In the development of central nervous system (CNS) drugs, the blood–brain barrier (BBB) restricts many drugs from entering the brain to exert therapeutic effects. Although many novel delivery methods of large molecule drugs have been designed to assist transport, small molecule drugs account for the vast majority of the CNS drugs used clinically. From this perspective, we review studies from the past five years that have sought to modify small molecules to increase brain exposure. Medicinal chemists make it easier for small molecules to cross the BBB by improving diffusion, reducing efflux, and activating carrier transporters. On the basis of their excellent work, we summarize strategies for structural modification of small molecules to improve BBB penetration. These strategies are expected to provide a reference for the future development of small molecule CNS drugs.

To discover novel BChE inhibitors, a hierarchical virtual screening protocol followed by biochemical evaluation was applied. The most potent compound 8012-9656 (eqBChE IC 50 = 0.18 ± 0.03 μM, hBChE IC 50 = 0.32 ± 0.07 μM) was purchased and synthesized. It inhibited BChE in a noncompetitive manner and could occupy the binding pocket forming diverse interactions with the target. 8012-9656 was proven to be safe in vivo and in vitro and showed comparable performance in ameliorating the scopolamine-induced cognition impairment to tacrine. Additionally, treatment with 8012-9656 could almost entirely recover the Aβ 1−42 (icv)-impaired cognitive function to the normal level and showed better behavioral performance than donepezil. The evaluation of the Aβ 1−42 total amount confirmed its anti-amyloidogenic profile. Moreover, 8012-9656 possessed blood−brain barrier (BBB) penetrating ability, a long T 1/2 , and low intrinsic clearance. Hence, the novel potential BChE inhibitor 8012-9656 can be considered as a promising lead compound for further investigation of anti-AD agents.

Structural information of butyrylcholinesterase (BChE) and its variants associated with several diseases are discussed here. Pure human BChE has been proved safe and effective in treating organophosphorus (OPs) poisoning and has completed Phase 1 and 2 pharmacokinetic (PK) and safety studies. The introduction of specific mutations into native BChE to endow it a self‐reactivating property has gained much progress in producing effective OPs hydrolases. The hydrolysis ability of native BChE on cocaine has been confirmed but was blocked to clinical application due to poor PK properties. Several BChE mutants with elevated cocaine hydrolysis activity were published, some of which have shown safety and efficiency in treating cocaine addiction of human. The increased level of BChE in progressed Alzheimer's disease patients made it a promising target to elevate acetylcholine level and attenuate cognitive status. A variety of selective BChE inhibitors with high inhibitory activity published in recent years are reviewed here. BChE could influence the weight and insulin secretion and resistance of BChE knockout (KO) mice through hydrolyzing ghrelin. The BChE‐ghrelin pathway could also regulate aggressive behaviors of BChE‐KO mice.

Butyrylcholinesterase (BChE) has been considered as a potential therapeutic target for Alzheimer’s disease (AD) because of its compensation capacity to hydrolyze acetylcholine (ACh) and its close association with Aβ deposit. Here, we identified S06-1011 (hBChE IC50 = 16 nM) and S06-1031 (hBChE IC50 = 25 nM) as highly effective and selective BChE inhibitors, which were proved to be safe and long-acting. Candidate compounds exhibited neuroprotective effects and the ability to improve cognition in scopolamine- and Aβ1–42 peptide-induced cognitive deficit models. The best candidate S06-1011 increased the level of ghrelin, a substrate of BChE, which can function as improving the mental mood appetite. The weight gain of the S06-1011-treated group remarkably increased. Hence, BChE inhibition not only plays a protective role against dementia but also exerts a great effect on treating and nursing care.

Tyrosinase is involved in the synthesis of neuromelanin in the substantia nigra, which is closely correlated with the pathogenesis of Parkinson’s disease. Herein, we identified S05014 (l-Tyr, IC50 = 6.25 ± 1.43 nM; l-Dopa, IC50 = 0.64 ± 0.40 μM) as a highly effective tyrosinase inhibitor. It could inhibit the tyrosinase function from different origins and decrease the expression of tyrosinase. S05014 presented good medication safety and inhibited melanogenesis in a dose-dependent manner. Moreover, as a resorcinol derivative, S05014 could scavenge the 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radical and significantly reduce the overproduction of LPS-induced reactive oxidative species (ROS), indicating its antioxidative profile. S05014 exhibited an excellent neuroprotective effect against methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) impairment in vitro and could remarkably alleviate movement abnormalities and exploratory activities in vivo. Altogether, S05014 is considered as a promising inhibitor for tyrosinase, melanogenesis, and oxidative stress and has great potential to be utilized in anti-Parkinsonian syndrome. From this point of view, tyrosinase inhibition has been further confirmed to be a novel strategy to improve locomotor capacity and treat Parkinson’s disease.