Solution-Phase Parallel Synthesis of Hsp90 Inhibitors

作者：Sujin Cho-Schultz, Monica Jo Patten, Buwen Huang, Jeff Elleraas, K.S. Gajiwala, Michael J. Hickey, Jeff Wang, Pramod P. Mehta, Ping Kang, Michael R. Gehring, Pei‐Pei Kung, Scott C. Sutton · 发表于：Journal of Combinatorial Chemistry · 年份：2009 · DOI：10.1021/cc900056d · 被引用次数：15 · 研究领域：Computational Drug Discovery Methods、Heat shock proteins research、Biochemical effects in animals

As part of an oncology chemistry program directed toward discovery of orally bioavailable inhibitors of the 90 kDa heat shock protein (Hsp90), several solution-phase libraries were designed and prepared. A 2 x 89 library of racemic resorcinol amides was prepared affording 131 purified compounds. After evaluation in a binding assay, followed by an AKT-Luminex cellular assay, three potent analogs had functional activity between 0.1 and 0.3 microM. Resolution by preparative chiral SFC chromatography led to (+)-15, (+)-16, and (+)-17 having functional IC(50) = 27, 43, and 190 nM, respectively. (+)-15 exhibited high clearance in human hepatocytes driven primarily by glucuronidation as confirmed by metabolite identification. A second 8 x 14 exploratory library was designed to investigate heterocyclic replacements of the resorcinol ring. The second library highlights the use of the (-)-sparteine-mediated enantioselective Pd-catalyzed alpha-arylation of N-Boc-pyrrolidine to prepare chiral 2-arylpyrrolidines in parallel.