The structure of ethyl 1-[N-(4-methyl-phen-yl)-N-(methyl-sulfon-yl)alan-yl]piperidine-4-carboxyl-ate, C19H28N2O5S, I, a compound of inter-est as activator of Ubiquitin C-terminal Hydro-lase-L1 (UCH-L1), was determined by single-crystal X-ray diffraction (SCXRD) analysis. In order to find new activators, a derivative of compound I, namely, 1-[N-(4-methyl-phen-yl)-N-(methyl-sulfon-yl)alan-yl]piperidine-4-carb-oxy-lic acid, C17H24N2O5S, II, was studied. The synthesis and crystal structure are also reported. Despite being analogues, different crystal packings are observed. Compound II bears a carb-oxy-lic group, which favors a strong hydrogen bond. A polymorph risk assessment was carried out to study inter-actions in compound II.
BACKGROUND/AIMS: LRRK2 (leucine-rich repeat protein kinase 2) is one of the most commonly accepted genes associated with Parkinson's disease (PD). The overexpression of disease-associated mutations in LRRK2 is toxic to the cells, while reduction or elimination of LRRK2 expression promotes cell health and growth. Thus, the identification of an LRRK2 inhibitor with good physiochemical and pharmacokinetic properties is of great interest for the treatment of PD. METHODS: In this study, we have investigated LRRK2 compounds, LRRK2-IN-1 and Compound 1, in vitro and in vivo to determine how suitable they are as a selective LRRK2 tool compound. RESULTS: We report that Compound 1, patented by GSK, is a potent and selective LRRK2 inhibitor with good blood-brain barrier permeability as reflected by its high brain to plasma ratio in rats. In addition, Compound 1 can significantly promote neurite outgrowth in a primary cortical culture, indicating an optimistic cellular function of this compound in a biological system. In contrast, LRRK2-IN-1 is a less selective LRRK2 inhibitor and has low brain penetration. Furthermore, LRRK2-IN-1 is cyto- and genotoxic, while Compound 1 does not exhibit any toxicity. CONCLUSIONS: These results suggest that Compound 1 may be a superior tool compound than LRRK2-IN-1 to advance future pharmacological research on LRRK2.
Benzodiazepinones/pharmacology , Drug Discovery/methods , Parkinson Disease/enzymology , Protein Kinase Inhibitors/pharmacology , Protein Serine-Threonine Kinases/antagonists & inhibitors , Pyrimidines/pharmacology , Animals , Benzodiazepinones/adverse effects , Benzodiazepinones/blood , Benzodiazepinones/pharmacokinetics , Blood-Brain Barrier/drug effects , Blood-Brain Barrier/metabolism , Caco-2 Cells , Cell Survival/drug effects , Drug Stability , Hep G2 Cells , Hepatocytes/drug effects , Hepatocytes/metabolism , Humans , Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 , Male , Metabolic Clearance Rate , Microsomes, Liver/drug effects , Microsomes, Liver/metabolism , Parkinson Disease/drug therapy , Protein Kinase Inhibitors/adverse effects , Protein Kinase Inhibitors/blood , Protein Kinase Inhibitors/pharmacokinetics , Protein Serine-Threonine Kinases/genetics , Pyrimidines/adverse effects , Pyrimidines/blood , Pyrimidines/pharmacokinetics , Rats, Sprague-Dawley , Substrate Specificity , Tissue Distribution
