Structure-activity relationships of a novel class of endothelin-A receptor antagonists and discovery of potent and selective receptor antagonist, 2-(benzo[1,3]dioxol-5-yl)-6-isopropyloxy-4-(4-methoxyphenyl)-2H-chromene-3-carboxylic acid (S-1255). 1. Study on structure-activity relationships and basic structure crucial for ET(A) antagonism.
A novel series of endothelin-A (ET(A)) selective receptor antagonists having a 2H-chromene skeleton are described. A lead compound, 2-(benzo[1,3]dioxol-5-yl)-2H-chromene-3-carboxylic acid (3), was found by modifications of our own angiotensin II antagonist. A structure-activity relationship (SAR) study of 3 reveals that the structural requirements essential for potent and selective ET(A) receptor binding affinity are the m,p-methylenedioxyphenyl, carboxyl, and isopropoxy groups at the 2-, 3-, and 6-positions, respectively, on the (R)-2H-chromene skeleton. The substituent at the 4-position is also important for improving the activity, and various hydrophobic functional groups of 6-9 A such as liner, branched, and cyclic aliphatic groups, unsubstituted and substituted aryl groups, and even halogen atoms were acceptable. These results suggest that (R)-2-(benzo[1,3]dioxol-5-yl)-6-isopropoxy-2H-chromene-3-carboxylic acid, formula 108, is the crucial basic structure to be recognized by the ET(A) receptor. The most potent compound is (R)-48 (S-1255), which binds to the ET(A) receptor with an IC(50) value of 0.19 nM and is 630-fold selective for the ET(A) receptor than for the ET(B) receptor. This compound has 55% oral bioavailability in rats. On the basis of the SAR, the roles of each substituent in the receptor binding are discussed.
Ishizuka
Natsuki
N
Shionogi Research Laboratories, Shionogi & Co., Ltd., 12-4, Sagisu 5-chome, Fukushima-ku, Osaka 553-0002, Japan. natsuki.ishizuka@shionogi.co.jp
Matsumura
Ken-ichi
K
Sakai
Katsunori
K
Fujimoto
Masafumi
M
Mihara
Shin-ichi
S
Yamamori
Teruo
T
D000818:Animals; D001578:Benzopyrans / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D006224:Cricetinae; D018360:Crystallography, X-Ray; D004353:Drug Evaluation, Preclinical; D065128:Endothelin Receptor Antagonists; D006801:Humans; D009130:Muscle, Smooth / Q000166:cytology / Q000378:metabolism; D051381:Rats; D044022:Receptor, Endothelin A; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013552:Swine
C436483:2-(benzo(1,3)dioxo-5-yl)-6-isopropyl-4-(4-methoxyphenyl)-2H-chromene-3-carboxylic acid; D001578:Benzopyrans; D065128:Endothelin Receptor Antagonists; D044022:Receptor, Endothelin A