TABLE 1.

Calculated CNS MPO score, log P-value and related factors that impact drug pharmacokinetics and brain entry under physiological conditions: Molecular weight, Log P-value, the quantity of hydrogen bond donors and acceptors, the topological polar surface area value, and the pKa were computed with Chemicalize for several clinically approved and available IMiDs as well as for the recent analogs 3,6′-dithio-pomalidomide (3,6′-DP), -thalidomide (3,6′-DTT) and the adamantyl moiety containing agent N-adamantyl pththalmidine.

Compound	Molecular weigh	Log P	Topological polar	Number of hydrogen	Number of hydrogen	Most basic center acidity*	CNS MPO
Compound	(g/mol)		surface area (Å2)	bond donors	bond acceptors	(calculated pKa)	score
Thalidomide (Thalidomid)	258.2	0.02	83.55	1	4	11.59**	4.8
Lenalidomide (Revlimid)	259.3	–0.71	92.50	2	4	2.31	5.4
Pomalidomide (Pomalyst)	273.2	–0.16	109.57	2	5	1.56	4.8
Apremilast (Otezla)	460.5	1.31	119.08	1	7	12.98**	3.1
3,6′-Dithiopomalidomide (3,6′-DP)	305.4	0.97	75.43	2	3	2.33	5.5
3,6′-Dithiothalidomide (3,6′-DTT)	290.4	1.80	49.41	1	2	9.8**	4.9
N-adamantyl phthalimidine (NAP)	295.4	3.86	20.31	0	1	–1.04	3.7
Dithiophthalimide	179.3	2.47	12.03	1	0	14.31**	3.6

Such IMiDs largely are in accord with the Lipinski rule of five, which predicts the likelihood of a drug being delivered to its target under human physiological conditions based on its physical properties (Banks and Greig, 2019). A CNS MPO Score, that provides an estimate of a drug’s BBB permeability, was computed using parameters described by Wager et al. (2010), with a greater score value associating with a higher drug BBB permeability. *Obtained from Chemicalize as the calculated “Strongest Basic pKa” and presumably as if the parent molecule were to function as a base. When such a value was not computed or available from the software, the Strongest Acidic pKa value was utilized instead. **Indicates the Strongest Acidic pKa value; subsequently used for MPO calculation.