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.
p62/SQSTM1, encoded by gene SQSTM1, is widely known as an adaptor protein of selective autophagy to promote aggregate-prone proteins for degradation. It is also a stress-induced scaffold protein involved in Nrf2 activation to resist oxidative stress. Multiple domains of p62 interact with several essential pathways implicated in cell differentiation and proliferation, placing p62 at a significant position to mediate cell survival and apoptosis. The p62 protein has been suggested as a potential target in recent years, since its abnormal expression or SQSTM1 gene mutation is tightly associated with various diseases including cancer such as hepatocellular carcinoma and prostate cancer, neurodegenerative disorders such as Alzheimer's disease and amyotrophic lateral sclerosis, atherosclerosis, and Paget's disease of bone. In this review, we will discuss the relationship between p62 and these diseases, and we attempt to put forward novel methods for current diagnosis or therapy by regulating the p62 expression level.
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.
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