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. 2014 May 8;57(9):3746-54.
doi: 10.1021/jm401919s. Epub 2014 Apr 16.

Discovery of a neuroprotective chemical, (S)-N-(3-(3,6-dibromo-9H-carbazol-9-yl)-2-fluoropropyl)-6-methoxypyridin-2-amine [(-)-P7C3-S243], with improved druglike properties

Jacinth Naidoo  1 , Hector De Jesus-Cortes, Paula Huntington, Sandi Estill, Lorraine K Morlock, Ruth Starwalt, Thomas J Mangano, Noelle S Williams, Andrew A Pieper, Joseph M Ready
Affiliations

Discovery of a neuroprotective chemical, (S)-N-(3-(3,6-dibromo-9H-carbazol-9-yl)-2-fluoropropyl)-6-methoxypyridin-2-amine [(-)-P7C3-S243], with improved druglike properties

Jacinth Naidoo et al. J Med Chem. .

Abstract

(-)-P7C3-S243 is a neuroprotective aminopropyl carbazole with improved druglike properties compared with previously reported compounds in the P7C3 class. It protects developing neurons in a mouse model of hippocampal neurogenesis and protects mature neurons within the substantia nigra in a mouse model of Parkinson's disease. A short, enantioselective synthesis provides the neuroprotective agent in optically pure form. It is nontoxic, orally bioavailable, metabolically stable, and able to cross the blood-brain barrier. As such, it represents a valuable lead compound for the development of drugs to treat neurodegenerative diseases and traumatic brain injury.

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Figures

Scheme 1
Scheme 1
Figure 1
Figure 1
Efficacy of 15 in a mouse model of neurogenesis. Compounds were administered using the indicated dose and method for 7 days, during which time mice were dosed IP daily with BrdU (50 mg kg–1 day–1) to label newborn hippocampal neurons. Data are shown as mean ± standard error of the mean (SEM).
Scheme 2
Scheme 2. Stereoselective Synthesis of (−)-15
Figure 2
Figure 2
Enantiomer-specific efficacy of 15 in a mouse model of neurogenesis. Compound was administered ICV at the indicated concentration (0.5 μL/h) for 7 days, during which time mice were dosed IP daily with BrdU (50 mg kg–1 day–1) to label newborn hippocampal neurons. The graph shows the mean ± SEM for each group (N = 4 or 5). Images are of representative stained sections. Scale bars = 0.3 mm.
Figure 3
Figure 3
Efficacy of 15 in the MPTP model of Parkinson’s disease. Mice were administered MPTP (30 mg kg–1 day–1) for 5 days. On the sixth day, treatment with drug was initiated at the indicated dose (IP, BID, 21 days) . Bars indicate numbers of tyrosine hydroxylase-positive (TH+) cells detected by immunohistochemical staining of the substantia nigra (mean ± SEM). Asterisks indicate p < 0.01 (*), p < 0.001 (**), or p < 0.0001 (***) relative to the vehicle (Veh) + MPTP group. The number of mice in each group is shown within the corresponding bar. Representative immunohistochemical pictures of TH staining in the SNc are shown for 5 mg kg–1 day–1 treatment groups. Scale bars = 300 μM.
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