Inhibitors of human mitotic kinesin Eg5: Characterization of the 4-phenyl-tetrahydroisoquinoline lead series

Abstract

In a high-throughput screening effort, a series of tetrahydroisoquinolines was identified as modest inhibitors of human Eg5. A medicinal chemistry optimization effort led to the identification of R-4-(3-hydroxyphenyl)- N, N-7,8-tetramethyl-3,4-dihydroisoquinoline-2(1 H)-carboxamide ( 32a) as a potent inhibitor of human Eg5 (ATPase IC 50 104 nM) with good anti-proliferative activity in A2780 cells (IC 50 234 nM).