A novel class of endothelin-A receptor antagonists, (R)-2-(benzo[1,3]dioxol-5-yl)-6-isopropyloxy-2H-chromene-3-carboxylic acids (S-1255). Conformational analysis of basic structure, crucial for ET(A) antagonism, in solution and solid states.
Conformational studies of potent and selective endothelin-A (ET(A)) receptor antagonists, 4-substituted (R)-2-(benzo[1,3]-dioxol-5-yl)-6-isopropoxy-2H-chromene-3-carboxylic acids, are reported. X-ray crystallography and NMR studies of the 4-anisyl derivative 2 (S-1255), the stable atropisomers 3 and the 4-n-butyl derivative 4 reveal that the A-, B- and C-rings in these compounds adopt a L-like conformation in both solution and solid states. Molecular mechanics calculation shows that this L-like conformation is an inevitable conformation as determined by intramolecular steric repulsions. These 2H-chromene derivatives bound to an ET(A) receptor with IC(50) values of less than 1 nM, whereas the dihydro compounds 7 and 9 not having the L-like conformation showed weaker affinities. These results suggest that the L-like conformation is specifically recognized by the active site of the ET(A) receptor. The roles of the L-like conformation in the receptor binding are discussed.
Ishizuka
Natsuki
N
Shionogi Research Laboratories, Shionogi & Co., Ltd., 12-4, Sagisu 5-chome, Fukushima-ku, Osaka, Japan. natsuki.ishizuka@shionogi.co.jp
Matsumura
Ken-ichi
K
Kikuchi
Junko
J
Nakai
Hiroshi
H
D000147:Acids, Heterocyclic / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D001011:Aorta; D018360:Crystallography, X-Ray; D065128:Endothelin Receptor Antagonists; D020128:Inhibitory Concentration 50; D009682:Magnetic Resonance Spectroscopy; D008968:Molecular Conformation; D015394:Molecular Structure; D009131:Muscle, Smooth, Vascular / Q000737:chemistry / Q000166:cytology; D051381:Rats; D044022:Receptor, Endothelin A; D012996:Solutions; D013329:Structure-Activity Relationship
D000147:Acids, Heterocyclic; D065128:Endothelin Receptor Antagonists; D044022:Receptor, Endothelin A; D012996:Solutions