Discovery and synthesis of (S)-3-[2-(3,4-dimethoxyphenyl)ethoxy]-2- (4,6-dimethylpyrimidin-2-yloxy)-3,3-diphenylpropionic acid (LU 302872), a novel orally active mixed ET(A)/ET(B) receptor antagonist.
Structural variation of the endothelin A-selective antagonist (S)-3-methoxy-2-(4,6-dimethoxypyrimidin-2-yloxy)-3, 3-diphenylpropionic acid (LU 135252) led to analogues which retain ET(A) affinity but exhibit substantial ET(B) affinity as well. The most active derivative obtained is (S)-3-[2-(3, 4-dimethoxyphenyl)ethoxy]-2-(4,6-dimethylpyrimidin-2-yloxy)- 3, 3-diphenylpropionic acid (LU 302872), which can be prepared in enantiomerically pure form in eight steps via an acid-catalyzed transetherification. It has a K(i) = 2.15 nM for binding to the ET(A) receptor and a K(i) = 4.75 nM for binding to the ET(B) receptor, is orally available, and antagonizes the big ET-induced blood pressure increase in rats and the big ET-induced bronchospasm in guinea pigs each time at a dose of 10 mg/kg.
Amberg
W
W
Hauptlaboratorium, BASF AG, 67056 Ludwigshafen, Germany, and Knoll AG, 67008 Ludwigshafen, Germany. wilhelm.amberg@basf-ag.de
Hergenröder
S
S
Hillen
H
H
Jansen
R
R
Kettschau
G
G
Kling
A
A
Klinge
D
D
Raschack
M
M
Riechers
H
H
Unger
L
L
D000284:Administration, Oral; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D016084:Bronchoconstriction / Q000187:drug effects; D016466:CHO Cells; D006224:Cricetinae; D065128:Endothelin Receptor Antagonists; D006168:Guinea Pigs; D008297:Male; D011422:Propionates / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011743:Pyrimidines / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D065128:Endothelin Receptor Antagonists; C113044:LU 224332; D011422:Propionates; D011743:Pyrimidines; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B