Exploring the pharmacokinetic properties of phosphorus-containing selective HDAC 1 and 2 inhibitors (SHI-12)》.pdfVIP

Bioorganic Medicinal Chemistry Letters 19 (2009) 2053–2058 Contents lists available at ScienceDirect Bioorganic Medicinal Chemistry Letters journal homepage: /locate/bmcl Exploring the pharmacokinetic properties of phosphorus-containing selective HDAC 1 and 2 inhibitors (SHI-1:2) Richard W. Heidebrecht Jr. a,*, Melissa Chenard c, Joshua Close a, William K. Dahlberg a, Judith Fleming b, Jonathan B. Grimm a, Julie E. Hamill a, Andreas Harsch a, Brian B. Haines c, Bethany Hughes a, Astrid M. Kral b, Richard E. Middleton a, Chandrasekhar Mushti a, Nicole Ozerova b, Alexander A. Szewczak a, Hongmei Wang b, Kevin Wilson a, David J. Witter a, J. Paul Secrist b, Thomas A. Miller 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: We report the preparation and structure–activity relationships of phosphorus-containing histone deace- Received 3 December 2008 tylase inhibitors. A strong trend between decreasing phosphorus functional group size and superior Revised 2 February 2009 mouse pharmacokinetic properties was identified. In addition, optimized candidates showed tumor Accepted 3 February 2009 growth inhibition in xenograft studies. Available online 8 February 2009