title: Pharmacokinetic properties of MH84, a γ-secretase modulator with PPARγ agonistic activity.
abstract: Alzheimer's disease (AD) is the most common cause of dementia. Since no causative treatment is available, new therapeutic options are utmost needed. Several pirinixic acid derivatives, including MH84 (2-((4,6-bis(4-(trifluoromethyl)phenethoxy)pyrimidin-2-yl)thio)hexanoic acid), have shown promising in vitro results as γ-secretase modulators as well as PPARγ activators as potential pharmacological compounds against AD. Using a newly developed and validated sensitive LC-MS (APCI-qTOF mass analyzer) method, the pharmacokinetic and long-term accumulating properties as well as the blood-brain-barrier permeability of MH84 were evaluated in a preclinical animal study. MH84 was administered to mice by oral gavage with a dose of 12 mg/kg. Nine time points from 0.5 to 48 h with 6 animals per point were investigated. Additionally 6 animals were fed daily, for 21 days with an identical dose to determine possible long-term accumulation in plasma and brain tissue. The sample preparation was performed by a liquid-liquid extraction on Extrelut(®) columns whereas the LC separation was operated on a MulthoHigh 100 RP 18-5 μ column (125 × 4 mm) using an isocratic mobile phase of formic acid (0.1% (v/v))-methanol mixture (11:89 (v/v)) at a flow rate of 1 ml/min. The validation confirmed the new LC-MS method to be precise, accurate and reliable. After oral application, Cmax and Tmax of unmetabolized MH84 was determined to be 10.90 μg/ml and 3h in plasma. In brain tissue a constant level of 300 to maximum 320.64 ng/g was found after 1.5-6h. Daily gavage for 21 days did not lead to a long-term drug accumulation in the brain. The efficacy of the obtained MH84 levels needs to be investigated in further preclinical pharmacodynamic animal studies.
authors.affiliation: Institute of Pharmaceutical Chemistry, Goethe-University, Max-von-Laue Str. 9, D-60438 Frankfurt, Germany. Electronic address: pellowska@pharmchem.uni-frankfurt.de.
authors.forename: M
authors.initials: M
authors.lastname: Pellowska
authors.affiliation: Department of Pharmacology, Goethe-University, Max-von-Laue Str. 9, D-60438 Frankfurt, Germany. Electronic address: ch.stein@em.uni-frankfurt.de.
authors.forename: C
authors.initials: C
authors.lastname: Stein
authors.affiliation: Department of Pharmacology, Goethe-University, Max-von-Laue Str. 9, D-60438 Frankfurt, Germany. Electronic address: maximilian.pohland@nutritional-neuroscience.com.
authors.forename: M
authors.initials: M
authors.lastname: Pohland
authors.affiliation: Institute of Pharmaceutical Chemistry, Goethe-University, Max-von-Laue Str. 9, D-60438 Frankfurt, Germany. Electronic address: merk@pharmchem.uni-frankfurt.de.
authors.forename: D
authors.initials: D
authors.lastname: Merk
authors.affiliation: Department of Pharmacology, Goethe-University, Max-von-Laue Str. 9, D-60438 Frankfurt, Germany. Electronic address: klein@em.uni-frankfurt.de.
authors.forename: J
authors.initials: J
authors.lastname: Klein
authors.affiliation: Department of Pharmacology, Goethe-University, Max-von-Laue Str. 9, D-60438 Frankfurt, Germany. Electronic address: g.p.eckert@em.uni-frankfurt.de.
authors.forename: G P
authors.initials: GP
authors.lastname: Eckert
authors.affiliation: Institute of Pharmaceutical Chemistry, Goethe-University, Max-von-Laue Str. 9, D-60438 Frankfurt, Germany. Electronic address: wurglics@pharmchem.uni-frankfurt.de.
authors.forename: M
authors.initials: M
authors.lastname: Schubert-Zsilavecz
authors.affiliation: Institute of Pharmaceutical Chemistry, Goethe-University, Max-von-Laue Str. 9, D-60438 Frankfurt, Germany. Electronic address: schubert-zsilavecz@pharmchem.uni-frankfurt.de.
authors.forename: M
authors.initials: M
authors.lastname: Wurglics
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D000818:Animals; D002208:Caproates / Q000737:chemistry / Q000493:pharmacokinetics*; D002853:Chromatography, Liquid / Q000379:methods; D013058:Mass Spectrometry / Q000379:methods; D051379:Mice; D047495:PPAR gamma / Q000819:agonists* / Q000378:metabolism*; D011743:Pyrimidines / Q000737:chemistry / Q000493:pharmacokinetics*; D013552:Swine; D053719:Tandem Mass Spectrometry / Q000379:methods*
chemical_list: D002208:Caproates; D047495:PPAR gamma; D011743:Pyrimidines; D053829:Amyloid Precursor Protein Secretases
keywords: Alzheimer's disease; CNS bioavailability; PPARγ agonist; Pharmacokinetics; γ-Secretase modulator