Development of morpholine ring-bearing halogenated α,β-unsaturated ketones as selective monoamine oxidase-B inhibitors

Applied Biological Chemistry

Table 4 ADME/T prediction of the MHC series

Code	Absorption			Distribution				Metabolism	Excretion total clearance (log ml/min/kg)	Hepatotoxicity
Code	Log S (log mol/L)	Caco-2 perm. (logP_app in 10⁻⁶ cm/s)	Int. abs. (% absorbed)	VDss (log L/kg)	Fract. Unb (Fu)	BBB perm. (log BB)	CNS perm. (log PS)	Metabolism	Excretion total clearance (log ml/min/kg)	Hepatotoxicity
MHC1	−3.58	1.738	98.42	0.532	0	0.449	−1.399	CYP2C9, CYP3A4 Substrate CYP1A2,CYP2C19,CYP2D6 inhibitor	0.305	No
MHC2	−4.56	1.664	96.687	0.454	0	0.378	−1.411	CYP2C9,CYP3A4,CYP1A2,CYP2C19, CYP2D6 inhibitor	0.124	Yes
MHC3	−4.87	1.664	96.62	0.47	0	0.364	−1.411	CYP2C9,CYP3A4,CYP1A2,CYP2C19, CYP2D6 inhibitor	0.103	Yes
MHC4	−4.12	1.792	97.589	0.284	0	0.422	−1.438	CYP2C9, CYP3A4 Substrate CYP1A2,CYP2C19,CYP2D6 inhibitor	0.175	Yes
MHC5	−4.56	1.67	96.508	0.427	0	0.364	−1.411	CYP2C9,CYP3A4,CYP1A2,CYP2C19, CYP2D6 inhibitor	0.243	No
MHC6	−4.87	1.669	96.441	0.442	0	0.351	−1.411	CYP2C9,CYP3A4,CYP1A2,CYP2C19, CYP2D6 inhibitor	0.221	Yes
MHC7	−4.12	1.798	97.41	0.257	0	0.408	−1.438	CYP3A4 Substrate CYP1A2,CYP2C9,CYP2C19,CYP2D6 inhibitor	0.182	Yes
MHC8	−4.56	1.691	97.537	0.463	0	0.362	−1.417	CYP2C9,CYP3A4,CYP1A2,CYP2C19, CYP2D6 inhibitor	0.315	No
MHC9	−4.12	1.819	98.439	0.292	0	0.407	−1.443	CYP2C9, CYP3A4 Substrate CYP1A2,CYP2C19,CYP2D6 inhibitor	0.131	Yes

SwissADME and pkCSM were used to calculate pharmacokinetic properties in silico (http://biosig.unimelb.edu.au/pkcsm/). While molecules with log BB < −1 are poorly disseminated to the brain, those with log BB > 0.3 are thought to cross the BBB with ease. Compounds with log PS > −2 are thought to penetrate the CNS, whereas those with log PS < −3 are thought to be unable to do so. Perm., permeability