Synthesis of a targeted library and thrombin inhibitors using organometallic chemistry

Abstract: The use of organometallic chemistry in the pursuit of novel scaffolds is outline d. A 4-phenyl- 2-carboxy-piperazine targeted combinatorial chemistry library has been synthesized aimed at the early lead discovery phase. This was done using a scaffold that was synthesized by palladium-catalyzed aromatic amination chemistry and subsequently derivatized with 8 electrophiles and I O nucleophiles. Furthermore, ring-closing metathesis chemistry reactions were employed to synthesize the scaffolds cyclopent-2-ene-l, 2-dicarboxylic acid 1-methyl ester and cyclohex-2-ene-1, 2-dicarboxylic acid 1-methyl ester. These were used as proline isosteres in the synthesis of thrombin inhibitors based on the D-Phe-Pro-Arg motif. The scaffolds were derivatized with para-amidino benzylamine and several secondary anilines. A structure-activity relationship study is also described that was based on crystallographic results for one of the inhibitors co-crystallized with thrombin.