Table 3. Structure–activity relationships for carbamate and urea based HDAC inhibitors³⁰ .

			HDAC isoform inhibition IC50 a (μM)			[Brain]/[plasma] and brain free fraction b (%)
Compound	R1 group	R2 group	HDAC1	HDAC2	HDAC3
13			0.611 ± 0.253	1.00 ± 0.34	2.60 ± 0.09	nd
14			0.069 ± 0.031	0.104 ± 0.028	0.861 ± 0.141	nd
15			0.071 ± 0.009	2.64 ± 1.13	13.05 ± 3.04	nd
16			0.216 ± 0.050	0.912 ± 0.155	13.2 ± 2.19	nd
17			0.010 ± 0.002	0.059 ± 0.021	1.47 ± 0.25	nd
BRD3321			0.019 ± 0.005	0.233 ± 0.053	1.75 ± 0.25	nd
BRD0302			0.113 ± 0.015	1.29 ± 0.55	9.22 ± 2.06	nd
			Ki (μM)
			0.111	2.74	17.7
			Residence time T 1/2 (min)
			308	375	231
BRD6688			0.021 ± 0.013	0.100 ± 0.048	11.48 ± 2.54	0.26
						54%
			Residence time T 1/2 (min)
			65	381	280
18			0.093 ± 0.022	0.176 ± 0.100	10.15 ± 3.27	nd
19			0.024 ± 0.001	0.271 ± 0.086	1.96 ± 1.34	nd
BRD3227			0.043 ± 0.024	0.291 ± 0.141	23.5 ± 6.7	0.01
20			0.035 ± 0.012	0.238 ± 0.107	5.07 ± 0.93	0.19
						21%
			Residence time T 1/2 (min)
			165	513	495
BRD3386			0.026 ± 0.007	0.178 ± 0.058	3.13 ± 0.90	0.34
						22%
			Residence time T 1/2 (min)
			570	660	495
BRD8951			0.001 ± 0.001	0.011 ± 0.003	0.544 ± 0.205	0.27
						2%
			Residence time T 1/2 (min)
			2100	788	ND
BRD4161			0.007 ± 0.002	0.045 ± 0.010	3.46 ± 0.89	0.11
						23%
			Residence time T 1/2 (min)
			430	788	770

^aValues are the mean of a minimum of two experiments. Data are shown as IC₅₀ values in μM ± standard deviation. Compounds were tested in duplicate in a 12-point dose curve with 3-fold serial dilution starting from 33.33 μM. nd = not determined.

^bBrain free fraction estimated based on brain tissue binding experiments.