A novel class of endothelin-A receptor ligands was discovered by high-throughput screening. Lead structure optimization led to highly potent antagonists which can be synthesized in a short sequence. The compounds are endothelin-A-selective, are orally available, and show a long duration of action.

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.

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Process research and pilot plant processes are described for three endothelin (ET) receptor antagonists. The efficient synthesis of the parent compound Darusentan proceeds via a Darzens reaction from chloroacetate with benzophenone, addition of methanol to the resulting epoxide, saponification of the alkyl propionate and optical resolution of the racemic acid by crystallisation with a chiral amine. The final stage of the synthetic sequence involves the introduction of a pyrimidine moiety. Intermediates formed during this process can be used as starting materials for the synthesis of the two other ET receptor antagonists BSF 420627 and BSF 302146. An ether exchange reaction, which replaces the methoxy with a phenethyloxy substituent, enabled BSF 420627 to be prepared. The synthetic route to BSF 302146 employs trimethylaluminum to methylate the epoxide produced by the Darzens reaction.