Thus, we undertook a polymorph screening by several crystallization experiments of compound II. This suggests that another potential polymorph could be obtained. The analysis also predicts other plausible hydrogen-bonded networks (Fig. 4 ), one that is statistically slightly more likely to be formed than the current one. We did not observe the carboxylic dimer but rather this group interacting with one oxygen of the sulfonyl methyl. A hydrogen-bonding interaction between two carboxylic groups is predicted with the highest probability. This quantifies the probability of hydrogen-bond formation and thus the different probable polymorphs that can arise from a specific compound. This statistical analysis allows us to estimate which atoms are the donors and the acceptors for hydrogen bonds in the crystal structure (Chemburkar et al., 2000 Galek et al., 2007 ). No comparable structures came out of this survey.Ī polymorph risk assessment based on the hydrogen bonds in the CSD was carried out. 2016 ) were carried out with the exact structures of compounds I and II and with substructures containing the significant fragments (alanylpiperidine with and without the sulfonyl methyl and tolyl group).
XCALIBUR 2097 UPDATE
Searches of the Cambridge Structural Database (CSD, version 5.42, update September 2021 Groom et al. A dimer synthon is observed in the crystal packing in both cases, but for compound I it is ensured by weak hydrogen bonds in contrast to compound II where the dimer is based on strong hydrogen bonds. As in compound I, no π– π interactions are noticed in the crystal structure. In addition, two intramolecular and one intermolecular weak hydrogen bonds are detected. In compound II, a hydrogen-bonded ring with an R 2 2(24) motif is formed by a strong hydrogen bond between H3 of the carboxylic acid group and O5 from an adjacent molecule. In compound II, a tubular arrangement (Fig. 3 ) can be observed, which is different from that of compound I. We report the crystal structures of these two compounds as well as a survey of the interactions observed in compound II.Ĭrystal packing of I with hydrogen bonds highlighted in green ( a) showing one layer of molecules, viewed down the a axis and ( b) showing adjacent layers of molecules.Ĭompound II bearing a carboxylic moiety instead of an ester has an impact on the hydrogen bonds and thus on the crystal packing. Compound II bears a carboxylic acid group, which opens up the possibility for co-crystallization and salification in order to modulate the physicochemical properties, such as the solubility. Derivatives of compound I were then investigated as potential activators and compound II was obtained after a saponification.
XCALIBUR 2097 ACTIVATOR
We studied the only known activator in the literature, compound I.
Ethyl 1-piperidine-4-carboxylate was discovered through in silico drug screening as an activator of UCH-L1, with a hydrolase activity up to 111% at 63 µ M (Mitsui et al., 2010 ). Finding potentiators of UCH-L1 could be a therapeutic pathway for these diseases (Mitsui et al., 2010 ). Studies have shown that several mutations have an impact on the hydrolase activity of UCH-L1 (Leroy et al., 1998 Maraganore et al., 1999 ) and that its down-regulation is associated with idiopathic Parkinson's disease (Choi et al., 2004 ). Ubiquitin C-terminal Hydrolase-L1 is a deubiquitinase that represents 2% of the neuronal soluble proteins in the brain and is involved in the neuropathogenesis of neurodegenerative diseases.
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