Abstract
Recently, the direct thrombin (thr) inhibitor dabigatran has proven to be beneficial in animal models of Alzheimer’s disease (AD). Aiming at discovering novel multimodal agents addressing thr and AD-related targets, a selection of previously and newly synthesized potent thr and factor Xa (fXa) inhibitors were virtually screened by the Multi-fingerprint Similarity Searching aLgorithm (MuSSeL) web server. The N-phenyl-1-(pyridin-4-yl)piperidine-4-carboxamide derivative 1, which has already been experimentally shown to inhibit thr with a Ki value of 6 nM, has been flagged by a new, upcoming release of MuSSeL as a binder of cholinesterase (ChE) isoforms (acetyl- and butyrylcholinesterase, AChE and BChE), as well as thr, fXa, and other enzymes and receptors. Interestingly, the inhibition potency of 1 was predicted by the MuSSeL platform to fall within the low-to-submicromolar range and this was confirmed by experimental Ki values, which were found equal to 0.058 and 6.95 μM for eeAChE and eqBChE, respectively. Thirty analogs of 1 were then assayed as inhibitors of thr, fXa, AChE, and BChE to increase our knowledge of their structure-activity relationships, while the molecular determinants responsible for the multiple activities towards the target enzymes were rationally investigated by molecular cross-docking screening.
Highlights
Alzheimer’s disease (AD) is a devastating neurodegenerative disorder, which accounts for the most elderly-related dementias
In the last decade we reported the rational design of several classes ofnipecotamide derivatives, acting as selective thrombin or factor Xa inhibitors [12,13,14,15,16]
Thr and factor Xa (fXa) are trypsin-like serine proteases that in sequence catalyze the conversion of soluble fibrinogen into insoluble fibrin in the final step of clot formation
Summary
Alzheimer’s disease (AD) is a devastating neurodegenerative disorder, which accounts for the most elderly-related dementias. The lowering of the level of cholinergic neurotransmitter acetylcholine (ACh) into the hippocampus, and progressively into the whole brain cortex, contributes to the typical AD-related cognitive and memory impairment and decline [2,3,4]. Vascular and thrombotic risk factors (i.e., hypertension, diabetes, and hyperlipidemia) have been described as potentially associated with an increased risk and progression of cognitive decline in AD and vascular and mixed dementia [5]. The cerebrovascular abnormalities are followed by formation of Aβ protein plaques co-aggregating with some coagulation factors; these deposits may induce leaking of the brain-blood-barrier (BBB), promoting a pro-thrombotic state, as well as enhancing release of pro-inflammatory mediators in the brain areas [7]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
