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

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.

journal_name

Bioorg Med Chem Lett

authors

Methot JL,Hamblett CL,Mampreian DM,Jung J,Harsch A,Szewczak AA,Dahlberg WK,Middleton RE,Hughes B,Fleming JC,Wang H,Kral AM,Ozerova N,Cruz JC,Haines B,Chenard M,Kenific CM,Secrist JP,Miller TA

doi

10.1016/j.bmcl.2008.10.052

subject

Has Abstract

pub_date

2008-12-01 00:00:00

pages

6104-9

issue

23

eissn

0960-894X

issn

1464-3405

pii

S0960-894X(08)01213-4

journal_volume

18

pub_type

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