endothelin B Receptor Antagonists; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D008958:Models, Molecular; D051381:Rats; D020303:Rats, Inbred Dahl; D017208:Rats, Wistar; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000959:Antihypertensive Agents; D065607:Cytochrome P-450 Enzyme Inhibitors; D065130:Endothelin A Receptor Antagonists; D065131:Endothelin B Receptor Antagonists; D001569:Benzodiazepines