title: Alternative to LRRK2-IN-1 for Pharmacological Studies of Parkinson's Disease.
abstract: OBJECTIVE
  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.
authors.affiliation: Neuroscience Therapeutic Area, UCB Biopharma SPRL, Braine-l'Alleud, Belgium.
authors.forename: Kyoko
authors.initials: K
authors.lastname: Koshibu
authors.forename: Judith
authors.initials: J
authors.lastname: van Asperen
authors.forename: Helga
authors.initials: H
authors.lastname: Gerets
authors.forename: Javier
authors.initials: J
authors.lastname: Garcia-Ladona
authors.forename: Olivier
authors.initials: O
authors.lastname: Lorthioir
authors.forename: Jean-Phillippe
authors.initials: JP
authors.lastname: Courade
mesh_terms: D000818:Animals; D001570:Benzodiazepinones / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism; D018938:Caco-2 Cells; D002470:Cell Survival / Q000187:drug effects; D055808:Drug Discovery / Q000379:methods*; D004355:Drug Stability; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D008297:Male; D008657:Metabolic Clearance Rate; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D010300:Parkinson Disease / Q000188:drug therapy / Q000201:enzymology*; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics; D011743:Pyrimidines / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D017207:Rats, Sprague-Dawley; D013379:Substrate Specificity; D014018:Tissue Distribution
chemical_list: D001570:Benzodiazepinones; C582847:LRRK2-IN1; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; C495280:LRRK2 protein, human; C547428:LRRK2 protein, rat; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017346:Protein Serine-Threonine Kinases