210109-95-8Relevant articles and documents
Selective endothelin a receptor antagonists. 4. Discovery and structure- activity relationships of stilbene acid and alcohol derivatives
Astles, Peter C.,Brown, Thomas J.,Halley, Frank,Handscombe, Caroline M.,Harris, Neil V.,McCarthy, Clive,McLay, Iain M.,Lockey, Peter,Majid, Tahir,Porter, Barry,Roach, Alan G.,Smith, Christopher,Walsh, Roger
, p. 2745 - 2753 (2007/10/03)
This publication describes the synthesis and optimization of a novel series of stilbene endothelin antagonists. Analysis of the SAR established for previous papers in this series prompted the design and synthesis of (Z)- 4-phenyl-5-(3-benzyloxyphenyl)pent-4-enoic acid 3 which was found to be a moderately active inhibitor of the binding of [125I]ET-1 to ET(A) receptors with an IC50 of 6 μM. More interestingly, the intermediate compound (E)-2-phenyl-3-(3-benzyloxyphenyl)propenoic acid 5 was equiactive with 3. Optimization of 5 resulted in the preparation of (E)2-phenyl-3-(2- cyano-5-(thien-3-ylmethoxy))phenylpropenoic acid 18 (RPR111723) which had an IC50 in the binding assay of 80 nM on the ET(A) receptor and a pK(B) of 6.5 in the functional assay, measured on rat aortic strips. Reduction of the acid group of 5 gave the first nonacidic ET(A) antagonist in our series, (E)-2- phenyl-3-(3-benzyloxyphenoxy)prop2-enol 6 with an IC50 of 20 μM. Optimization of 6 resulted in the preparation of 2-(2-methylphenyl)-3-(2- cyano-5-(thien3-ylmethyl)phenyl)prop-2-enol 33 with an IC50 of 300 nM on the ET(A) receptor.
