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    • More polar substituents introduced on the position

    2021-10-18

    More polar substituents introduced on the 5-position of the aniline ring (e.g., dimethyl amine in ) decreased the lipophilicity of the compounds (4.3 for vs 5.1 for ), but did not affect their potency. For instance, was highly potent in vitro and demonstrated a surprising 51% lowering of Aβ42 in mice at 30mg/kg, 4h from administration, despite a poor Azacyclonol australia penetration (B/P=0.2) and low mouse free brain concentrations (=4nM, 6-fold lower than mIC). Introduction of a heteroatom on the aniline ring was detrimental to potency as exemplified by . Introduction of a N-atom in the anisole ring (compounds –, ) reduced the log by 0.5 while maintaining the in vitro and in vivo potency. This modification led to a reduced brain penetration and a suboptimal B/P ratio for most of the methoxypyridyl derivatives (, ). On the other hand, the of these compounds increased versus their anisole analogs (see – vs , and , respectively). An interesting compound was which, although relatively weak in vitro, was moderately potent in vivo, showing 39% Aβ42 lowering in mice at 30mg/kg, 4h after administration. Compounds and had comparable in vitro potencies, both in human and in mouse. Aniline was a less brain penetrant (B/P=0.1 vs 0.8 for ), which combined with a low (0.3%) resulted in a free brain concentration 10-fold lower than the IC (). This might explain the difference in the in vivo activity of the two anilines: while reduced Aβ42 levels significantly 4h after dosing in mouse at 30mg/kg, had no effect on the Aβ peptides. Compound was one of the most potent methoxypyridyl derivative both in vitro and in vivo, and maintained a relatively high B/P ratio (0.8). Methylation of the aniline nitrogen of led to a 14-fold loss of potency (, ), which underlined the importance of the N–H bond. Other structural modifications were made, seeking to improve the efficacy in this series of compounds. Replacement of the imidazole ring (see –, , vs ) or of the anisole B ring (see –, , vs ) did not improve the in vitro potency. Compound , three times less potent than parent , was one of the most potent compounds resulting from this exercise. Nevertheless when tested at 30mg/kg in mice, showed no significant lowering of Aβ42 levels 4h after dosing. Bioanalysis of in mice 4h post dosing showed that this compound suffered from low exposure both in plasma (0.78μM) and in brain (0.34μM), which could be explained by its poor solubility (<1.5mg/mL in 20% captisol). Replacement of the methyl group on the triazole ring with other aliphatic substituents at best maintained the in vitro potency (–, ), at the expense of the physicochemical properties, such as MW and lipophilicity. Attempts to reduce aromaticity, as in and () resulted in a loss of potency. The most interesting compound in this series remained , with a good balance of the in vitro and in vivo potency. As expected for a GSM, did not affect the total level of Aβ peptides and it did not inhibit Notch processing. Compared with , had improved drug-like properties (reduced aromaticity, lower log, better lipophilic efficiency) which was reflected in the compound’s ADMET profile: improved kinetic solubility, weak CyP inhibition potential (IC >10μM overall). The moderate inhibition of the potassium membrane current by (52% at 3μM) did not translate in vivo in anesthetized guinea pigs. When tested orally in mice at 30mg/kg, showed a significant modulation of the Aβ peptides, inhibiting secretion of Aβ42 by 55% and stimulating production of Aβ38 levels by 53%—again in line with a typical profile of a GSM. While was still highly bound to both plasma and brain proteins, it did show an improvement over benzimidazole (see ). The duration of action of was examined in more detail in a time-course experiment after a single oral dose of 30mg/kg in non-transgenic mice. Reduction of Aβ42 levels (38%) was observed 1h after dosing, a maximum inhibition of Aβ42 levels being reached 6h after treatment. 12h after dosing, Aβ42 levels remained moderately reduced below vehicle values and returned to normal 24h after administration (A). Similarly, Aβ38 levels in brain were significantly increased from 1 to 12h post dosing, a 64% increase being reached 6h after treatment (B). Total levels of Aβ in brain remained unchanged.