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.

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Human aldo-keto reductase family 1 member C3 (AKR1C3) is known as a hormone activity regulator and prostaglandin F (PGF) synthase that regulates the occupancy of hormone receptors and cell proliferation. Because of the overexpression in metabolic diseases and various hormonedependent and -independent carcinomas, as well as the emergence of clinical drug resistance, an increasing number of studies have investigated AKR1C3 inhibitors. Here, we briefly review the physiological and pathological function of AKR1C3 and then summarize the recent development of selective AKR1C3 inhibitors. We propose our viewpoints on the current problems associated with AKR1C3 inhibitors with the aim of providing a reference for future drug discovery and potential therapeutic perspectives on novel, potent, selective AKR1C3 inhibitors.

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.