title: Novel benzo[1,4]diazepin-2-one derivatives as endothelin receptor antagonists.
abstract: 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.
authors.affiliation: Drug Discovery Chemistry and Preclinical Research, Actelion Pharmaceuticals Ltd., Gewerbestrasse 16, CH-4123 Allschwil, Switzerland. martin.bolli@actelion.com
authors.forename: Martin H
authors.initials: MH
authors.lastname: Bolli
authors.forename: Judith
authors.initials: J
authors.lastname: Marfurt
authors.forename: Corinna
authors.initials: C
authors.lastname: Grisostomi
authors.forename: Christoph
authors.initials: C
authors.lastname: Boss
authors.forename: Christoph
authors.initials: C
authors.lastname: Binkert
authors.forename: Patrick
authors.initials: P
authors.lastname: Hess
authors.forename: Alexander
authors.initials: A
authors.lastname: Treiber
authors.forename: Eric
authors.initials: E
authors.lastname: Thorin
authors.forename: Keith
authors.initials: K
authors.lastname: Morrison
authors.forename: Stephan
authors.initials: S
authors.lastname: Buchmann
authors.forename: Daniel
authors.initials: D
authors.lastname: Bur
authors.forename: Henri
authors.initials: H
authors.lastname: Ramuz
authors.forename: Martine
authors.initials: M
authors.lastname: Clozel
authors.forename: Walter
authors.initials: W
authors.lastname: Fischli
authors.forename: Thomas
authors.initials: T
authors.lastname: Weller
mesh_terms: 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
chemical_list: D000959:Antihypertensive Agents; D065607:Cytochrome P-450 Enzyme Inhibitors; D065130:Endothelin A Receptor Antagonists; D065131:Endothelin B Receptor Antagonists; D001569:Benzodiazepines