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SAR profiles of spirocyclic nicotinamide derived selective HDAC1/HDAC2 inhibitors (SHI-1:2) |
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| Authors: | Methot Joey L Hamblett Christopher L Mampreian Dawn M Jung Joon Harsch Andreas Szewczak Alexander A Dahlberg William K Middleton Richard E Hughes Bethany Fleming Judith C Wang Hongmei Kral Astrid M Ozerova Nicole Cruz Jonathan C Haines Brian Chenard Melissa Kenific Candia M Secrist J Paul Miller Thomas A |
| Affiliation: | Department of Drug Design and Optimization, Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA. joey_methot@merck.com |
| Abstract: | A potent family of spirocyclic nicotinyl aminobenzamide selective HDAC1/HDAC2 inhibitors (SHI-1:2) is profiled. The incorporation of a biaryl zinc-binding motif into a nicotinyl scaffold resulted in enhanced potency and selectivity versus HDAC3, but also imparted hERG activity. It was discovered that increasing polar surface area about the spirocycle attenuates this liability. Compound 12 induced a 4-fold increase in acetylated histone H2B in an HCT-116 xenograft model study with acute exposure, and inhibited tumor growth in a 21-day efficacy study with qd dosing. |
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