Table 4.

Lipinski’s rule of 5 violations and ADME properties of PH011669 and its optimised version.

Lipinski’s rule of 5
150 Da ≤ MW ≤500 Da	518.9 Da	332.3 Da
−0.7 ≤ Log P ≤ 5	2.06	0.19
≤10 H-bond acceptors	12	8
≤5 H-bond donors	5	3
Other pharmacokinetic properties
20 Å2 ≤ TPSA ≤150 Å2	262.5 Å2	162.8 Å2
−6 ≤ Log S ≤ 0	−4.38	−2.17
No. of rotatable bonds ≤ 7a	5	3
Presence of azo group	Yes	No
Gastrointestinal absorptionb	Low	Low
Interactions with CYP isoenzymesc	No	No

MW: molecular weight; TPSA: topological polar surface area; CYP: cytochromes P450; BBB: blood-brain barrier.

^aDrugs with more than seven rotatable bonds are flexible and can lead to unfavourable ADME properties, as the increased conformational entropy can distort target binding.

^bFor a drug to be effective, its gastrointestinal absorption should be high to enter the bloodstream.

^cAssessing the inhibitory interactions of a drug with the CYP isoenzymes CYP1A2, CYP2C19, CYP2C9, CYP2D6 and CYP3A4 is essential because inhibition of these isoenzymes can lead to drug–drug interactions, increasing the risk of adverse effects. In this category, “no” means that the drug is not an inhibitor of any CYP isoenzyme.