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  • Optimization of the tetrahydroindazole series

    2022-01-20

    Optimization of the tetrahydroindazole series led to the discovery of two moderately potent γ-secretase modulators, 2-cyclobutane and 2-hydroxy-2-methylpropane which were subsequently evaluated in a kinetic aqueous solubility assay. Unfortunately, neither analog demonstrated improved solubility (). However, the incorporation of heteroatoms within the D-ring does lead to compounds which exhibit ideal solubility as demonstrated by analogs , and , albeit at the expense of modulator activity. Modest improvements in aqueous solubility were also observed for 1-methylpiperidine and 2-methoxyethane , thus validating our synthetic strategy for addressing this property related shortcoming. In addition, integrating heteroatoms within the 2-position substituent of the tetrahydroindazole family of compounds was found to result in ligands with poor microsomal stability (data not shown). Thus, our efforts to maintain activity for inhibiting the formation of Aβ42 while improving ligand solubility through the introduction of novel tetrahydroindazole D-ring scaffolds provided ligands with fair activity, but lacking the desired physicochemical properties of a drug-like compound. Therefore, additional analogs were explored which retain the pyrazole core of this series to determine the effect of the fused ring system on ligand activity, as well as on aqueous solubility. In order to improve upon the tetrahydroindazole family of compounds, as well as further enhance our understanding of D-ring interactions with the γ-secretase enzyme, a novel set of 1-substituted 3--butylpyrazole ligands was designed and synthesized with the goal of simultaneously increasing potency and improving aqueous solubility. The placement of substituents was again modeled on preserving favorable Cy3 RNA interactions present in the D-ring of AGSM . Additionally, the -butyl substitution was envisaged to allow the exploration of new regions within the target through the use of a bulky substituent directed into a specific region of space while simultaneously increasing overall ligand flexibility when compared to its fused ring counterpart. Alkylated pyrazole analogs – were prepared based on the moderate Aβ42 reduction observed in the 2-substituted tetrahydroindazole series (). The novel 1,3-disubstitiuted pyrazole compounds displayed modest to good activity, with -ethyl derivative displaying the best Aβ42-lowering activity with an IC=63nM. The incorporation of longer alkyl chains did not lead to improved potency as observed with the tetrahydroindazoles. Also distinct, the larger -isopropyl analog and -butyl analog did not adversely impact the potency of this series. The improved activity of compounds – was also accompanied by a modest improvement in aqueous solubility; pyrazoles , and displayed improved solubility, while compound maintained the poor solubility associated with many of the ligands developed thus far. The initially prepared 1-substituted 3--butylpyrazole ligands (–) demonstrated consistent potency over a wide range of alkyl substitutions. The improved properties of the 3--butylpyrazole set of ligands led us to explore additional analogs of -ethyl pyrazole . Ligand design focused on potential modifications to the pyrazole substitution pattern which probe the subtle interactions between the compound and the target. Introduction of a 3-isopropyl substituent () within the pyrazole resulted in a 6-fold reduction in activity when compared to compound (). On the other hand, 3-methylcyclopropyl maintained potency, suggesting the Cy3 RNA overall hydrophobic bulk within the 3-position of the pyrazole is relevant to binding affinity. Surprisingly, the integration of a smaller 3-trifluoromethyl substituent in pyrazole was tolerated. In addition, similar to the loss in potency observed between 3--butylpyrazoles and , -butyl-3-trifluoromethyl analog only showed a minor loss in activity associated with the larger amino substituent. The preservation of activity associated with the 3-trifluoromethyl analogs and is hypothesized to result from the maintained favorable hydrophobic interactions of the -substituent within the enzyme target, as well as a substantial reduction in the penalty associated with the lost interactions of the 3-butyl substituent through unanticipated electronic effects of the trifluoromethyl replacement. The incorporation of -trifluoroethyl was also explored resulting in derivative which showed comparable activity to 3-trifluoromethyl pyrazole . However, -trifluoroethyl-3-trifluoromethyl pyrazole displays a greater than 10-fold loss in activity lending support to the notion that the presence of a hydrophobic substituent within the D-ring is required in order to maintain ligand affinity. Furthermore, the removal of the 3-position substituent as illustrated by -ethylpyrazole analog results in a complete loss of activity for the suppression of Aβ42 formation.