Exploration of the internal cavity of histone deacetylase (HDAC) with selective HDAC1HDAC2 inhibitors (SHI-12)》.pdfVIP

Available online at Bioorganic Medicinal Chemistry Letters 18 (2008) 973–978 Exploration of the internal cavity of histone deacetylase (HDAC) with selective HDAC1/HDAC2 inhibitors (SHI-1:2) Joey L. Methot,a,* Prasun K. Chakravarty,d Melissa Chenard,c Joshua Close,a Jonathan C. Cruz,c William K. Dahlberg,a Judith Fleming,b Christopher L. Hamblett,a Julie E. Hamill,a Paul Harrington,a, Andreas Harsch,a Richard Heidebrecht,a Bethany Hughes,a Joon Jung,a Candia M. Kenific,c Astrid M. Kral,b Peter T. Meinke,d Richard E. Middleton,a Nicole Ozerova,b David L. Sloman,a Matthew G. Stanton,a Alexander A. Szewczak,a Sriram Tyagarajan,d David J. Witter,a J. Paul Secristb and Thomas A. Millera aDepartment of Drug Design and Optimization, Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA bDepartment of Cancer Biology and Therapeutics, Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA cDepartment of Oncology and Pharmacology, Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA dDepartment of Medicinal Chemistry, Merck Research Laboratories, 126 E. Lincoln Avenue, Rahway, NJ 07065, USA Received 21 November 2007; revised 11 December 2007; accepted 13 December 2007 Available online 7 January 2008 Abstract—We report herein the initial exploration of novel selective HDAC1/HDAC2 inhibitors (SHI-1:2). Optimized SHI-1:2 structures exhibit enhanced intrinsic activity against HDAC1 and HDAC2, and are greater than 100-fold selective versus other HDACs, including HDAC3. Based on the SAR of these agents and our current understanding of the HDAC active site, we pos- tulate that the SHI-