Oxidative stress plays a crucial role in the pathogenesis of Parkinson disease (PD), and one strategy for neuroprotective therapy for PD is to scavenge reactive species using a catalytic antioxidant. Previous studies in our laboratory revealed that pretreatment of lipophilic metalloporphyrins showed protective effects in a mouse PD model. In this study, we optimized the formulations of these metalloporphyrins to deliver them orally and tested their efficacy on disease outcomes in a second species after initiation of an insult (i.e., disease modification). In this study, a pharmaceutical formulation of two metalloporphyrin catalytic antioxidants, AEOL11207 and AEOL11114, was tested for oral drug delivery. Both compounds showed gastrointestinal absorption, achieved high plasma concentrations, and readily penetrated the blood-brain barrier after intravenous or oral delivery. AEOL11207 and AEOL11114 bioavailabilities were calculated to be 24% and 25%, respectively, at a dose of 10 mg/kg via the oral route. In addition, both compounds significantly attenuated 6-hydroxydopamine (6-OHDA)-induced neurotoxic damage, including dopamine depletion, cytokine production, and microglial activation in the striata; dopaminergic neuronal loss in the substantia nigra; oxidative/nitrative stress indices (glutathione disulfide and 3-nitrotyrosine) in the ventral midbrain; and rotation behavioral abnormality in rats. These results indicate that AEOL11207 and AEOL11114 are orally active metalloporphyrins and protect against 6-OHDA neurotoxicity 1-3 days postlesioning, suggesting disease-modifying properties and translational potential for PD. SIGNIFICANCE STATEMENT: Two catalytic antioxidants showed gastrointestinal absorption, achieved high plasma concentrations, and readily penetrated the blood-brain barrier. Both compounds significantly attenuated dopamine depletion, cytokine production, microglial activation, dopaminergic neuronal loss, oxidative/nitrative stress indices, and behavioral abnormality in a Parkinson disease rat model. The results suggest that both metalloporphyrins possess disease-modifying properties that may be useful in treating Parkinson disease.

01 Jan 2021·Journal of Inorganic BiochemistryQ2 · BIOLOGY

Reduction of peroxynitrite by some manganoporphyrins of AEOL series: DFT approach with dispersion correction and NBO analysis

Q2 · BIOLOGY

Article

Author: Choe, Sung-Jub ; Sin, Kye-Ryong ; Maeng, Tae-Won ; Ko, Sun-Gyong ; Kim, Chol-Jin ; Ri, Kum-Ryong

The AEOL series of manganoporphyrins (MnP; AEOL compounds were named by US Aeolus pharmaceuticals) designed as superoxide dismutase mimic are well-known for their powerful catalytic activity to neutralize reactive oxygen and nitrogen species. Reductive oxygen atom cleavage from peroxynitrite (ONOO^-) to form NO₂ in aqueous solution by some AEOL compounds (AEOL-10113, AEOL-10150, AEOL-11114 and AEOL-11203) was studied by DFT/M06-2X computations with D3 dispersion correction and gCP (geometrical counterpoise correction) for basis set superposition error. DFT computation showed that AEOL-10150 can form the most stable association complex {MnP^…OONO} among four AEOL models. AEOL-10150 complex with ONOO^- has the lowest deformation energy. In AEOL compounds and their association complexes with ONOO^-, Mn atom prefered the high spin state (S = 2) to the intermediate spin state (S = 1). Natural bond orbital analysis showed that electron transfer from the most negative oxygen atom in ONOO^- to Mn atom in MnP has the biggest interaction energy among all kinds of donor-acceptor interactions between ONOO^- and MnP.

01 Jul 2017·Toxicology and Applied PharmacologyQ3 · MEDICINE

Pre-clinical therapeutic development of a series of metalloporphyrins for Parkinson's disease

Q3 · MEDICINE

Article

Author: Day, Brian J ; Fulton, Ruth ; Pearson-Smith, Jennifer N ; Huang, Jie ; Patel, Manisha ; Liang, Li-Ping

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.

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Indication	Highest Phase	Country/Location	Organization	Date
Parkinson Disease	Discovery	US	Aeolus Pharmaceuticals, Inc.	-

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