Referenced in: none

Automatically associated channels: Kv11.1

Title: SAR profiles of spirocyclic nicotinamide derived selective HDAC1/HDAC2 inhibitors (SHI-1:2).

Authors: Joey L Methot, Christopher L Hamblett, Dawn M Mampreian, Joon Jung, Andreas Harsch, Alexander A Szewczak, William K Dahlberg, Richard E Middleton, Bethany Hughes, Judith C Fleming, Hongmei Wang, Astrid M Kral, Nicole Ozerova, Jonathan C Cruz, Brian Haines, Melissa Chenard, Candia M Kenific, J Paul Secrist, Thomas A Miller

Journal, date & volume: Bioorg. Med. Chem. Lett., 2008 Dec 1 , 18, 6104-9

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/18951790

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.