A promising idea is to explore a medically accepted vehicle (for example: nanocarriers/particles) in combination with A ligands or fluorinated molecules to cross the BBB

A promising idea is to explore a medically accepted vehicle (for example: nanocarriers/particles) in combination with A ligands or fluorinated molecules to cross the BBB. superb neuroprotective profile Stock answer of A42 peptide, SH-SY5Y cells, hippocampal slices of male young rat (6C8 weeks aged)[65]Fluorinated surface (Teflon)A40 peptidePromotes -helix reformationStock answer of A40 peptide[66] Open in a separate windows 2.2. The Part of Fluorine-Containing Compounds in the Modulation of the Secretases -Site amyloid precursor protein cleaving enzyme (BACE1) takes on a crucial part in controlling the formation of A peptide as it is the only enzyme responsible for the -secretase activity in the brain [69]. Consequently, BACE1 inhibitors present the possibility of disease-modifying treatment for AD. Since 1999, after the recognition of the potential pharmacological target along with the results from the BACE1 Hapln1 knockout mice [70], many research organizations and companies possess invested in developing BACE1 inhibitors (Table 2). Several companies like Pfizer, Bristol-Meyers Squibb (BMS), Lilly, Roche, Novartis, etc. have launched fluorine atom and fluoro-methyl substituents to the BACE1 inhibitors to increase potency, improve cellular activity and metabolic stability. We are showing selected BACE1 inhibitors comprising at least one fluorine element in the chemical structure that have been designed and tested between Clenbuterol hydrochloride 2010 and 2020 [69]. Table 2 Fluorinated BACE1 inhibitors for the Alzheimers disease (AD) treatment.

Chemical substances Site of Action Observed Effects Magic size Used Reference

Fluorinated ethanolamines -secretase (BACE1)Inhibits BACE1 activityEnzymatic assay (human being BACE1), human being neuroblastoma SKNBE2 cells[72]LY-2886721Decreases the A levels in CSFHuman. Terminated after phase 2 due to liver toxicity[75] Fluorinated LY-2886721Reduces the amyloid levelsHEK293 cells (Human being BACE1)PDAPP young mice[76]1,3 oxazine-based BACE1 inhibitor (difluoroethyl substituted analogue)Display good BACE1/2 selectivity;
Reduce A levels in CSFHEK293 cells (Both human being BACE1 and BACE2)
male beagle dogs[78]Eisais BACE1 inhibitor [1,3] thiazine series Fluoro(methyl) analoguesEnhance the basicity and Clenbuterol hydrochloride display selectivity over BACE2 Human being/Rat A42; neuronal cultures of rats fetus mind[80,81]Organofluorine substituted BACE1 inhibitorsImprove the drug effectiveness (non-P-gp substrates)Neuroblastoma SH-SY5Y cells, human being liver microsomes,
ICR mice (7C9 weeks aged)[82]Fluorinated oxazines analoguesEnhance potency and basicity;
Reduce the A levels at low dosesEnzymatic assays (BACE1 and BACE2), HEK293 cells, LLC-PK1 cells,
woman WT-mice[88] Open in a separate windows Inspired from the work by Elan and Pfizer [71], Fustero et al. [72] synthesized fluorinated ethanolamines (Number 3A) to analyze the essential fragments for the stereo-selective synthesis of hydroethyl secondary amine (HEA). They substituted phenyldifluoromethyl in the -carbon of the HEA and explored the chemical space of the inhibitor by replacing hydrogen atoms in the benzylic position by fluorine atoms for enhancing the pharmacological profile of the series [44,73,74]. The biological evaluation of these derivatives disclosed a notable BACE1 inhibitor activity. Docking studies showed the potential of fluorine atoms in influencing the potency of the inhibitors [72]. Open in a separate window Number 3 Chemical constructions of the fluorine-decorated BACE1 inhibitors (A) Fluorinated ethanolamines; (B)LY-2886721(N-(3-((4aS,7aR)-2-amino-4a,5-dihydro-4H-furo[3,4-d][1,3]thiazin-7a(7H)-yl)-4-fluorophenyl)-5-fluoropicolinamide); Clenbuterol hydrochloride (C) Fluorinated analogue of LY-2886721(N-(3-((4aR,7aR)-2-amino- 4a-fluoro-4a,5-dihydro-4H-furo[3,4-d][1,3]thiazin-7a(7H)-yl)-4-fluorophenyl)-5-cyanopicolinamide); (D) Lillys Fluorinated Inhibitor (N-(3-((4aR,5S,7aR)-2-amino-5-(1,1-difluoroethyl)-4a,5-dihydro-4H-furo[3,4-d][1,3]oxazin-7a(7H)-yl)-4-fluorophenyl)-5-(trifluoromethyl)picolinamide); (E): Eisais BACE1 inhibitor [1,3] thiazine series Fluoro(methyl) analogues; F, G and H) Shingoi Clenbuterol hydrochloride and Janssens organofluorine substituted BACE1 inhibitors; (F) N-(3-((4S,6S)-2-amino-6-(difluoromethyl)-4-methyl-5,6-dihydro-4H-1,3-thiazin-4-yl)-4-fluorophenyl)-5-(fluoromethoxy)pyrazine-2-carboxamide; (G) N-(3-((4S,6S)-2-amino-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-thiazin-4-yl)-4-fluorophenyl)-5-(fluoromethoxy)picolinamide; (H) N-(3-((4S,6S)-2-amino-6-(1,1-difluoroethyl)-4-methyl-5,6-dihydro-4H-1,3-thiazin-4-yl)-4-fluorophenyl)-5-(fluoromethoxy)picolinamide); and (I) Roches Fluorinated 1,3-oxazines inhibitors.In red color are represented fluorine molecules (F) and trifluoromethyl organizations (CF3). In 2015, Lillys LY-2886721 [75] (Number 3B) was the 1st 1,3-thiazine centered BACE1 inhibitor improving to a phase 2 trial. In the phase 1 trial, LY-2886721 was found efficient and decreased the A levels in cerebrospinal fluid (CSF). However, this inhibitor was terminated by the company due to liver toxicity. Later on, they reported a modification of LY-2886721 by introducing a fluorine atom in the ring junction and total enhancing the basicity of the compound. The fluorinated analogue 4a-Fluoro-furo[3,4-d][1,3]thiazine [76] (Number 3C) showed improvement in biological parameters and potent reduction of amyloid levels in in vitro and in vivo as compared to LY-2886721. Similar to the 1, 3-thiazine analogue,.