title: Pre-clinical therapeutic development of a series of metalloporphyrins for Parkinson's disease.
abstract: Reactive oxygen species are a well-defined therapeutic target for Parkinson's disease (PD) and pharmacological agents that catalytically scavenge reactive species are promising neuroprotective strategies for treatment. Metalloporphyrins are synthetic catalytic antioxidants that mimic the body's own antioxidant enzymes i.e. superoxide dismutases and catalase. The goal of this study was to determine if newly designed metalloporphyrins have enhanced pharmacodynamics including oral bioavailability, longer plasma elimination half-lives, penetrate the blood brain barrier, and show promise for PD treatment. Three metalloporphyrins (AEOL 11216, AEOL 11203 and AEOL 11114) were identified in this study as potential candidates for further pre-clinical development. Each of these compounds demonstrated blood brain barrier permeability by the i.p. route and two of three compounds (AEOL 11203 and AEOL 11114) were orally bioavailable. All of these compounds protected against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurotoxicity, including dopamine depletion in the striatum, dopaminergic neuronal loss in the substantial nigra, and increased oxidative/nitrative stress indices (glutathione disulfide and 3-nitrotyrosine) in the ventral midbrain of the mice without inhibiting MPTP metabolism. Daily therapeutic dosing of these metalloporphyrins were well tolerated without accumulation of brain manganese levels or behavioral alterations assessed by open field and rotarod tests. The study identified two orally active metalloporphyrins and one injectable metalloporphyrin as clinical candidates for further development in PD.
authors.affiliation: Department of Pharmaceutical Sciences, University of Colorado Denver, Aurora, CO, United States.
authors.forename: Li-Ping
authors.initials: LP
authors.lastname: Liang
authors.affiliation: Department of Medicine, National Jewish Health, Denver, CO, United States.
authors.forename: Jie
authors.initials: J
authors.lastname: Huang
authors.affiliation: Department of Pharmaceutical Sciences, University of Colorado Denver, Aurora, CO, United States.
authors.forename: Ruth
authors.initials: R
authors.lastname: Fulton
authors.affiliation: Department of Pharmaceutical Sciences, University of Colorado Denver, Aurora, CO, United States.
authors.forename: Jennifer N
authors.initials: JN
authors.lastname: Pearson-Smith
authors.affiliation: Department of Pharmaceutical Sciences, University of Colorado Denver, Aurora, CO, United States; Department of Medicine, National Jewish Health, Denver, CO, United States.
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Day
authors.affiliation: Department of Pharmaceutical Sciences, University of Colorado Denver, Aurora, CO, United States. Electronic address: manisha.patel@ucdenver.edu.
authors.forename: Manisha
authors.initials: M
authors.lastname: Patel
mesh_terms: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D000284:Administration, Oral; D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D000978:Antiparkinson Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects; D001682:Biological Availability; D015415:Biomarkers / Q000378:metabolism; D001812:Blood-Brain Barrier / Q000378:metabolism; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D002199:Capillary Permeability; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D006207:Half-Life; D007274:Injections, Intraperitoneal; D020267:MPTP Poisoning / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D008297:Male; D008665:Metalloporphyrins / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects*; D045442:Rotarod Performance Test
chemical_list: D000975:Antioxidants; D000978:Antiparkinson Agents; D015415:Biomarkers; D008665:Metalloporphyrins; D018696:Neuroprotective Agents; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D004298:Dopamine
keywords: Antioxidants; Dopamine; Drug development; MPTP; Oxidative stress; Pharmacokinetic analysis