Parallel medicinal chemistry approaches to selective HDAC1HDAC2 inhibitor (SHI-12) optimization》.pdfVIP

Bioorganic Medicinal Chemistry Letters 19 (2009) 1168–1172 Contents lists available at ScienceDirect Bioorganic Medicinal Chemistry Letters journal homepage: /locate/bmcl Parallel medicinal chemistry approaches to selective HDAC1/HDAC2 inhibitor (SHI-1:2) optimization Solomon D. Kattar a,*, Laura M. Surdi a, Anna Zabierek a, Joey L. Methot a, Richard E. Middleton a, Bethany Hughes a, Alexander A. Szewczak a, William K. Dahlberg a, Astrid M. Kral b, Nicole Ozerova b, Judith C. Fleming b, Hongmei Wang b, Paul Secrist b, Andreas Harsch a, Julie E. Hamill a, Jonathan C. Cruz c, Candia M. Kenific c, Melissa Chenard c, Thomas A. Miller a, Scott C. Berk a, Paul Tempest a a Department of Drug Design and Optimization, Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA b Department of Cancer Biology and Therapeutics, Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA c Department of Oncology Pharmacology, Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA a r t i c l e i n f o a b s t r a c t Article history: The successful application of both solid and solution phase library synthesis, combined with tight inte- Received 3 November 2008 gration into the medicinal chemistry effort, resulted in the efficient optimization of a novel structural ser- Revised 17 December 2008 ies of selective HDAC1/HDAC2 inhibitors by the MRL-Boston Parallel Medicinal Chemistry group. An Accepted 19 December 2008 initial lead from a small parallel library was found to be potent and selective in