Kinetics-Driven Drug Design Strategy for Next-Generation Acetylcholinesterase Inhibitors to Clinical Candidate

Abstract

The acetylcholinesterase (AChE) inhibitors remain key therapeutic drugs for the treatment of Alzheimer's disease (AD). However, the low-safety window limits their maximum therapeutic benefits. Here, a novel kinetics-driven drug design strategy was employed to discover new-generation AChE inhibitors that possess a longer drug-target residence time and exhibit a larger safety window. After detailed investigations, compound 12 was identified as a highly potent, highly selective, orally bioavailable, and brain preferentially distributed AChE inhibitor. Moreover, it significantly ameliorated cognitive impairments in different mouse models with a lower effective dose than donepezil. The X-ray structure of the cocrystal complex provided a precise binding mode between 12 and AChE. Besides, the data from the phase I trials demonstrated that 12 had good safety, tolerance, and pharmacokinetic profiles at all preset doses in healthy volunteers, providing a solid basis for its further investigation in phase II trials for the treatment of AD.

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“…[29] Hence, improving the level of ACh by inhibiting AChE is a crucial method for treatment of the cognitive impairment of AD patients. [30] Thus, AChE inhibitors (AChEIs) are currently the first-line drugs approved by the FDA to treat AD (donepezil, galantamine, rivastigmine, and tacrine) (Scheme 2). However, this short effective treatment limits their therapeutic benefits.…”

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“…To note, another natural product with therapeutic application in AD is huperzine A ( 6 ), extracted from Huperzia serrata . It was approved by the Chinese authorities and is marketed in the USA as a dietary supplement [ 28 ].…”

“…To overcome this limitation, novel ChEIs are still studied in clinical trials with the aim of reducing the dose of administration and enhance the safety profile of the current drugs. In fact, new AChEIs that possess a longer drug-target residence time and exhibit a larger safety window, have been recently reported [ 28 ]. A novel fluorinated derivative of donepezil ( 7 ; Figure 1 ) demonstrated to be a highly potent, selective, orally bioavailable, and brain penetrant AChEI, able to ameliorate the cognitive impairments in different mice models at a lower effective dose than donepezil [ 28 ].…”

“…In fact, new AChEIs that possess a longer drug-target residence time and exhibit a larger safety window, have been recently reported [ 28 ]. A novel fluorinated derivative of donepezil ( 7 ; Figure 1 ) demonstrated to be a highly potent, selective, orally bioavailable, and brain penetrant AChEI, able to ameliorate the cognitive impairments in different mice models at a lower effective dose than donepezil [ 28 ]. In China, phase I trials of 7 (CTR20181428 and CTR20190664) showed good safety, tolerance, and pharmacokinetic profiles.…”

“…Particularly, we sought to link the cardanol skeleton, which might interact with the PAS through its aromatic end, with a fragment able to fish the CAS, to obtain dual binding AChE inhibitors (Figure 7) [81]. As a CAS key molecular feature, we selected fragments bearing a cationic head, which included a protonatable amino moiety belonging to different systems: heterocyclic amines such as pyrrolidine (25), piperidine (26), morpholine (27), thiomorpholine (28), N-substituted piperazines (29)(30)(31)(32)(33), hydroxylated pyrrolidine (34) and piperidines (35)(36)(37) and their corresponding O-acetyl (38)(39)(40)(41) and O-dimethylcarbamates (42)(43)(44)(45). Since the N-ethyl-N-(2-methoxybenzyl)amino moiety has been successfully exploited by us and others to obtain powerful dual binding AChEIs [82][83][84][85][86][87], we also synthesized hybrids 46-48 (Figure 7).…”