Table 3.

Calculated absorption, distribution, metabolism, excretion and toxicity properties (ADMET) descriptors related to absorption and distribution properties. The most promising amidine-containing derivative 15 has been highlighted in yellow, as well as the reference compounds β-PEA and RO5263397. The other most interesting analogues, 2, 6, 9 and 16, are shown in light cyan. The only one derivative predicted as unable to pass the blood–brain barrier (BBB) is reported in gray.

Comp.	cLogP	LogBB a	LogPS b	HIA (%) c	Vd (l/kg) d	%PPB	LogKa HSA	%F (oral)
β-PEA	1.56	0.19	−2.4	99	3.0	34.79	2.78	91.1
1	0.31	−0.08	−3.6	50	1.2	33.14	2.84	28.9
2	0.71	−0.03	−3.4	58	1.4	33.91	2.85	35.7
3	1.15	−0.04	−3.2	74	1.3	48.25	3.19	49.7
4	0.99	−0.08	−3.2	68	1.5	49.24	3.11	44.5
5	0.81	−0.13	−3.3	61	1.4	49.93	3.15	38.5
6	0.33	−0.08	−3.7	45	1.2	33.69	2.90	27.1
7	0.36	−0.08	−3.7	46	1.3	33.00	2.82	27.1
8	0.16	−0.09	−3.9	41	1.1	31.42	2.86	23.2
9	1.26	−0.05	−3.1	77	1.6	52.86	3.34	54.1
10	−0.31	−0.13	−4.0	43	1.0	32.87	2.68	25.2
11	−0.43	−0.09	−4.1	42	0.7	25.03	2.49	25.2
12	0.04	−0.04	−3.8	40	1.2	21.76	2.51	22.9
13	0.45	−0.03	−3.5	53	1.2	29.16	2.97	32.3
14	0.37	−0.01	−3.5	51	1.1	23.28	2.51	30.6
15	1.72	0.13	−2.9	92	1.5	50.18	3.57	66.9
16	1.88	0.19	−2.8	95	1.6	50.85	3.52	76.9
RO5263397	1.85	0.35	−2.0	100	2.4	27.57	3.12	99.0

^a Extent of brain penetration based on ratio of total drug concentrations in tissue and plasma at steady-state conditions; ^b Rate of brain penetration. The permeability–surface area product (PS) is derived from the kinetic equation of capillary transport; ^c human intestinal absorption (HIA) is expressed as percentage of the molecule able to pass through the intestinal membrane; ^d prediction of volume of distribution (Vd) of the compound in the body.